A Clinical Trial to Evaluate the Efficacy and Safety of Testosterone Gel in Adult Hypogonadal Males

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02149264
• Collaborator: (none)
• Enrollment: 160
• Locations: 22
• Arm: 1
• Duration (Months): 11
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This is a phase 3, open-label, non-randomized, clinical trial to evaluate the efficacy and safety of FE 999303 (Testosterone gel) in adult hypogonadal males.

Condition or Disease	Intervention/Treatment	Phase
Adult Male Hypogonadism	Drug: Testosterone gel (FE 999303)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-Label, Non-Randomized, Clinical Trial to Evaluate the Efficacy and Safety of FE 999303 (Testosterone Gel) in Adult Hypogonadal Males
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Testosterone gel (FE 999303) Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (upto three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.	Drug: Testosterone gel (FE 999303)

Outcome Measures

Primary Outcome Measures

1. The Percentage of Subjects Whose Average Concentration (Cave(0-24)) Serum Total Testosterone Levels Are ≥300 and ≤1050 ng/dL [At Day 90]

   The data were presented using descriptive statistics. The 95% confidence interval (CI) of the proportion (response) was estimated using the normal approximation to the binomial distribution. The study was considered to have met its efficacy criteria if the percentage was ≥ 75% and the lower bound of the 95% CI was ≥ 65%.

Secondary Outcome Measures

1. The Percentage of Subjects Whose Cave(0-24) Serum Total Testosterone Levels Are ≥300 and ≤1050 ng/dL [At 14, 35 and 56]

   The data were presented using descriptive statistics. No statistical analysis was performed.

2. Change From Baseline in International Index of Erectile Function (IIEF) Score [At Days 35 and 90]

   Data collected from the five domains of sexual functions were summarized by descriptive statistics. The domains were: Erectile function (6 items, questions 1-5 and 15) (Score range:1-30) Orgasmic function (2 items, questions 9-10) (Score range: 0-10) Sexual desire (2 items, questions 11-12) (Score range: 2-10) Intercourse satisfaction (3 items, questions 6-8) (Score range: 0-15) Overall satisfaction (2 items, questions 13-14) (Score range: 2-10) A score of 0-5 is awarded to questions 1 to 10 and a score of 1-5 is awarded to questions 11 to 15. Total score was calculated by summing up scores of each domain and ranged from 5 to 75. Low score indicates severe dysfunction and a high score indicates no dysfunction in sexual function.

3. Change From Baseline in Multidimensional Assessment of Fatigue (MAF) Score [At Days 35 and 90]

   The MAF contains four sub-domains: Severity (2 items, questions 1-2) (Score range: 2-20) Distress (1 item, question 3) (Score range: 1-10) Degree of interference in activities of daily living (11 items, questions 4-14) (Score range: 11-110) Timing (2 items, questions 15-16) (Score range: 5-20) A score of 1-10 is awarded to each of the 14 questions across the 3 domains. The timing domain (categorical in nature) are scored from 1-4. The scores are converted to 1-10 scale by multiplying each score by 2.5. Lower score in each domain indicates improvement in fatigue. To calculate GFI : Score of question 15 is converted to a 0-10 scale by multiplying each score by 2.5 and then sum questions 1, 2, 3, average of 4-14, and newly scored question 15. A score of zero is assigned to question 2-16, if patient select 'no fatigue' to question 1. Question 16 is not included in GFI calculation. The GFI ranged from 1 (no fatigue) to 50 (severe fatigue).

4. Change From Baseline in Short Form-12 Health Survey (SF-12) Score [At Days 35 and 90]

   Data collected from the SF-12 questionnaire, based on the norm-based scores was used to assess improvement in the psychometrically-based physical component summary (PCS) and mental component summary (MCS). Both PCS and MCS contained four sub-domains: PCS: Physical Functioning (2 items, questions 2-3) Role-Physical (2 items, questions 4-5) Bodily Pain (1 item, question 8) General Health (1 item, question 1) MCS: Vitality (1 item, question 10) Social Functioning (1 item, question 12) Role-Emotional (2 items, questions 6-7) Mental Health (2 items, questions 9 and 11) PCS and MCS composite scores are computed using the scores of the 12 questions and range from 0-100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. Positive change from baseline indicated improvement in physical and mental health.

5. Pharmacokinetic Parameter - Average Concentration (Cave) for Total Testosterone and Dihydrotestosterone [Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90]

   A validated high pressure liquid chromatography with tandem mass spectrometry detection (LC/MS/MS) method was used to determine the levels of total testosterone and dihydrotestosterone.

6. Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUCτ) for Total Testosterone and Dihydrotestosterone [Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90]

   A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.

7. Pharmacokinetic Parameter - Time at Which the Maximum Concentration Occurs (Tmax) for Total Testosterone and Dihydrotestosterone [Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90]

   A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.

8. Pharmacokinetic Parameter - Maximum Concentration Observed (Cmax) for Total Testosterone and Dihydrotestosterone [Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90]

   A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.

9. Pharmacokinetic Parameter - Minimum Concentration Observed (Cmin) for Total Testosterone and Dihydrotestosterone [Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90]

   A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males between 18-75 years of age

• Two fasting serum testosterone levels <300 ng/dL

Exclusion Criteria:

• Previous use of the study drug

• History of prostate or breast cancer

• Prostate-Specific Antigen (PSA) ≥3 ng/mL

• Subject is sexually active and not willing to use adequate contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational site	Anniston	Alabama	United States
2	Investigational site	Huntsville	Alabama	United States
3	Investigational site	Newport Beach	California	United States
4	Investigational site	Denver	Colorado	United States
5	Investigational site	New Haven	Connecticut	United States
6	Investigational site	Aventura	Florida	United States
7	Investigational site	Clearwater	Florida	United States
8	Investigational site	Mishawaka	Indiana	United States
9	Investigational site	Watertown	Massachusetts	United States
10	Investigational site	Troy	Michigan	United States
11	Investigational site	Edison	New Jersey	United States
12	Investigational site	Lawrence Township	New Jersey	United States
13	Investigational site	Garden City	New York	United States
14	Investigational site	New York	New York	United States
15	Investigational site	Poughkeepsie	New York	United States
16	Investigational site	Purchase	New York	United States
17	Investigational site	Bala-Cynwyd	Pennsylvania	United States
18	Investigational site	Warwick	Rhode Island	United States
19	Investigational site	Mount Pleasant	South Carolina	United States
20	Investigational site	Nashville	Tennessee	United States
21	Investigational site	Webster	Texas	United States
22	Investigational site	Norfolk	Virginia	United States

Sponsors and Collaborators

• Ferring Pharmaceuticals

Investigators

• Study Director: Clinical Development Support, Ferring Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02149264
• Other Study ID Numbers: 000127
• First Posted: May 29, 2014
• Last Update Posted: Oct 26, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Hypogonadism; Testosterone

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from 23 study sites in the United States.
Pre-assignment Detail	Of the 940 screened subjects, 160 subjects were eligible to be enrolled into the study.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Period Title: Overall Study
STARTED	159
COMPLETED	139
NOT COMPLETED	20

Baseline Characteristics

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Overall Participants	159
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	138 86.8%
>=65 years	21 13.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.1 (9.3)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	159 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 13.8%
Not Hispanic or Latino	137 86.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 1.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	31 19.5%
White	123 77.4%
More than one race	2 1.3%
Unknown or Not Reported	0 0%
Height (inches) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [inches]	69.8 (2.5)
Weight (lbs) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [lbs]	213.2 (28.2)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.7 (3.2)
Total International Index of Erectile Function Score - All Domains (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	36.3 (18.7)
Multidimensional Assessment of Fatigue (units on a scale) [Mean (Standard Deviation) ]
Severity domain	12.0 (4.9)
Distress domain	5.1 (2.6)
Degree of interference domain	47.7 (22.9)
Timing domain	13.0 (3.0)
Global Fatigue Index (GFI)	27.5 (11.1)
Short Form -12 (SF-12) Health survey (units on a scale) [Mean (Standard Deviation) ]
Physical Component Summary	48.4 (8.8)
Mental Component Summary	43.7 (11.0)

Outcome Measures

1. Primary Outcome

Title	The Percentage of Subjects Whose Average Concentration (Cave(0-24)) Serum Total Testosterone Levels Are ≥300 and ≤1050 ng/dL
Description	The data were presented using descriptive statistics. The 95% confidence interval (CI) of the proportion (response) was estimated using the normal approximation to the binomial distribution. The study was considered to have met its efficacy criteria if the percentage was ≥ 75% and the lower bound of the 95% CI was ≥ 65%.
Time Frame	At Day 90

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
Number (95% Confidence Interval) [percentage of subjects]	76.1

2. Secondary Outcome

Title	The Percentage of Subjects Whose Cave(0-24) Serum Total Testosterone Levels Are ≥300 and ≤1050 ng/dL
Description	The data were presented using descriptive statistics. No statistical analysis was performed.
Time Frame	At 14, 35 and 56

