inTUne: A Study of Oral Testosterone Undecanoate (TU) in Hypogonadal Men

• Sponsor: Clarus Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02722278
• Collaborator: Syneos Health (Other)
• Enrollment: 222
• Location: 1
• Arms: 2
• Actual Duration (Months): 8
• Patients Per Site Per Month: 27.6

Study Details

Study Description

Brief Summary

A Phase 3, Randomized, Active-controlled, Open-label Study of the Safety and Efficacy of Oral Testosterone Undecanoate (TU) in Hypogonadal Men

Condition or Disease	Intervention/Treatment	Phase
Hypogonadism	Drug: Oral Testosterone Undecanoate; Drug: Axiron Testosterone Topical Solution	Phase 3

Detailed Description

This is a multicenter, Phase 3, randomized, open-label, active-comparator group, efficacy (based on Cavg of T), and safety study in adult hypogonadal male subjects. Enrollment is based on criteria designed to select the general population of hypogonadal men. Study drug doses will be titrated using a dose-titration algorithm based on total T Cavg. Subjects may be androgen treatment-naïve or washed out of prior androgen replacement therapies.

Subjects must have 2 total T levels < 300 ng/dL based on 2 blood samples obtained in the morning (AM) on 2 separate days approximately 7 days apart.

Approximately 180 subjects will be randomly assigned to receive open-label treatment in a 3:1 ratio of oral TU to Axiron (ie, approximately 135 subjects will be randomly assigned to oral TU and approximately 45 subjects will be randomly assigned to Axiron topical solution). Subjects who complete the study will receive approximately 105 days of treatment. Dose titrations will be based on the T Cavg from serial PK sampling obtained on day 21 and 56 of treatment. Primary efficacy will be based on percentage of subjects within eugonadal range at Visit 7.

A subset of approximately 30 subjects will participate in a cosyntropin stimulation test on Day 1 (before administration of study drug) and Day 106 after the last 24-hour PK sample has been drawn.

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase 3, Randomized, Active-controlled, Open-label Study of the Safety and Efficacy of Oral Testosterone Undecanoate (TU) in Hypogonadal Men
• Actual Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral Testosterone Undecanoate Approximately 135 subjects will receive oral TU treatment during the study for approximately 3.5 months. Subjects randomly assigned to the oral TU treatment group will begin treatment at a dose of 237 mg TU twice daily (BID).	Drug: Oral Testosterone Undecanoate; Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.; Other Names: Oral TU
Active Comparator: Axiron Testosterone Topical Solution Subjects randomly assigned to the Axiron treatment group will begin treatment at a dose of 60 mg every morning.	Drug: Axiron Testosterone Topical Solution; Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.; Other Names: Axiron solution

Outcome Measures

Primary Outcome Measures

1. Number of Oral TU Treated Subjects Who Have a Total T Cavg in the Eugonadal Range of 252 to 907 ng/dL at Visit 7 [Day 105]

Other Outcome Measures

1. Number of Participants With Post-stimulation Cortisol Level of >18 ug/dL at Visit 8 [Approximately 4.5 months]

   Compare the Oral TU-treated subjects and the Topical Axiron®-treated subjects with respect to number of subjects in the cosyntropin stimulation test substudy with a normal maximum post-stimulation (cosyntropin stimulation) cortisol level at Visit 8.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Man 18 to 65 years of age, inclusive, with hypogonadism as defined by 2 AM total T values of <300 ng/dL drawn on 2 separate days ([approximately 7 days apart]).

2. Adequate venous access

3. Must be naïve to androgen-replacement therapy or washed out of prior androgen replacement therapies; willing to cease current T treatment or currently not be taking T treatment. Subjects must remain off all forms of T, except for dispensed study drug, throughout the entire study.

4. Subjects on replacement therapy for hypopituitarism or multiple endocrine deficiencies must be on stable doses of thyroid hormone and adrenal replacement hormones for at least 14 days before Screen 1.

5. Voluntarily given written informed consent to participate in this study.

Exclusion Criteria:

1. Received oral topical, intranasal, or buccal T therapy within the previous 2 weeks, intramuscular T injection of short-acting duration within the previous 4 weeks, intramuscular T injection of long-acting duration within the previous 20 weeks, or T implantable pellets within the previous 6 months.

