Efficacy and Safety of Oral Testosterone Undecanoate in Hypogonadal Men

Hypogonadism, Male Clinical Trial

Official title:

A 12-Month, Randomized, Active-controlled, Open-label Study of the Efficacy and Safety of Oral Testosterone Undecanoate in Hypogonadal Men (RE-TUne)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03198728
• Other study ID #: MRS-TU-2019
• Status: Completed
• Phase: Phase 3
• Start date: July 5, 2017
• Est. completion date: May 1, 2020

Study information

• Verified date: June 2023
• Source: Marius Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This will be a randomized, multicenter, open-label, active-controlled, efficacy, and safety study in adult hypogonadal men. The study duration is 12 months (365 days), including a 90-day, open-label efficacy period and a 9-month (275-day) safety evaluation period.

Description:

MRS-TU-2019 was a 12-month study designed to determine the efficacy of oral SOV2012-F1 as measured by the percentage of male hypogonadal subjects with average total testosterone (T Cavg) in plasma within the normal range after 90 days of treatment. This study included an AndroGel™ arm as a safety comparator; after the 90-day efficacy period, dosing continued for 9 additional months in both arms to gather safety data. This study also examined the percentage of SOV2012-F1-treated subjects with maximum total testosterone (Cmax) in plasma values after 90 days of treatment: a. ≤1.5 X upper limit of normal (ULN); b. 1.8 X ULN to 2.5 X ULN' and c. >2.5 X ULN. The study also included an adrenal cortical function substudy conducted in 30 SOV2012-F1 subjects and 15 AndroGel subjects. Four patient-reported outcome measures were also used during the study: IPSS, PDQ, SF-36 and IIEF.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 314
• Est. completion date: May 1, 2020
• Est. primary completion date: May 1, 2020
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Male aged 18 to 65 years, inclusive, at the time of providing informed consent to participate in the study.

2. Hypogonadism defined as having 2 consecutive serum total T levels= 281 ng/dL based on a blood sample, drawn at least 3 days apart, between 7 a.m. and 10 a.m.

3. At least 1 clinical feature consistent with male hypogonadism. If a subject is receiving commercial TRT prior to Screening Visit 1, he must have a history of at least 1 clinical feature consistent with male hypogonadism.

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

5. No unstable ongoing concomitant medical conditions. Treated and well-controlled conditions such as type 2 diabetes, hypertension, or dyslipidemia are acceptable with stable medication in place for at least 3 months prior to study entry:

1. Hemoglobin A1c = 8.0%

2. BP < 150/90 mm Hg

3. Low-density lipoprotein cholesterol < 190 mg/dL.

6. Subjects with an endocrine disorder requiring treatment other than hypogonadism must be on a stable dose of replacement medication for at least 3 months prior to study entry.

7. Adequate venous access to allow collection of a number of blood samples via a venous cannula.

8. Written informed consent to participate in the study and ability to comply with all study requirements.

Exclusion Criteria:

1. Serum PSA > 2.5 ng/ml and/or abnormal prostate gland on palpation, eg, palpable nodes, at Screening Visit 2.

2. 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.

3. Use of any drug that could interfere with measurement or assessment of serum androgen levels, including 5 alpha-reductase inhibitors, anabolic steroids, and drugs with antiandrogenic properties (eg, spironolactone, cimetidine, flutamide, bicalutamide, and ketoconazole). These drugs must be stopped for at least 1 month prior to study entry (6 months in the case of dutasteride). Patients taking potent, long-acting opiate therapy on a daily basis are not eligible for the study. Conversely, ad hoc use of potent, short-acting opiates for a period of less than 7 days may be permitted after discussion with the Marius Pharmaceuticals medical monitor.

4. Use of over-the-counter products, including natural health products (eg, food supplements and herbal supplements such as saw palmetto or phytoestrogens) that may affect total T levels, within 7 days prior to study entry.

5. History of drug or alcohol abuse within the past 2 years that in the opinion of the investigator could interfere with study participation and/or influence study efficacy and safety endpoints assessments.

6. Unstable or chronic disease that could interfere with participation in the study or patient safety, including psychiatric disorders.

7. Myocardial infarction, coronary artery surgery, heart failure, stroke, unstable angina, or other unstable cardiovascular disease within the past 6 months.

8. Abnormal ECG considered clinically significant by investigator at Screening.

9. Diagnosis of any cancer within the previous 5 years other than basal or squamous cell skin cancer with clear margins.

10. Any surgical or medical condition that might alter administration of the study drug or comparator, including history of gastric surgery, cholecystectomy, vagotomy, bowel resection, or any surgical procedure that might interfere with gastrointestinal motility, pH, or absorption of TU.

11. Duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to screening.

12. Chronic skin conditions on the chest or upper arms that would prevent administration of AndroGel in a manner designed to ensure reliable and consistent absorption thereof.

13. Human immunodeficiency virus (HIV) infection.

14. Chronic hepatitis B virus and/or hepatitis C virus (HCV) infection (as determined by positive testing for hepatitis B virus surface antigen or HCV antibody with confirmatory testing, ie, detectable serum HCV ribonucleic acid [RNA]).

15. Clinically significant abnormal laboratory values at screening including but not limited to:

1. Elevated liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT] > 2x upper limit of normal)

2. Estimated glomerular filtration rate < 60 ml/min/1.73m2 as calculated by the Modification of Diet in Renal Disease formula

3. Hemoglobin < 11.0 g/dL or > 16.0 g/dL. For a subject previously on testosterone replacement therapy with less than 30 days washout prior to screening Visit 2, hemoglobin < 11.0 g/dL or > 17.0 g/dL.

16. Severe and untreated obstructive sleep apnea syndrome.

17. Severe lower urinary tract symptoms (American Urological Association/ IPSS = 19).

18. History of any clinically significant illness, infection, or surgical procedure within 1 month prior to study entry.

19. Past, current, or suspected prostate or breast cancer.

20. History of long QT syndrome or unexplained sudden death in a first-degree relative (parent, sibling, or child).

21. Concurrent treatment with medications that may impact the absorption, distribution, metabolism, or excretion of TU or place the subject at risk for treatment with T.

22. Subject has a partner who is currently pregnant or planning pregnancy during the course of the study.

23. Treatment with any other investigational drug within 30 days of study entry or > 5 half-lives (whichever is longer) and at any time during the study.

24. History of noncompliance to medical regimens or potential unreliability in the opinion of the investigator.

25. Unwilling or unable to comply to the dietary requirements for this study.

26. History of polycythemia, either idiopathic or associated with TRT.

27. Donated blood (= 500 mL) within the 12-week period prior to study entry.

28. History of an abnormal bleeding tendency or thrombophlebitis within the previous 2 years that is not linked to venipuncture or intravenous cannulation.

29. Onset of gynecomastia within the previous 6 months.

30. For adrenocorticotropic hormone (ACTH) stimulation substudy only: Primary or secondary adrenal insufficiency.

31. For Bioanalytical Sample Stability Substudy only: subjects with a hemoglobin less than 13 g/dL at most recent assessment* [should be excluded].

Related Conditions & MeSH terms

• Hypogonadism
• Hypogonadism, Male

Intervention

Drug:
• SOV2012-F1
oral preparation of testosterone undecanoate (TU)
• AndroGel
topical testosterone gel 1.62%

Locations

Country	Name	City	State
United States	Primary Care Research Group	Atlanta	Georgia
United States	South Florida Medical Research	Aventura	Florida
United States	Urologic Consultants of SE Pennsylvania	Bala-Cynwyd	Pennsylvania
United States	Alabama Clinical Therapeutics, LLC	Birmingham	Alabama
United States	Central Research Associates, Inc.	Birmingham	Alabama
United States	Northwest Clinical Trials	Boise	Idaho
United States	PAB Clinical Research	Brandon	Florida
United States	University Diabetes Endocrine Consultants	Chattanooga	Tennessee
United States	Men's Health Boston	Chestnut Hill	Massachusetts
United States	Innovative Research of West Florida, Inc.	Clearwater	Florida
United States	Aventiv Research, Inc.	Columbus	Ohio
United States	Rapha Institute For Clinical Research	Fayetteville	North Carolina
United States	Accumed Research Associates	Garden City	New York
United States	Centex Studies, Inc.	Houston	Texas
United States	Pioneer Research Solutions, Inc.	Houston	Texas
United States	Jacksonville Impotence Treatment Center	Jacksonville	Florida
United States	Health Awareness, Inc.	Jupiter	Florida
United States	Centex Studies, Inc.	Lake Charles	Louisiana
United States	Meridien Research	Lakeland	Florida
United States	Palm Research Center, Inc.	Las Vegas	Nevada
United States	Central Kentucky Research Associates	Lexington	Kentucky
United States	Advanced Clinical Research	Meridian	Idaho
United States	My Community Research Center	Miami	Florida
United States	Coastal Clinical Research, Inc.	Mobile	Alabama
United States	Coastal Carolina Research Center	Mount Pleasant	South Carolina
United States	Manhattan Medical Research Practice, PLLC	New York	New York
United States	Clinical Research Associates of Tidewater	Norfolk	Virginia
United States	Quality Clinical Research, Inc.	Omaha	Nebraska
United States	Oviedo Medical Research, LLC	Oviedo	Florida
United States	Rainier Clinical Research Center, Inc.	Renton	Washington
United States	Mid-Columbia Research	Richland	Washington
United States	National Clinical Research, Inc.	Richmond	Virginia
United States	Meridien Research	Saint Petersburg	Florida
United States	San Diego Sexual Medicine	San Diego	California
United States	Quality of Life Medical and Research Centers, LLC	Tucson	Arizona
United States	Advanced Clinical Research	West Jordan	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Marius Pharmaceuticals	Syneos Health