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
Day 14	29.1
Day 35	58.2
Day 56	71.2

3. Secondary Outcome

Title	Change From Baseline in International Index of Erectile Function (IIEF) Score
Description	Data collected from the five domains of sexual functions were summarized by descriptive statistics. The domains were: Erectile function (6 items, questions 1-5 and 15) (Score range:1-30) Orgasmic function (2 items, questions 9-10) (Score range: 0-10) Sexual desire (2 items, questions 11-12) (Score range: 2-10) Intercourse satisfaction (3 items, questions 6-8) (Score range: 0-15) Overall satisfaction (2 items, questions 13-14) (Score range: 2-10) A score of 0-5 is awarded to questions 1 to 10 and a score of 1-5 is awarded to questions 11 to 15. Total score was calculated by summing up scores of each domain and ranged from 5 to 75. Low score indicates severe dysfunction and a high score indicates no dysfunction in sexual function.
Time Frame	At Days 35 and 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
Day 35	8.4 (13.2)
Day 90	14.4 (16.9)

4. Secondary Outcome

Title	Change From Baseline in Multidimensional Assessment of Fatigue (MAF) Score
Description	The MAF contains four sub-domains: Severity (2 items, questions 1-2) (Score range: 2-20) Distress (1 item, question 3) (Score range: 1-10) Degree of interference in activities of daily living (11 items, questions 4-14) (Score range: 11-110) Timing (2 items, questions 15-16) (Score range: 5-20) A score of 1-10 is awarded to each of the 14 questions across the 3 domains. The timing domain (categorical in nature) are scored from 1-4. The scores are converted to 1-10 scale by multiplying each score by 2.5. Lower score in each domain indicates improvement in fatigue. To calculate GFI : Score of question 15 is converted to a 0-10 scale by multiplying each score by 2.5 and then sum questions 1, 2, 3, average of 4-14, and newly scored question 15. A score of zero is assigned to question 2-16, if patient select 'no fatigue' to question 1. Question 16 is not included in GFI calculation. The GFI ranged from 1 (no fatigue) to 50 (severe fatigue).
Time Frame	At Days 35 and 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
Severity domain score at Day 35	-3.6 (4.8)
Distress domain score at Day 35	-1.7 (2.6)
Degree of interference domain score at Day 35	-13.6 (24.1)
Timing domain score at Day 35	-2.6 (3.3)
GFI score at Day 35	-8.3 (10.1)
Severity domain score at Day 90	-5.2 (4.9)
Distress domain score at Day 90	-2.2 (2.5)
Degree of interference domain score at Day 90	-16.7 (24.5)
Timing domain score at Day 90	-3.0 (3.4)
GFI score at Day 90	-12.0 (11.1)

5. Secondary Outcome

Title	Change From Baseline in Short Form-12 Health Survey (SF-12) Score
Description	Data collected from the SF-12 questionnaire, based on the norm-based scores was used to assess improvement in the psychometrically-based physical component summary (PCS) and mental component summary (MCS). Both PCS and MCS contained four sub-domains: PCS: Physical Functioning (2 items, questions 2-3) Role-Physical (2 items, questions 4-5) Bodily Pain (1 item, question 8) General Health (1 item, question 1) MCS: Vitality (1 item, question 10) Social Functioning (1 item, question 12) Role-Emotional (2 items, questions 6-7) Mental Health (2 items, questions 9 and 11) PCS and MCS composite scores are computed using the scores of the 12 questions and range from 0-100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. Positive change from baseline indicated improvement in physical and mental health.
Time Frame	At Days 35 and 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
PCS Day 35	1.2 (7.0)
PCS Day 90	1.8 (7.1)
MCS Day 35	6.3 (9.5)
MCS Day 90	6.5 (10.1)

