Effects of TAK-448 in Middle-aged and Older Men With Low Testosterone

Phase 2

Terminated

• Conditions: Low Testosterone
• Interventions: Drug: TAK-448; Drug: TAK-448 Placebo

• Registration Number: NCT02381288
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to evaluate the effects on serum testosterone (ST) after 6 weeks of subcutaneous (SC) administration of different doses and dosing frequencies of TAK-448 to middle-aged and older men with low ST levels.

Detailed Description

The drug tested in this study is called TAK-448. TAK-448 was tested to define a dose and dose frequency which results in a clinically relevant improvement in ST in middle-aged and older men with low ST levels. This study looked at ST levels in men who took TAK-448.

The study enrolled 17 participants. Participants were randomly assigned (by chance, like flipping a coin) to one of the following treatment groups-which remained undisclosed to the participants and study doctor during the study (unless there is an urgent medical need):

* TAK-448 0.1 µg

* TAK-448 0.3 µg

* TAK-448 1.0 µg

* Placebo (dummy inactive injection) - this was a injection that looks like the study drug but has no active ingredient All participants received subcutaneous injection either once daily on Days 1 through 42, or twice weekly on Days 1 through 39 or once weekly on Days 1 through 36.

This single-center trial was conducted in the United States. The overall time to participate in this study is up to 56 days. Participants made daily visits to the clinic for 8 weeks, and were contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Study Timeline

• Study First Submitted: 2015-03-02
• Study First Submitted QC: 2015-03-02
• Study First Posted: 2015-03-06
• Study Start: 2015-09-10
• Primary Completion: 2016-04-08
• Study Completion: 2016-04-08
• Disposition First Submitted: 2017-02-02
• Disposition First Submitted QC: 2017-02-02
• Disposition First Posted: 2017-02-06
• Status Verified: 2017-04
• Results First Submitted: 2017-04-07
• Results First Submitted QC: 2017-04-07
• Last Update Submitted: 2017-04-07
• Results First Posted: 2017-05-17
• Last Update Posted: 2017-05-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 17

Inclusion Criteria

1. Has total serum testosterone (ST) levels less than 300 ng/dL at Screening.
2. Has a body mass index (BMI) between 20.0 and 40.0 kg/m^2, inclusive at Screening.
3. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from the time of signing of informed consent throughout the duration of the study and for 12 weeks after the last dose.

Exclusion Criteria

1. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality that may impact the ability of the participant to participate or potentially confound the study results. Participants will be excluded based on:

   1. Has a serum creatinine >2.0 milligrams per deciliter (mg/dL) at Screening.
   2. Is receiving dialysis treatment.
   3. Has an American Urological Association (AUA)/ International Prostate Symptom Score (I-PSS) score of >19 or serum prostate-specific antigen (PSA) >4 nanogram per milliliter (ng/mL) at Screening.
   4. Has thyrotropin (TSH) levels less than (<) 0.3 or >7.5 milli-international units per liter (mIU/L) at Screening.
   5. Has systolic blood pressure >160 millimeter of mercury (mm Hg) or diastolic blood pressure >100 mm Hg (if out of range may be repeated once for eligibility determination) at Screening.
   6. Has luteinizing hormone (LH) >9.4 units per liter (U/L) at Screening.
   7. Is receiving insulin therapy.
   8. Has a hematocrit <30 percent (%) or >48% at Screening.
   9. Has a glycosylated hemoglobin (HbA1c) >8.0 at Screening (Cohort 1).

2. Has type 2 diabetes mellitus defined as fasting blood glucose >125 mg/dL, glycosylated hemoglobin (HbA1c) >6.2%, or use of antidiabetic medication (Cohort 2 only).

3. Has clinical evidence of anatomic or pathological hypothalamic/pituitary/testicular disease, such as (but not limited to) Klinefelter's syndrome, Kallmann's syndrome, systemic infiltrative diseases (hemochromatosis, sarcoidosis, Wilson's disease), or prior pituitary surgery.

4. Has used gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, antiandrogens, clomiphene, or other reproductive hormone-related agents within 6 months prior to Screening.

5. Has used anabolic therapies (testosterone, dehydroepiandrosterone [DHEA], androstendione, any other androgen, or recombinant human growth hormone) within 1 year of Screening.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TAK-448 0.1 mcg	TAK-448	TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.
TAK-448 0.3 mcg	TAK-448	TAK-448 0.3 mcg, injection, subcutaneously, twice-weekly on Days 1 through 39.
TAK-448 1.0 mcg	TAK-448	TAK-448 1.0 mcg, injection, subcutaneously, once-weekly on Days 1 through 36.
Placebo	TAK-448 Placebo	TAK-448 placebo matching injection, subcutaneously, either once daily on Days 1 through 42, or twice weekly on Days 1 through 39 or once weekly on Days 1 through 36.
Placebo	TAK-448	TAK-448 placebo matching injection, subcutaneously, either once daily on Days 1 through 42, or twice weekly on Days 1 through 39 or once weekly on Days 1 through 36.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing	Once-daily regimen Day 42; Twice-weekly regimen Day 39; Once-weekly regimen Day 36	Cav is the average serum concentration of the dosing interval, calculated as area under the effect curve (AUEC) divided by the duration of the dosing interval.
Trough Serum Concentration (Ctrough) of ST	Once-daily regimen Day 42; Twice-weekly regimen Day 39; Once-weekly regimen Day 36	Trough serum concentration of total and free ST, defined as lowest Baseline concentration.

Secondary Outcome Measures

Name	Time	Method
Terminal Elimination Half-life (T1/2) for TAK-448F	Once-daily Dosing Days 1 and 42, Twice-weekly Dosing Days 1 and 39, Once-weekly Dosing Days 1 and 36, predose and at multiple time intervals (up to 8 hours) post-dose.	T1/2 is the time required for half of the drug to be eliminated from the plasma.
Serum Testosterone Cmax: Maximum Observed Plasma Concentration	Day 1 (first dose) and Day 42 for once-daily regimen, Day 39 for twice-weekly regimen, or Day 36 for once-weekly regimen (last dose)	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Assessments were done Day 1 and Day 42 for once daily regimen, on Day 36 for once weekly regimen and on Day 39 for twice-weekly regimen (Day 42/36/39).
Cmax: Maximum Observed Plasma Concentration for the Free Form of TAK-448 (TAK-448F)	Once-daily Dosing Days 1 and 42, Twice-weekly Dosing Days 1 and 39, Once-weekly Dosing Days 1 and 36, predose and at multiple time intervals (up to 8 hours) post-dose.	Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
AUCt: Area Under the Plasma Concentration-Time Curve for TAK-448F	Once-daily Dosing Days 1 and 42, Twice-weekly Dosing Days 1 and 39, Once-weekly Dosing Days 1 and 36, predose and at multiple time intervals (up to 8 hours) post-dose.	Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.