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

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02381288
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arms: 4
• Actual Duration (Months): 6.9
• Patients Per Site Per Month: 2.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Low Testosterone	Drug: TAK-448; Drug: TAK-448 Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Randomized, Single-Blind, Placebo-Controlled Phase 2a Study to Evaluate the Stimulatory Effects of TAK-448, a Kisspeptin Analog, Administered Intermittently in Middle-aged and Older Men With Low Testosterone
• Actual Study Start Date: Sep 10, 2015
• Actual Primary Completion Date: Apr 8, 2016
• Actual Study Completion Date: Apr 8, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-448 0.1 mcg TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.	Drug: TAK-448; TAK-448 solution for subcutaneous injection
Experimental: TAK-448 0.3 mcg TAK-448 0.3 mcg, injection, subcutaneously, twice-weekly on Days 1 through 39.	Drug: TAK-448; TAK-448 solution for subcutaneous injection
Experimental: TAK-448 1.0 mcg TAK-448 1.0 mcg, injection, subcutaneously, once-weekly on Days 1 through 36.	Drug: TAK-448; TAK-448 solution for subcutaneous injection
Placebo Comparator: 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.	Drug: TAK-448; TAK-448 solution for subcutaneous injection; Drug: TAK-448 Placebo; TAK-448 placebo-matching solution for subcutaneous injection

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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).

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: Male
• Accepts 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:

2. Has a serum creatinine >2.0 milligrams per deciliter (mg/dL) at Screening.

3. Is receiving dialysis treatment.

4. 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.

5. Has thyrotropin (TSH) levels less than (<) 0.3 or >7.5 milli-international units per liter (mIU/L) at Screening.

6. 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.

7. Has luteinizing hormone (LH) >9.4 units per liter (U/L) at Screening.

8. Is receiving insulin therapy.

9. Has a hematocrit <30 percent (%) or >48% at Screening.

10. Has a glycosylated hemoglobin (HbA1c) >8.0 at Screening (Cohort 1).

11. 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).

12. 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.

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Boston	Massachusetts	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02381288
• Other Study ID Numbers: TAK-448-2002; U1111-1150-2776
• First Posted: Mar 6, 2015
• Last Update Posted: May 17, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Takeda: Drug therapy

Study Results

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 Detail	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.

Arm/Group Title	Placebo	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	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.	TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Period Title: Overall Study
STARTED	5	2	5	5
COMPLETED	5	2	5	5
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg	Total
Arm/Group Description	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.	TAK-448 0.1 µg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.	Total of all reporting groups
Overall Participants	5	2	5	5	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.0 (3.24)	71.0 (11.31)	70.6 (9.32)	65.2 (1.48)	67.1 (6.54)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%
Male	5 100%	2 100%	5 100%	5 100%	17 100%
Race/Ethnicity, Customized (participants) [Number]
Non-Hispanic and Latino	5 100%	2 100%	5 100%	5 100%	17 100%
Race/Ethnicity, Customized (participants) [Number]
Asian	0 0%	0 0%	0 0%	3 60%	3 17.6%
Black or African American	0 0%	1 50%	1 20%	0 0%	2 11.8%
White	5 100%	1 50%	4 80%	2 40%	12 70.6%
Region of Enrollment (participants) [Number]
United States	5 100%	2 100%	5 100%	5 100%	17 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	173.6 (5.81)	173.5 (3.54)	172.4 (7.80)	174.6 (6.77)	173.5 (6.05)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	93.0 (16.6)	101.6 (11.3)	99.4 (17.3)	91.5 (21.5)	95.5 (16.8)
Baseline Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.7 (4.3)	33.9 (5.2)	33.3 (4.2)	30.0 (6.5)	31.6 (4.9)
Smoking Classification (participants) [Number]
Participant has never smoked	3 60%	1 50%	3 60%	4 80%	11 64.7%
Participant is an ex-smoker	2 40%	1 50%	2 40%	1 20%	6 35.3%
Alcohol Classification (participants) [Number]
Participant has never drunk	1 20%	1 50%	0 0%	0 0%	2 11.8%
Participant is a current drinker	3 60%	1 50%	3 60%	5 100%	12 70.6%
Participant is an ex-drinker	1 20%	0 0%	2 40%	0 0%	3 17.6%
Caffeine Consumption (participants) [Number]
Yes	3 60%	2 100%	3 60%	4 80%	12 70.6%
No	2 40%	0 0%	2 40%	1 20%	5 29.4%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Average Serum Concentration (Cav) of Total ST After 6 Weeks of Dosing
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	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.	TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Measure Participants	5	2	5	5
Mean (Standard Deviation) [percent change]	14.32 (29.186)	7.100 (18.102)	10.60 (12.594)	15.80 (26.531)