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline in the IPSS	Patient reported outcomes will be assessed by the International Prostate Symptom Score (I-PSS) Reporting a score on a scale 0 to 35 (asymptomatic to very symptomatic). Mean change from baseline is reported and is the difference between the score at Baseline (pre-treatment) and at Day 90 and Day 365. Thus, a positive value at Day 90 or Day 365 represents an increase in the score from baseline.	Baseline (pre-treatment) to 90 days and 365 days
Other	Change From Baseline in the Psychosexual Daily Questionnaire (PDQ)	Patient reported outcomes are 7-day average score at baseline, and average change from baseline (CfB) at Day 90 and Day 365. Weekly daily average scores calculated for diaries completed at least 3 of 7 days.; The three domains are: Sexual desire subscale 0=None, 1=very low to 7=Very High. Sexual enjoyment with/without partner subscale 0=None to 7=Very high enjoyment/pleasure. Partner availability not used in scoring. Positive CfB desirable.; Positive and negative mood subscales 0=Not at all true to 7=Very true (Likert 7-point scale, 7-day average reported). Positive mood (sum of 4 questions) score range = 0 to 28; positive changes from baseline desirable. Negative mood (sum of 5 questions) score range = 0 to 35; negative CfB desirable.; Weekly sexual activity subscale score is 7*(# of activities per week / # of days reported). Percent full erection uses scale of 0-100% (10% steps). Satisfaction with erection 0=not satisfactory to 7=very satisfactory. Positive CfB desirable.	Baseline (pre-treatment) to 90 days and 365 days
Other	Change From Baseline in the SF-36	Patient reported outcomes assessed by the Short-Form Survey (SF-36). This scale assesses 8 health concepts: limitations in physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems; bodily pain; general mental health (psychological distress and well-being); limitations in usual role activities because of emotional problems; vitality (energy and fatigue); general health perceptions.; Each domain is scored from 0-100 with a score of 0 = maximum disability and a score of 100 = no disability.; End of Treatment (EOT) occurred either at time of early withdrawal from the study or at Day 365. The reported value is the change from baseline. A positive value at EOT indicates improvement in the measure towards less disability. The EOT Change from Baseline is simply the arithmetic difference between the Baseline and EOT scores.	Baseline (Day 1, pre-treatment) and change from baseline at the End of Treatment (EOT)
Other	Change From Baseline in the IIEF	Patient reported outcomes are assessed by the International Index of Erectile Function (IIEF). A score of 0-5 (higher score indicating improvement) is awarded to each of the 15 questions that examine overall satisfaction (2 questions, total possible score=10), and the 4 main domains of male sexual function: erectile function (6 questions, total possible score=30), orgasmic function (2 questions, total possible score=10), sexual desire (2 questions, total possible score=10), and intercourse satisfaction (3 questions, total possible score=15).; The IIEF results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at the End of Treatment (EOT). EOT occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. A positive value at EOT indicates improvement in the measure. The EOT Change from Baseline is simply the arithmetic difference between the Baseline and End of Treatment scores.	Baseline (Day 1, pre-treatment) and change from baseline at the End of Treatment (EOT)
Other	Change From Baseline in Fasting Serum Glucose (FSG) Concentration	The measured value is the FSG concentration reported as mg/dL. The FSG results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and measured values.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment.
Other	Change From Baseline in Fasting Insulin Concentration	The measured value is the insulin concentration reported as in units of uU/mL. The insulin results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and measured values.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment.
Other	Change From Baseline in Blood Pressures After Oral Testosterone Undecanoate and Testosterone Gel	Changes from baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), as mmHg.; The blood pressure results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value. A positive value for Change in Baseline represents an increase in the measured SBP or DBP.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment.
Other	Change From Baseline in Liver Function Tests	Liver function tests (ALT, AST, total bilirubin, alkaline phosphatase). The liver function test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value. A positive value for Change in Baseline represents an increase in the liver function test value	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment.
Other	Change in Bilirubin	Change in bilirubin from Baseline The bilirubin test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value. A positive value for Change in Baseline represents an increase in the bilirubin value.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270 and the End of Treatment.
