Obese Hypogonadotropic Hypogonadism
Conditions
Keywords
Obese, obesity, hypogonadism, hypogonadotropic, hyperestrogenemic, testosterone, hypogonadal
Brief summary
This study is designed as a 2-part study, with Part 1 being open-label to best determine the appropriate dose levels to use in Part 2, which has a randomized, double-blind, placebo controlled design. The study aims to assess the safety and tolerability of BGS649, and determine whether or not BGS649 is able to normalize testosterone levels and improve insulin sensitivity in obese, hypogonadotropic hypogonadal (OHH) men
Interventions
DRUGInvestigational new drug company code: BGS649
DRUGPlacebo
Sponsors
Novartis
Mereo BioPharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Open-label in Part 1 and double-blind in Part 2.
Eligibility
Sex/Gender
MALE
Age
30 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males who meet the criteria of obese, hypogonadotropic hypogonadism defined as: * Patients with a Body Mass Index (BMI) ≥ 30 kg/m2 * Patients with a morning serum total testosterone level \< 300 ng/dL on at least two separate occasions during the Screening and/or Baseline periods. * Patients with inappropriately low gonadotropins at screening given the low testosterone: * Luteinizing hormone (LH) ≤ ULN * Follicle stimulating hormone (FSH) ≤ ULN * Estradiol within or above the normal range (defined as ≥ LLN of the approved assay) * Normal hypothalamic/pituitary function, including: * Prolactin: within the normal range * Thyroid stimulating hormone (TSH): within the normal range * Ferritin: within the normal range * Patients agree to use a barrier method of contraception (e.g., condom), for the duration of the study and for at least 3 months following their Study Completion visit to prevent BGS649 exposure to their partners.
Exclusion criteria
* Patients with hypogonadism, not related to obesity or as a result of other underlying issues * Patients with significant major organ class illness (e.g. kidney or liver disease). * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving Normal Testosterone Levels | At Week 4 and 12 | Percentage of patients achieving normal testosterone (2.50 - 9.50 ng/mL) levels at Week 4 and Week 12 |
| Part 2: Change From Baseline at Homeostatic Model Assessment of Insulin Resistance (HOMA-IR & QUICKI Scores) at Week 4 and 12 | Baseline, Week 4 and Week 12 | Pharmacodynamic change from baseline in HOMA-IR. Score at week 4 and week 12 as an assessment of insulin resistance. Low score representing high insulin sensitivity and a high score representing low insulin sensitivity or insulin resistance. HOMA-IR is a ration of Fasting insulin (mIU/L) : Fasting glucose (mmol). Pharmacodynamic change in QUICKI score at week 4 and week 12 as an assessment of insulin resistance. The QUICKI scale is a log score and a high score representing high insulin sensitivity and low score indicating low insulin sensitivity. Patients with a score below 0.3 are considered diabetic. Week 12 data is missing because there were inaccuracies in dosing of patients and so the study was terminated, only safety data was collected. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Area Under the Concentration-time Curve From Time Zero to Time 't' (AUC0-168) | 11 weeks | PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11. The AUC 0-168 measures the amount of drug within the subjects blood over the 168h post-dosing at these timepoints. |
| Part 2: Pharmacokinetics of BGS649: Maximum (Peak) Observed Blood Drug Concentration After Single Dose Administration (Cmax) | Week 1 to Week 11 | PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11. |
| Part 2: Pharmacokinetics of BGS649: Time to Reach Maximum (Peak) Blood Drug Concentration After Single Dose Administration (Tmax) | Week 1 to Week 11 | PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11. |
| PK of BGS649 Elimination Half-life Associated With the Terminal Slope of a Semi Logarithmic Concentration-time Curve (T1/2) | Week 1 to Week 11 | PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11. |
Countries
Canada, United States
Participant flow
Recruitment details
14 participants enrolled in Part 1 and 15 participants enrolled in part 2.