2. Received oral TU in a previous Clarus-sponsored investigational study.

3. Significant intercurrent disease of any type; in particular, liver, kidney, uncontrolled or poorly controlled heart disease, including hypertension, congestive heart failure or coronary heart disease, or psychiatric-illness, including severe depression.

4. Recent (within 2 years) history of stroke, transient ischemic attack, or acute coronary event.

5. A mean of the triplicate assessment of systolic blood pressure (sBP) > 150 mm Hg and/or diastolic blood pressure (dBP) > 90 mm Hg at screening.

6. Recent (within 2 years) history of angina or stent (coronary or carotid) placement.

7. Untreated, severe obstructive sleep apnea.

8. Clinically significant abnormal laboratory values (serum transaminases > 2 × ULN, serum bilirubin > 1.5 × ULN and serum creatinine > 1.5 × ULN).

9. Hematocrit (HCT) value of < 35% or > 48%.

10. Has a history of polycythemia, either idiopathic or associated with testosterone replacement therapy (TRT).

11. Glycosylated hemoglobin (A1C) > 8.5%.

12. BMI ≥ 38 kg/m2.

13. If receiving the following medications:

• Has been on stable doses of lipid-lowering medication for < 3 months;

• Has been on stable doses of oral medication for diabetes for < 2 months; or

• Has been on stable doses of antihypertensive medication for < 3 months.

1. Abnormal prostate digital rectal examination (palpable nodules), elevated Prostate Specific Antigen (serum PSA > 4.0 ng/mL), International Prostate Symptom Score (I-PSS)

19 points at screening, and/or history of, or current or suspected, prostate cancer.

1. History of, or current or suspected, breast cancer.

2. History of abnormal bleeding tendencies or thrombophlebitis unrelated to venipuncture or intravenous cannulation within the previous 2 years.

3. Use of dietary supplements such as saw palmetto or phytoestrogens and any dietary supplements that may increase total T, such as androstenedione or dehydroepiandrosterone within the previous 4 weeks.

4. Known malabsorption syndrome and/or current treatment with oral lipase inhibitors and bile acid-binding resins.

5. Inability to refrain from smoking during the confinement periods as required by the individual study center.

6. History of alcohol abuse or any drug substance within the previous 2 years.

7. Poor compliance or unlikely to keep clinic appointments.

8. Has received any drug as part of another research study within 30 days of initial dose administration in this study.

9. Donated blood (≥ 500 mL) within the 12-week period before the initial study dose.

10. Currently uses antiandrogens, 5-alpha-reductase inhibitors, estrogens, potent oral CYP3A4 inducers, potent CYP3A4 inhibitors, or long acting opioid analgesics.

11. Unwilling or unable to follow the dietary guidelines for this study, related to taking oral TU with meals that contain approximately 20 to 40 g of fat

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Multiple Sites in the United States	Northbrook	Illinois	United States	60062

Sponsors and Collaborators

• Clarus Therapeutics, Inc.
• Syneos Health

Investigators

• Principal Investigator: Ronald Swerdloff, MD, Primary Principal Investigator

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Clarus Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02722278
• Other Study ID Numbers: CLAR-15012
• First Posted: Mar 29, 2016
• Last Update Posted: Feb 23, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Hypogonadism; Methyltestosterone; Pharmaceutical Solutions; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate

Study Results

Participant Flow

Arm/Group Title	Oral Testosterone Undecanoate	Axiron Testosterone Topical Solution
Arm/Group Description	166 subjects received oral TU treatment during the study for approximately 3.5 months. Subjects randomly assigned to the oral TU treatment group will begin treatment at a dose of 237 mg TU twice daily (BID). Oral Testosterone Undecanoate: Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.	56 subjects were randomly assigned to the Axiron treatment group and began treatment at a dose of 60 mg every morning. Axiron Testosterone Topical Solution: Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.
Period Title: Overall Study
STARTED	166	56
COMPLETED	154	49
NOT COMPLETED	12	7

