Low Testosterone
Conditions
Keywords
Drug therapy
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.
Interventions
DRUGTAK-448
TAK-448 solution for subcutaneous injection
DRUGTAK-448 Placebo
TAK-448 placebo-matching solution for subcutaneous injection
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
60 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in the United States from 10 September 2015 to 08 April 2016.
Pre-assignment details
Middle-aged and older male participants with low testosterone levels were enrolled in once daily TAK-448 0.1 µg, twice weekly TAK-448 0.3 µg, once weekly TAK-448 1 µg or Placebo groups.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 5 |
| TAK-448 0.1 µg TAK-448 0.1 µg, injection, subcutaneously, once daily on Days 1 through 42. | 2 |
| TAK-448 0.3 µg TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39. | 5 |
| TAK-448 1.0 µg TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36. | 5 |
| Total | 17 |
Baseline characteristics
| Characteristic | TAK-448 0.1 µg | Total | TAK-448 1.0 µg | Placebo | TAK-448 0.3 µg |
|---|---|---|---|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 11.31 | 67.1 years STANDARD_DEVIATION 6.54 | 65.2 years STANDARD_DEVIATION 1.48 | 64.0 years STANDARD_DEVIATION 3.24 | 70.6 years STANDARD_DEVIATION 9.32 |
| Alcohol Classification Participant has never drunk | 1 participants | 2 participants | 0 participants | 1 participants | 0 participants |
| Alcohol Classification Participant is a current drinker | 1 participants | 12 participants | 5 participants | 3 participants | 3 participants |
| Alcohol Classification Participant is an ex-drinker | 0 participants | 3 participants | 0 participants | 1 participants | 2 participants |
| Baseline Body Mass Index (BMI) | 33.9 kg/m^2 STANDARD_DEVIATION 5.2 | 31.6 kg/m^2 STANDARD_DEVIATION 4.9 | 30.0 kg/m^2 STANDARD_DEVIATION 6.5 | 30.7 kg/m^2 STANDARD_DEVIATION 4.3 | 33.3 kg/m^2 STANDARD_DEVIATION 4.2 |
| Caffeine Consumption No | 0 participants | 5 participants | 1 participants | 2 participants | 2 participants |
| Caffeine Consumption Yes | 2 participants | 12 participants | 4 participants | 3 participants | 3 participants |
| Height | 173.5 cm STANDARD_DEVIATION 3.54 | 173.5 cm STANDARD_DEVIATION 6.05 | 174.6 cm STANDARD_DEVIATION 6.77 | 173.6 cm STANDARD_DEVIATION 5.81 | 172.4 cm STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized Asian | 0 participants | 3 participants | 3 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 2 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Non-Hispanic and Latino | 2 participants | 17 participants | 5 participants | 5 participants | 5 participants |
| Race/Ethnicity, Customized White | 1 participants | 12 participants | 2 participants | 5 participants | 4 participants |
| Region of Enrollment United States | 2 participants | 17 participants | 5 participants | 5 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 17 Participants | 5 Participants | 5 Participants | 5 Participants |
| Smoking Classification Participant has never smoked | 1 participants | 11 participants | 4 participants | 3 participants | 3 participants |
| Smoking Classification Participant is an ex-smoker | 1 participants | 6 participants | 1 participants | 2 participants | 2 participants |
| Weight | 101.6 kg STANDARD_DEVIATION 11.3 | 95.5 kg STANDARD_DEVIATION 16.8 | 91.5 kg STANDARD_DEVIATION 21.5 | 93.0 kg STANDARD_DEVIATION 16.6 | 99.4 kg STANDARD_DEVIATION 17.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 5 | 1 / 2 | 4 / 5 | 2 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 2 | 0 / 5 | 0 / 5 |
Outcome results
Primary
Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing
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.
Time frame: Once-daily regimen Day 42; Twice-weekly regimen Day 39; Once-weekly regimen Day 36
Population: Pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of study drug or placebo and who had at least 1 valid PD measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing | 14.32 percent change | Standard Deviation 29.186 |
| TAK-448 0.1 µg | Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing | 7.100 percent change | Standard Deviation 18.102 |
| TAK-448 0.3 µg | Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing | 10.60 percent change | Standard Deviation 12.594 |
| TAK-448 1.0 µg | Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing | 15.80 percent change | Standard Deviation 26.531 |
Primary
Trough Serum Concentration (Ctrough) of ST
Trough serum concentration of total and free ST, defined as lowest Baseline concentration.
Time frame: Once-daily regimen Day 42; Twice-weekly regimen Day 39; Once-weekly regimen Day 36
Population: PD analysis set included all participants who received at least 1 dose of study drug or placebo and who had at least 1 valid PD measure. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough Serum Concentration (Ctrough) of ST | 285.4 ng/dL | Standard Deviation 94.952 |
| TAK-448 0.1 µg | Trough Serum Concentration (Ctrough) of ST | 255.5 ng/dL | Standard Deviation 102.53 |
| TAK-448 0.3 µg | Trough Serum Concentration (Ctrough) of ST | 135.3 ng/dL | Standard Deviation 44.515 |
| TAK-448 1.0 µg | Trough Serum Concentration (Ctrough) of ST | 244.4 ng/dL | Standard Deviation 61.756 |
Secondary
AUCt: Area Under the Plasma Concentration-Time Curve for TAK-448F
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.
Time frame: 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.
Population: Due to early termination of the study pharmacokinetic data was not collected and reported.
Secondary
Cmax: Maximum Observed Plasma Concentration for the Free Form of TAK-448 (TAK-448F)
Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: 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.
Population: Due to early termination of the study pharmacokinetic data was not collected and reported.
Secondary
Serum Testosterone Cmax: Maximum Observed Plasma Concentration
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).
Time frame: 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)
Population: PD analysis set included all participants who received at least 1 dose of study drug or placebo and who have at least 1 valid PD measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 1 | 287.6 ng/dL | Standard Deviation 58.518 |
| Placebo | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 42/36/39 | 354.8 ng/dL | Standard Deviation 136.09 |
| TAK-448 0.1 µg | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 42/36/39 | 287.0 ng/dL | Standard Deviation 57.983 |
| TAK-448 0.1 µg | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 1 | 306.5 ng/dL | Standard Deviation 68.589 |
| TAK-448 0.3 µg | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 1 | 351.2 ng/dL | Standard Deviation 87.434 |
| TAK-448 0.3 µg | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 42/36/39 | 263.8 ng/dL | Standard Deviation 82.914 |
| TAK-448 1.0 µg | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 1 | 427.8 ng/dL | Standard Deviation 67.054 |
| TAK-448 1.0 µg | Serum Testosterone Cmax: Maximum Observed Plasma Concentration | Day 42/36/39 | 343.0 ng/dL | Standard Deviation 57.524 |
Secondary
Terminal Elimination Half-life (T1/2) for TAK-448F
T1/2 is the time required for half of the drug to be eliminated from the plasma.
Time frame: 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.
Population: Due to early termination of the study pharmacokinetic data was not collected and reported.