6. Secondary Outcome

Title	Pharmacokinetic Parameter - Average Concentration (Cave) for Total Testosterone and Dihydrotestosterone
Description	A validated high pressure liquid chromatography with tandem mass spectrometry detection (LC/MS/MS) method was used to determine the levels of total testosterone and dihydrotestosterone.
Time Frame	Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons. Number of subjects was less than 155 in some group(s) as parameter could not be calculated due to missing concentrations for that time-point.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
Total testosterone on Day 14 at 23 mg dose	268 (80)
Total testosterone on Day 35 at 23 mg dose	359 (116)
Total testosterone on Day 35 at 46 mg dose	361 (152)
Total testosterone on Day 56 at 23 mg dose	278 (73)
Total testosterone on Day 56 at 46 mg dose	429 (127)
Total testosterone on Day 56 at 69 mg dose	464 (271)
Total testosterone on Day 90 at 23 mg dose	368 (121)
Total testosterone on Day 90 at 46 mg dose	506 (207)
Total testosterone on Day 90 at 69 mg dose	438 (164)
Dihydrotestosterone on Day 14 at 23 mg dose	40.9 (18.8)
Dihydrotestosterone on Day 35 at 23 mg dose	56.3 (18.0)
Dihydrotestosterone on Day 35 at 46 mg dose	63.1 (29.9)
Dihydrotestosterone on Day 56 at 23 mg dose	44.2 (11.1)
Dihydrotestosterone on Day 56 at 46 mg dose	78.7 (32.8)
Dihydrotestosterone on Day 56 at 69 mg dose	75.2 (43.3)
Dihydrotestosterone on Day 90 at 23 mg dose	65.9 (24.1)
Dihydrotestosterone on Day 90 at 46 mg dose	91.2 (38.9)
Dihydrotestosterone on Day 90 at 69 mg dose	77.7 (39.7)

7. Secondary Outcome

Title	Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUCτ) for Total Testosterone and Dihydrotestosterone
Description	A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.
Time Frame	Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons. Number of subjects was less than 155 in some group(s) as parameter could not be calculated due to missing concentrations for that time-point.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	155
Total testosterone on Day 14 at 23 mg dose	6431 (1938)
Total testosterone on Day 35 at 23 mg dose	8552 (2800)
Total testosterone on Day 35 at 46 mg dose	8665 (3664)
Total testosterone on Day 56 at 23 mg dose	6624 (1765)
Total testosterone on Day 56 at 46 mg dose	10320 (3042)
Total testosterone on Day 56 at 69 mg dose	11152 (6507)
Total testosterone on Day 90 at 23 mg dose	8831 (2829)
Total testosterone on Day 90 at 46 mg dose	12245 (5010)
Total testosterone on Day 90 at 69 mg dose	10590 (3979)
Dihydrotestosterone on Day 14 at 23 mg dose	980 (452)
Dihydrotestosterone on Day 35 at 23 mg dose	1343 (435)
Dihydrotestosterone on Day 35 at 46 mg dose	1515 (719)
Dihydrotestosterone on Day 56 at 23 mg dose	1057 (270)
Dihydrotestosterone on Day 56 at 46 mg dose	1893 (797)
Dihydrotestosterone on Day 56 at 69 mg dose	1811 (1046)
Dihydrotestosterone on Day 90 at 23 mg dose	1579 (560)
Dihydrotestosterone on Day 90 at 46 mg dose	2210 (956)
Dihydrotestosterone on Day 90 at 69 mg dose	1876 (956)

8. Secondary Outcome

Title	Pharmacokinetic Parameter - Time at Which the Maximum Concentration Occurs (Tmax) for Total Testosterone and Dihydrotestosterone
Description	A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.
Time Frame	Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons. Of 155 subjects, one subject discontinued due to adverse event after Day 14 visit and not included in the analysis.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	154
Total testosterone on Day 14 at 23 mg dose	2.04
Total testosterone on Day 35 at 23 mg dose	2.15
Total testosterone on Day 35 at 46 mg dose	2.00
Total testosterone on Day 56 at 23 mg dose	2.00
Total testosterone on Day 56 at 46 mg dose	2.08
Total testosterone on Day 56 at 69 mg dose	2.00
Total testosterone on Day 90 at 23 mg dose	4.02
Total testosterone on Day 90 at 46 mg dose	2.02
Total testosterone on Day 90 at 69 mg dose	2.08
Dihydrotestosterone on Day 14 at 23 mg dose	3.97
Dihydrotestosterone on Day 35 at 23 mg dose	3.04
Dihydrotestosterone on Day 35 at 46 mg dose	2.94
Dihydrotestosterone on Day 56 at 23 mg dose	2.00
Dihydrotestosterone on Day 56 at 46 mg dose	2.08
Dihydrotestosterone on Day 56 at 69 mg dose	3.87
Dihydrotestosterone on Day 90 at 23 mg dose	4.12
Dihydrotestosterone on Day 90 at 46 mg dose	3.75
Dihydrotestosterone on Day 90 at 69 mg dose	3.95