Baseline Characteristics

Arm/Group Title	Oral Testosterone Undecanoate	Axiron Testosterone Topical Solution	Total
Arm/Group Description	Approximately 135 subjects will receive oral TU treatment during the study for approximately 3.5 months. Subjects randomly assigned to the oral TU treatment group will begin treatment at a dose of 237 mg TU twice daily (BID). Oral Testosterone Undecanoate: Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.	Subjects randomly assigned to the Axiron treatment group will begin treatment at a dose of 60 mg every morning. Axiron Testosterone Topical Solution: Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.	Total of all reporting groups
Overall Participants	166	56	222
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	160 96.4%	54 96.4%	214 96.4%
>=65 years	6 3.6%	2 3.6%	8 3.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.6 (9.08)	53.4 (7.86)	52 (8.81)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	166 100%	56 100%	222 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	25 15.1%	15 26.8%	40 18%
Not Hispanic or Latino	141 84.9%	41 73.2%	182 82%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.8%	1 0.5%
Asian	3 1.8%	2 3.6%	5 2.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	29 17.5%	11 19.6%	40 18%
White	133 80.1%	42 75%	175 78.8%
More than one race	1 0.6%	0 0%	1 0.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	166 100%	56 100%	222 100%

Outcome Measures

1. Primary Outcome

Title	Number of Oral TU Treated Subjects Who Have a Total T Cavg in the Eugonadal Range of 252 to 907 ng/dL at Visit 7
Time Frame	Day 105

Outcome Measure Data

Analysis Population Description

Intent-to-treat study population All subjects randomized to either Oral TU or Axiron

Arm/Group Title	Oral Testosterone Undecanoate	Axiron Testosterone Topical Solution
Arm/Group Description	166 subjects received oral TU treatment during the study for approximately 3.5 months. Subjects randomly assigned to the oral TU treatment group will begin treatment at a dose of 237 mg TU twice daily (BID). Oral Testosterone Undecanoate: Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.	56 subjects were randomly assigned to the Axiron treatment group and began treatment at a dose of 60 mg every morning. Axiron Testosterone Topical Solution: Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.
Measure Participants	166	56
Count of Participants [Participants]	145 87.3%	48 85.7%

2. Other Pre-specified Outcome

Title	Number of Participants With Post-stimulation Cortisol Level of >18 ug/dL at Visit 8
Description	Compare the Oral TU-treated subjects and the Topical Axiron®-treated subjects with respect to number of subjects in the cosyntropin stimulation test substudy with a normal maximum post-stimulation (cosyntropin stimulation) cortisol level at Visit 8.
Time Frame	Approximately 4.5 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral TU Cosyntropin Substudy Subjects	Axiron Cosyntropin Substudy Subjects
Arm/Group Description	Subjects receiving Oral TU participating in cosyntropin substudy
Measure Participants	24	8
Count of Participants [Participants]	19 11.4%	8 14.3%

