A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism

Phase 2

Terminated

• Conditions: Hypogonadotropic Hypogonadism
• Interventions: Drug: TAK-448

• Registration Number: NCT02369796
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to evaluate the effects on serum testosterone after 4 weeks of subcutaneous (SC) dose administration, with different doses and dosing frequencies of TAK-448 to overweight/obese males with hypogonadotropic hypogonadism.

Detailed Description

The drug being tested in this study is called TAK-448. TAK-448 is being tested to treat overweight/obese males with hypogonadotropic hypogonadism. This study will look at the effects of TAK-448 on serum testosterone at different doses and different dosing frequencies.

The study will enroll 15 patients. There will be 5 cohorts and participants will be assigned to cohorts in sequential order. Cohorts will be assigned to the following treatment groups:

* TAK-448 3 µg once weekly

* TAK-448 1 µg once weekly

* TAK-448 0.3 µg once weekly

* TAK-448 0.3 µg twice weekly

* TAK-448 0.1 µg twice weekly

All participants will be administered study drug via SC injection once or twice a week depending on their assigned cohort for four weeks.

This single-center trial will be conducted in the United Kingdom. The overall time to participate in this study is up to 32 days. Participants will make multiple visits to the clinic (depending once-weekly or twice-weekly dosing), and will be contacted by telephone 1 week after last dose of study drug for a follow-up assessment.

Study Timeline

• Study Start: 2015-02
• Study First Submitted: 2015-02-17
• Study First Submitted QC: 2015-02-17
• Study First Posted: 2015-02-24
• Primary Completion: 2015-10
• Study Completion: 2015-11
• Results First Submitted: 2016-11-01
• Status Verified: 2017-02
• Results First Submitted QC: 2017-02-13
• Last Update Submitted: 2017-02-13
• Results First Posted: 2017-03-31
• Last Update Posted: 2017-03-31

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 15

Inclusion Criteria

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The participant has two morning total serum testosterone (ST) concentrations ≤12.0 nmol/L (≤3.46 ng/mL) taken during the Screening period.
4. Is male and aged 18 to 60 years, inclusive.
5. Has a body mass index (BMI) between 25.0 and 50.0 kg/m^2, inclusive.
6. If diagnosed with type II diabetes mellitus (T2DM), has a glycosylated hemoglobin (HbA1c) concentration <12% at Screening and is on a stable dose of up to 4 diabetes therapies (including insulin and/or glucagon-like peptide-1 therapies).
7. Has a luteinizing hormone (LH) concentration <8 IU/L at Screening.
8. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.

Exclusion Criteria

1. Has received any investigational compound within 30 days prior to Screening.
2. Has received TAK-448 in a previous clinical study, or previous cohort.
3. Is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
4. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality (other than T2DM, its complications and associated conditions), which may impact the ability of the participant to participate or potentially confound the study results.
5. Has a recent history or clinical manifestations of significant cardiovascular disease (CVD) - such as a history of myocardial infarction or stroke in the 6 months preceding the Screening visit or has untreated peripheral arterial disease.
6. Has a history of hypersensitivity or allergies to any component of the formulation of TAK-448.
7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to Screening.
8. Is required to take excluded medications, supplements, or food products.
9. Intends to donate sperm during the course of this study or for 12 weeks after the last dose of study drug.
10. Has clinical evidence of anatomic or pathological hypothalamic/pituitary disease.
11. Is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking TAK-448, or a similar drug in the same class that might interfere with the conduct of the study.
12. Has a history of cancer (including prostate cancer), with the exception of basal cell carcinoma which has been in remission for at least 5 years prior to Screening.
13. Has a history of or present prostate disease (including benign prostatic hyperplasia) or prostate-specific antigen (PSA) is >4 ng/mL at Screening.
14. Has a known history of human immunodeficiency virus infection at Screening.
15. Is deemed by the study team to have poor peripheral venous access.
16. Has donated or lost 450 mL or more of his blood volume (including plasmapheresis), or had a transfusion of any blood product within 45 days prior to Screening, or is planning to donate blood for 12 weeks after the last dose of study medication.
17. Has a Screening or Day -1 abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature of the principal investigator or medically qualified subinvestigator.
18. Has abnormal Screening or Day -1 laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2× the upper limits of normal (ULN).
19. The participant, in the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.
20. Has had more than two severe hypoglycemic events (requiring third party assistance) within 6 months prior to the Screening Visit.
21. Has a diagnosis of type 1 diabetes mellitus.
22. Has a history of diabetic ketoacidosis.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TAK-448 3 µg once weekly	TAK-448	TAK-448 3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.
TAK-448 1 µg once weekly	TAK-448	TAK-448 1 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.
TAK-448 0.1 µg twice weekly	TAK-448	TAK-448 0.1 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.
TAK-448 0.3 µg once weekly	TAK-448	TAK-448 0.3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.
TAK-448 0.3 µg twice weekly	TAK-448	TAK-448 0.3 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

Primary Outcome Measures

Name	Time	Method
Trough Serum Concentration (Ctrough) of Total Serum Testosterone for Twice Weekly Dosing Group	Day 25 pre-dose	Trough serum concentration of total ST, defined as lowest baseline concentration compared to pre-dose of the last dose.
Trough Serum Concentration (Ctrough) of Free Serum Testosterone for Once Weekly Dosing Groups	Day 22 pre-dose	Trough serum concentration of free ST, defined as lowest baseline concentration compared to pre-dose of the last dose.
Trough Serum Concentration (Ctrough) of Total Serum Testosterone for Once Weekly Dosing Groups	Day 22 pre-dose	Trough serum concentration of total ST, defined as lowest baseline concentration compared to pre-dose of the last dose.
Trough Serum Concentration (Ctrough) of Free Serum Testosterone for Twice Weekly Dosing Groups	Day 25 pre-dose	Trough serum concentration of free ST, defined as lowest baseline concentration compared to pre-dose of the last dose.
Percent Change From Baseline in Mean Area Under the Effect Curve From Time 0 to 72 Hours (AUEC72) of Free Serum Testosterone for Twice Weekly Dosing Groups	Baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose	Area under the PD free ST concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose.
Percent Change From Baseline in Mean Area Under the Effect Curve From Time 0 to 72 Hours (AUEC72) of Total Serum Testosterone for Once Weekly Dosing Groups	Baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose	Area under the pharmacodynamic (PD) total serum testosterone (ST) concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose.
Percent Change From Baseline in Mean Area Under the Effect Curve From Time 0 to 72 Hours (AUEC72) of Total Serum Testosterone for Twice Weekly Dosing Groups	Baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose	Area under the PD total ST concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose.
Percent Change From Baseline in Mean Area Under the Effect Curve From Time 0 to 72 Hours (AUEC72) of Free Serum Testosterone for Once Weekly Dosing Groups	Baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose	Area under the PD free ST concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose.

Secondary Outcome Measures

Name	Time	Method
AUC(0-∞): Mean Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-448F	Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose	AUC(0-∞) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Mean Terminal Phase Elimination Half-life (T1/2) for TAK-448F	Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose	Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Cmax: Mean Maximum Observed Plasma Concentration for TAK-448 Free Base Form (TAK-448F)	Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
AUC(0-tlqc): Mean Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-448F	Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose	AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).