2. Primary Outcome

Title	Trough Serum Concentration (Ctrough) of ST
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	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.	TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Measure Participants	5	2	4	5
Mean (Standard Deviation) [ng/dL]	285.4 (94.952)	255.5 (102.53)	135.3 (44.515)	244.4 (61.756)

3. Secondary Outcome

Title	Serum Testosterone Cmax: Maximum Observed Plasma Concentration
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	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.	TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Measure Participants	5	2	5	5
Day 1	287.6 (58.518)	306.5 (68.589)	351.2 (87.434)	427.8 (67.054)
Day 42/36/39	354.8 (136.09)	287.0 (57.983)	263.8 (82.914)	343.0 (57.524)

4. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for the Free Form of TAK-448 (TAK-448F)
Description	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.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study pharmacokinetic data was not collected and reported.

Arm/Group Title	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	TAK-448 0.1 µg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Measure Participants	0	0	0

5. Secondary Outcome

Title	AUCt: Area Under the Plasma Concentration-Time Curve for TAK-448F
Description	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.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study pharmacokinetic data was not collected and reported.

Arm/Group Title	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	TAK-448 0.1 µg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Measure Participants	0	0	0

6. Secondary Outcome

Title	Terminal Elimination Half-life (T1/2) for TAK-448F
Description	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.

Outcome Measure Data

Analysis Population Description

Due to early termination of the study pharmacokinetic data was not collected and reported.

Arm/Group Title	TAK-448 0.1 µg	TAK-448 0.3 µg	TAK-448 1.0 µg
Arm/Group Description	TAK-448 0.1 µg, injection, subcutaneously, once daily on Days 1 through 42.	TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.	TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
Measure Participants	0	0	0

Adverse Events

Time Frame	Baseline up to Day 56
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		TAK-448 0.1 µg		TAK-448 0.3 µg		TAK-448 1.0 µg
Arm/Group Description	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.		TAK-448 0.1 mcg, injection, subcutaneously, once daily on Days 1 through 42.		TAK-448 0.3 µg, injection, subcutaneously, twice-weekly on Days 1 through 39.		TAK-448 1.0 µg, injection, subcutaneously, once-weekly on Days 1 through 36.
All Cause Mortality
	Placebo		TAK-448 0.1 µg		TAK-448 0.3 µg		TAK-448 1.0 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		TAK-448 0.1 µg		TAK-448 0.3 µg		TAK-448 1.0 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TAK-448 0.1 µg		TAK-448 0.3 µg		TAK-448 1.0 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		1/2 (50%)		4/5 (80%)		2/5 (40%)
Cardiac disorders
Palpitations	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Eye disorders
Lacrimation increased	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Gastrointestinal disorders
Diarrhoea	0/5 (0%)		1/2 (50%)		1/5 (20%)		0/5 (0%)
Constipation	0/5 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)
Flatulence	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
General disorders
Feeling abnormal	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Pyrexia	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Infections and infestations
Nasopharyngitis	1/5 (20%)		0/2 (0%)		1/5 (20%)		1/5 (20%)
Tooth infection	0/5 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)
Injury, poisoning and procedural complications
Procedural pain	0/5 (0%)		0/2 (0%)		0/5 (0%)		1/5 (20%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)
Nervous system disorders
Dizziness	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Psychiatric disorders
Insomnia	1/5 (20%)		0/2 (0%)		0/5 (0%)		0/5 (0%)
Renal and urinary disorders
Urinary incontinence	0/5 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/5 (20%)		0/2 (0%)		1/5 (20%)		0/5 (0%)
Cough	0/5 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)
Vascular disorders
Phlebitis	0/5 (0%)		0/2 (0%)		1/5 (20%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.