Other	Change From Baseline in Hematology Parameters	Hematology parameters (HbA1c) with diabetes mellitus and Without diabetes mellitus.; The HbA1c test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value at End of Treatment is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and the End of Treatment value. Normal range for HbA1c is 4 to 5.6%, pre-diabetic is 5.7 to 6.4%, and diabetic is equal to or greater than 6.5%.	Baseline (Day 1, pre-treatment) and the change from baseline at the End of Treatment
Other	Change From Baseline in Hormone Levels	Hormone levels (luteinizing hormone [LH], follicle-stimulating hormone [FSH], sex hormone-binding globulin [SHBG], TSH).; The hormone level test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value at Day 90 or Day 365. A positive value for Change in Baseline represents an increase in the hormone level.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, and the End of Treatment
Other	Change in Hormone SHBG	Change in hormone Sex Hormone Binding Globulin (SHBG). The hormone level test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value at Day 90 or Day 365. A positive value for Change in Baseline represents an increase in the hormone level.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, and the End of Treatment
Other	Change in TSH (Thyrotropin)	Change from Baseline in Thyroid stimulating Hormone (TSH). The TSH test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, and the End of Treatment. End of treatment occurred either at time of early withdrawal from the study or at Day 365.; The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value at Day 90 or Day 365. A positive value for Change in Baseline represents an increase in the TSH level.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, and the End of Treatment
Other	Change From Baseline in Lipid Profiles	Lipid profiles (high and low-density lipoproteins, total cholesterol, triglycerides).; The lipid test results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270, Day 365 and the End of Treatment. End of Treatment occurred either at time of early withdrawal from the study or at Day 365.; The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value. A positive value for Change in Baseline represents an increase in the lipid value.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270, Day 365 and the End of Treatment
Other	Change From Baseline in PSA	Serum prostate-specific antigen (PSA). The PSA results are reported at Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270, Day 365 and the End of Treatment. End of Treatment occurred either at time of early withdrawal from the study or at Day 365.; The reported value is the change from baseline. The Change from Baseline is simply the arithmetic difference between the Baseline and the measured value. A positive value for Change in Baseline represents an increase in the PSA value.	Baseline (Day 1, pre-treatment) and the change from baseline at Day 90, Day 180, Day 270, Day 365 and the End of Treatment
Other	Effect of SOV2012-F1 on Adrenal Cortical Function as Assessed by Measuring the Cortisol Response to Synthetic ACTH at Baseline in Subjects	To determine the effect of SOV2012-F1 on adrenal cortical function as assessed by measuring the cortisol response to synthetic ACTH at baseline and after 52 weeks of treatment in a subset of SOV2012-F1 subjects. . The sample size was calculated based on a assumed common Standard Deviation of 93 nmol/L to yield a half-width of not more than 60 nmol/L; hence a sample size of 30 was targeted for the investigational (SOV2012-F1) arm, and 15 for the safety control arm (AndroGel).	52 weeks
Primary	Percentage of Male Hypogonadal Subjects With Average NaF/EDTA Plasma Total Testosterone (T Cavg) Within the Normal Range Using Oral SOV2012-F1.	Efficacy assessment includes T Cavg calculated from NaF/EDTA plasma testosterone. The T Cavg is calculated as the 24-hour area under the curve (AUC), divided by 24, at Day 90, based on a fifteen blood samples (PK samples) taken over the 24-hours. The T concentration in each sample is measured using a validated LC-MS/MS method. The use of NaF/EDTA plasma tubes chilled after sample collection provides the most accurate values, as the prodrug TU may degrade post-sample collection, artificially inflating testosterone values.	90 days
Secondary	Percentages of Participants in Each Category for Maximum Plasma Concentration	To determine the percentage of treated subjects with maximum plasma testosterone concentration (T Cmax) values (a) < 1.5X Upper Limit of Normal (ULN); (b) 1.8X to 2.5X ULN; and (c) > 2.5X ULN. For NaF/EDTA plasma, thresholds are 1200, 1440 and 2000 ng/dL of T. For serum, thresholds are 1500, 1800 and 2500 ng/dL of T. Note that the endpoint concerns only the investigational treatment SOV2012-F1 and the AndroGel results are reported for completeness. The reported percentages do not sum to 100% as the FDA criteria do not specify the percentage of subjects in the window of = 1.5X and = 1.8X the ULN.	90 days

External Links

•   Effects of Oral Testosterone Undecanoate (Kyzatrex) Versus Testosterone Gel (Androgel) on Long-Term (to 12 months) Blood Pressure Levels
•   MRS-TU-2019EXT study