9. Secondary Outcome

Title	Pharmacokinetic Parameter - Maximum Concentration Observed (Cmax) for Total Testosterone and Dihydrotestosterone
Description	A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.
Time Frame	Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons. Of 155 subjects, one subject discontinued due to an adverse event after Day 14 visit and not included in the analysis.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	154
Total testosterone on Day 14 at 23 mg dose	435 (195)
Total testosterone on Day 35 at 23 mg dose	642 (238)
Total testosterone on Day 35 at 46 mg dose	732 (387)
Total testosterone on Day 56 at 23 mg dose	637 (300)
Total testosterone on Day 56 at 46 mg dose	890 (424)
Total testosterone on Day 56 at 69 mg dose	987 (652)
Total testosterone on Day 90 at 23 mg dose	721 (254)
Total testosterone on Day 90 at 46 mg dose	1228 (640)
Total testosterone on Day 90 at 69 mg dose	1099 (595)
Dihydrotestosterone on Day 14 at 23 mg dose	56.5 (26.9)
Dihydrotestosterone on Day 35 at 23 mg dose	79.2 (26.0)
Dihydrotestosterone on Day 35 at 46 mg dose	91.5 (43.3)
Dihydrotestosterone on Day 56 at 23 mg dose	68.6 (19.0)
Dihydrotestosterone on Day 56 at 46 mg dose	113 (62)
Dihydrotestosterone on Day 56 at 69 mg dose	106 (57)
Dihydrotestosterone on Day 90 at 23 mg dose	91.4 (34.8)
Dihydrotestosterone on Day 90 at 46 mg dose	138 (66)
Dihydrotestosterone on Day 90 at 69 mg dose	118 (55)

10. Secondary Outcome

Title	Pharmacokinetic Parameter - Minimum Concentration Observed (Cmin) for Total Testosterone and Dihydrotestosterone
Description	A validated LC/MS/MS method was used to determine the levels of total testosterone and dihydrotestosterone.
Time Frame	Samples collected at pre-dose, 2, 4, 6, 8 & 24 hours post-dose on Days 14, 35 & 56, and at pre-dose, 2, 4, 6, 8, 10, 12, 18 & 24 hours post-dose on Day 90

Outcome Measure Data

Analysis Population Description

FAS population was used and included subjects who had sufficient pharmacokinetic data to determine a Cave(0-24) on Days 14, 35, 56, or 90, or discontinued the study early due to medical or safety reasons. Of 155 subjects, one subject discontinued due to an adverse event after Day 14 visit and not included in the analysis.

Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
Measure Participants	154
Total testosterone on Day 14 at 23 mg dose	194 (64)
Total testosterone on Day 35 at 23 mg dose	203 (74)
Total testosterone on Day 35 at 46 mg dose	216 (93)
Total testosterone on Day 56 at 23 mg dose	175 (49)
Total testosterone on Day 56 at 46 mg dose	262 (115)
Total testosterone on Day 56 at 69 mg dose	261 (200)
Total testosterone on Day 90 at 23 mg dose	191 (49)
Total testosterone on Day 90 at 46 mg dose	277 (140)
Total testosterone on Day 90 at 69 mg dose	229 (82)
Dihydrotestosterone on Day 14 at 23 mg dose	30.7 (15.6)
Dihydrotestosterone on Day 35 at 23 mg dose	41.0 (12.7)
Dihydrotestosterone on Day 35 at 46 mg dose	43.9 (24.7)
Dihydrotestosterone on Day 56 at 23 mg dose	33.2 (9.6)
Dihydrotestosterone on Day 56 at 46 mg dose	58.0 (26.7)
Dihydrotestosterone on Day 56 at 69 mg dose	52.9 (32.3)
Dihydrotestosterone on Day 90 at 23 mg dose	45.1 (21.0)
Dihydrotestosterone on Day 90 at 46 mg dose	62.5 (26.4)
Dihydrotestosterone on Day 90 at 69 mg dose	53.1 (29.7)