Adverse Events

Time Frame	9 months
Arm/Group Title	Oral Testosterone Undecanoate		Axiron Testosterone Topical Solution
Arm/Group Description	166 subjects received oral TU treatment during the study for approximately 3.5 months. Subjects randomly assigned to the oral TU treatment group will begin treatment at a dose of 237 mg TU twice daily (BID). Oral Testosterone Undecanoate: Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.		56 subjects were randomly assigned to the Axiron treatment group and began treatment at a dose of 60 mg every morning. Axiron Testosterone Topical Solution: Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg < 350 ng/dL, decreased if > 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.
All Cause Mortality
	Oral Testosterone Undecanoate		Axiron Testosterone Topical Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/166 (0%)		0/56 (0%)
Serious Adverse Events
	Oral Testosterone Undecanoate		Axiron Testosterone Topical Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/166 (1.2%)		0/55 (0%)
Gastrointestinal disorders
Small intestinal obstruction	1/166 (0.6%)	1	0/55 (0%)	0
Infections and infestations
Periumbilical abscess	1/166 (0.6%)	1	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	Oral Testosterone Undecanoate		Axiron Testosterone Topical Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/166 (18.7%)		8/55 (14.5%)
Blood and lymphatic system disorders
Anaemia	1/166 (0.6%)	1	1/55 (1.8%)	1
Eye disorders
Vitreous floaters	0/166 (0%)	0	1/55 (1.8%)	1
Gastrointestinal disorders
Nausea	4/166 (2.4%)	4	0/55 (0%)	0
Dyspepsia	3/166 (1.8%)	3	0/55 (0%)	0
Gastrooesophageal reflux disease	3/166 (1.8%)	3	0/55 (0%)	0
Abdominal distension	2/166 (1.2%)	2	0/55 (0%)	0
Diarrhoea	2/166 (1.2%)	2	0/55 (0%)	0
Dry mouth	2/166 (1.2%)	2	0/55 (0%)	0
Eructation	2/166 (1.2%)	2	0/55 (0%)	0
General disorders
Oedema Peripheral	3/166 (1.8%)	3	1/55 (1.8%)	1
Application site pain	0/166 (0%)	0	1/55 (1.8%)	1
Feeling jittery	0/166 (0%)	0	1/55 (1.8%)	1
Infusion site thrombosis	0/166 (0%)	0	1/55 (1.8%)	1
Infections and infestations
Upper respiratory tract infection	6/166 (3.6%)	6	0/55 (0%)	0
Atypical pneumonia	2/166 (1.2%)	2	0/55 (0%)	0
Cellulitis	1/166 (0.6%)	1	1/55 (1.8%)	1
Sinusitis	1/166 (0.6%)	1	1/55 (1.8%)	1
Acute Sinusitis	0/166 (0%)	0	1/55 (1.8%)	1
Otitis Externa	0/166 (0%)	0	1/55 (1.8%)	1
Injury, poisoning and procedural complications
Contusion	2/166 (1.2%)	2	0/55 (0%)	0
Muscle Strain	1/166 (0.6%)	1	1/55 (1.8%)	1
Overdose	1/166 (0.6%)	1	2/55 (3.6%)	3
Pelvic Facture	0/166 (0%)	0	1/55 (1.8%)	1
Investigations
High Density Lipoprotein Decreased	5/166 (3%)	5	0/55 (0%)	0
Blood triglycerides increased	1/166 (0.6%)	1	0/55 (0%)	0
Blood pressure increased	2/166 (1.2%)	2	1/55 (1.8%)	1
Prostatic specific antigen increased	2/166 (1.2%)	2	0/55 (0%)	0
Haematocrit Increased	8/166 (4.8%)	8	0/55 (0%)	0
Weight Increased	1/166 (0.6%)	1	1/55 (1.8%)	1
Metabolism and nutrition disorders
Diabetes mellitus	1/166 (0.6%)	1	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	2/166 (1.2%)	2	0/55 (0%)	0
Myalgia	2/166 (1.2%)	2	0/55 (0%)	0
Osteoarthritis	2/166 (1.2%)	2	0/55 (0%)	0
Muscle Spasms	0/166 (0%)	0	1/55 (1.8%)	1
Neck Pain	0/166 (0%)	0	1/55 (1.8%)	1
Rotator Cuff Syndrome	0/166 (0%)	0	1/55 (1.8%)	1
Nervous system disorders
Headache	8/166 (4.8%)	8	1/55 (1.8%)	1
Hypoaesthesia	2/166 (1.2%)	2	0/55 (0%)	0
Dizziness	1/166 (0.6%)	1	1/55 (1.8%)	1
Presyncope	1/166 (0.6%)	1	1/55 (1.8%)	1
Disturbance in attention	0/166 (0%)	0	1/55 (1.8%)	1
Nerve Compression	0/166 (0%)	0	1/55 (1.8%)	1
Psychiatric disorders
Insomnia	3/166 (1.8%)	3	0/55 (0%)	0
Anxiety	2/166 (1.2%)	2	1/55 (1.8%)	1
Depression	2/166 (1.2%)	2	0/55 (0%)	0
Libido increases	0/166 (0%)	0	1/55 (1.8%)	1
Renal and urinary disorders
Hematuria	2/166 (1.2%)	2	0/55 (0%)	0
Pollakiuria	1/166 (0.6%)	1	1/55 (1.8%)	1
Urinary incontinence	0/166 (0%)	0	1/55 (1.8%)	1
Reproductive system and breast disorders
Ejaculation disorder	0/166 (0%)	0	1/55 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/166 (1.2%)	2	0/55 (0%)	0
Skin and subcutaneous tissue disorders
Rash	2/166 (1.2%)	3	2/55 (3.6%)	2
Drug Eruption	0/166 (0%)	0	1/55 (1.8%)	1
Rash maculo-papular	0/166 (0%)	0	1/55 (1.8%)	1
Sunburn	0/166 (0%)	0	1/55 (1.8%)	1
Surgical and medical procedures
Tooth extraction	0/166 (0%)	0	1/55 (1.8%)	1
Vascular disorders
Hypertension	5/166 (3%)	5	0/55 (0%)	0
Flushing	2/166 (1.2%)	2	0/55 (0%)	0

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 results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.