Adverse Events

Time Frame	Overall study period (From Day 1 to Day 120 [last visit])
Adverse Event Reporting Description	Adverse event occurring after start of study drug administration and within the time of residual drug effect (5 days), or a pre-treatment adverse event or pre-existing medical condition that worsened in intensity after treatment with the study drug and within the time of residual drug effect, are presented for the safety analysis set.
Arm/Group Title	Testosterone Gel (FE 999303)
Arm/Group Description	Subjects received at least one dose of testosterone gel (23 mg), which was further titrated, if needed (up to three doses [69 mg]), based on serum testosterone concentrations. Testosterone gel was delivered using an applicator to the contralateral shoulder/upper arm.
All Cause Mortality
	Testosterone Gel (FE 999303)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Testosterone Gel (FE 999303)
	Affected / at Risk (%)	# Events
Total	5/159 (3.1%)
Cardiac disorders
Angina unstable	1/159 (0.6%)	1
Myocardial infarction	1/159 (0.6%)	1
Injury, poisoning and procedural complications
Upper limb fracture	1/159 (0.6%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/159 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	1/159 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Testosterone Gel (FE 999303)
	Affected / at Risk (%)	# Events
Total	54/159 (34%)
Congenital, familial and genetic disorders
Hydrocele	1/159 (0.6%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	1/159 (0.6%)
Nausea	2/159 (1.3%)
Toothache	1/159 (0.6%)
General disorders
Application site dermatitis	1/159 (0.6%)
Application site erythema	4/159 (2.5%)
Application site pruritus	1/159 (0.6%)
Application site rash	3/159 (1.9%)
Cyst	1/159 (0.6%)
Fatigue	1/159 (0.6%)
Influenza like illness	1/159 (0.6%)
Oedema peripheral	1/159 (0.6%)
Pain	1/159 (0.6%)
Pyrexia	2/159 (1.3%)
Sluggishness	1/159 (0.6%)
Infections and infestations
Bronchitis	5/159 (3.1%)
Cellulitis	1/159 (0.6%)
Gangrene	1/159 (0.6%)
Hordeolum	1/159 (0.6%)
Nasopharyngitis	4/159 (2.5%)
Perineal abscess	1/159 (0.6%)
Sinusitis	1/159 (0.6%)
Tinea infection	1/159 (0.6%)
Upper respiratory tract infection	5/159 (3.1%)
Urinary tract infection	1/159 (0.6%)
Viral infection	2/159 (1.3%)
Injury, poisoning and procedural complications
Foot fracture	1/159 (0.6%)
Joint sprain	2/159 (1.3%)
Tendon rupture	1/159 (0.6%)
Thermal burn	1/159 (0.6%)
Traumatic haematoma	1/159 (0.6%)
Wound	1/159 (0.6%)
Investigations
Alanine aminotransferase increased	1/159 (0.6%)
Aspartate aminotransferase increased	1/159 (0.6%)
Blood cholesterol increased	1/159 (0.6%)
Blood creatinine increased	1/159 (0.6%)
Blood glucose increased	2/159 (1.3%)
Blood pressure increased	1/159 (0.6%)
Blood triglycerides increased	3/159 (1.9%)
Gamma-glutamyl transferase increased	2/159 (1.3%)
Glycosylated haemoglobin increased	1/159 (0.6%)
Haematocrit decreased	1/159 (0.6%)
Haemoglobin decreased	1/159 (0.6%)
Prostatic specific antigen increased	2/159 (1.3%)
Weight increased	1/159 (0.6%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	2/159 (1.3%)
Increased appetite	1/159 (0.6%)
Type 2 diabetes mellitus	1/159 (0.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/159 (0.6%)
Arthropathy	1/159 (0.6%)
Back pain	2/159 (1.3%)
Muscle spasms	1/159 (0.6%)
Muscular weakness	1/159 (0.6%)
Pain in extremity	1/159 (0.6%)
Nervous system disorders
Hyposmia	1/159 (0.6%)
Psychiatric disorders
Anxiety	1/159 (0.6%)
Insomnia	2/159 (1.3%)
Renal and urinary disorders
Dysuria	1/159 (0.6%)
Nephrolithiasis	1/159 (0.6%)
Reproductive system and breast disorders
Breast tenderness	1/159 (0.6%)
Epididymitis	2/159 (1.3%)
Erectile dysfunction	2/159 (1.3%)
Nipple pain	1/159 (0.6%)
Prostatic pain	1/159 (0.6%)
Testicular atrophy	1/159 (0.6%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/159 (0.6%)
Cough	5/159 (3.1%)
Dyspnoea	1/159 (0.6%)
Nasal congestion	1/159 (0.6%)
Pleural effusion	1/159 (0.6%)
Pneumothorax	1/159 (0.6%)
Pulmonary embolism	1/159 (0.6%)
Sinus congestion	1/159 (0.6%)
Skin and subcutaneous tissue disorders
Erythema	1/159 (0.6%)
Rash	1/159 (0.6%)
Vascular disorders
Hot flush	1/159 (0.6%)
Hypertension	2/159 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.