Participants by arm
| Arm | Count |
|---|---|
| BGS649 (Part 1) BGS649 1mg and 0.1mg in hard gelatin capsules. In part 1 there was individualised dosing to titrate the subject's testosterone into the normal range. If the dose was lower than 0.1mg then specific instructions for dilution of an oral solution of BGS649 were provided. | 14 |
| BGS649 (Part 2) BGS649 0.3mg hard gelatin capsule given orally on Day 1 and 0.1mg BGS649 capsule on other treatment visits (week 1 to 11). | 7 |
| Placebo to BGS649 (Part 2) Matching placebo to BGS649 (0.3 and 0.1mg). 0.3mg placebo capsule given on Day 1 and 0.1mg placebo capsule on other treatment visits (week 1 to 11). | 8 |
| Total | 29 |
Baseline characteristics
| Characteristic | BGS649 (Part 1) | Total | Placebo to BGS649 (Part 2) | BGS649 (Part 2) |
|---|---|---|---|---|
| Age, Continuous Age (Part 1) | 50 years STANDARD_DEVIATION 9.54 | 50 years STANDARD_DEVIATION 10.1 | — | — |
| Age, Continuous Age (Part 2) | — | 50 years STANDARD_DEVIATION 10.3 | 50 years STANDARD_DEVIATION 11.1 | 51 years STANDARD_DEVIATION 10.1 |
| Body Mass Index BMI (Part 1) | 34 kg/m2 STANDARD_DEVIATION 3.21 | 36.6 kg/m2 STANDARD_DEVIATION 4.1 | — | — |
| Body Mass Index BMI (Part 2) | — | 38 kg/m2 STANDARD_DEVIATION 4.9 | 39 kg/m2 STANDARD_DEVIATION 6.2 | 37 kg/m2 STANDARD_DEVIATION 2.9 |
| Race/Ethnicity, Customized Part 1 Black | 2 Participants | 2 Participants | — | — |
| Race/Ethnicity, Customized Part 1 Caucasian | 12 Participants | 12 Participants | — | — |
| Race/Ethnicity, Customized Part 1 Native American | 0 Participants | 0 Participants | — | — |
| Race/Ethnicity, Customized Part 2 Black | — | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Part 2 Caucasian | — | 13 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Part 2 Native American | — | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 14 participants | 29 participants | 8 participants | 7 participants |
| Sex: Female, Male Sex (Part 1) Female | 0 Participants | 0 Participants | — | — |
| Sex: Female, Male Sex (Part 1) Male | 14 Participants | 14 Participants | — | — |
| Sex: Female, Male Sex (Part 2) Female | — | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Sex (Part 2) Male | — | 15 Participants | 8 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 14 | 5 / 7 | 7 / 8 |
| serious Total, serious adverse events | 0 / 14 | 0 / 7 | 1 / 8 |
Outcome results
Primary
Part 2: Change From Baseline at Homeostatic Model Assessment of Insulin Resistance (HOMA-IR & QUICKI Scores) at Week 4 and 12
Pharmacodynamic change from baseline in HOMA-IR. Score at week 4 and week 12 as an assessment of insulin resistance. Low score representing high insulin sensitivity and a high score representing low insulin sensitivity or insulin resistance. HOMA-IR is a ration of Fasting insulin (mIU/L) : Fasting glucose (mmol). Pharmacodynamic change in QUICKI score at week 4 and week 12 as an assessment of insulin resistance. The QUICKI scale is a log score and a high score representing high insulin sensitivity and low score indicating low insulin sensitivity. Patients with a score below 0.3 are considered diabetic. Week 12 data is missing because there were inaccuracies in dosing of patients and so the study was terminated, only safety data was collected.
Time frame: Baseline, Week 4 and Week 12
Population: Could not be analysed due to drug administration errors. Week 12 data is missing because they were inaccuracies in the dosing of patients and so the study was terminated early and efficacy data not reported for the affected patients.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| BGS649 (Part 1) | Part 2: Change From Baseline at Homeostatic Model Assessment of Insulin Resistance (HOMA-IR & QUICKI Scores) at Week 4 and 12 | HOMA-IR at 4 weeks | 7.94 units on a scale |
| BGS649 (Part 1) | Part 2: Change From Baseline at Homeostatic Model Assessment of Insulin Resistance (HOMA-IR & QUICKI Scores) at Week 4 and 12 | QUICKI at 4 weeks | 0.12 units on a scale |
| Placebo to BGS649 | Part 2: Change From Baseline at Homeostatic Model Assessment of Insulin Resistance (HOMA-IR & QUICKI Scores) at Week 4 and 12 | HOMA-IR at 4 weeks | 7.45 units on a scale |
| Placebo to BGS649 | Part 2: Change From Baseline at Homeostatic Model Assessment of Insulin Resistance (HOMA-IR & QUICKI Scores) at Week 4 and 12 | QUICKI at 4 weeks | 0.13 units on a scale |
Primary
Percentage of Patients Achieving Normal Testosterone Levels
Percentage of patients achieving normal testosterone (2.50 - 9.50 ng/mL) levels at Week 4 and Week 12
Time frame: At Week 4 and 12
Population: Number/percentage of patients achieving normal sex hormone levels at Week 4 and Week 12 (Part 1 Only)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BGS649 (Part 1) | Percentage of Patients Achieving Normal Testosterone Levels | Week 4 | 14 Participants |
| BGS649 (Part 1) | Percentage of Patients Achieving Normal Testosterone Levels | Week 12 | 13 Participants |
Secondary
Part 2: Area Under the Concentration-time Curve From Time Zero to Time 't' (AUC0-168)
PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11. The AUC 0-168 measures the amount of drug within the subjects blood over the 168h post-dosing at these timepoints.
Time frame: 11 weeks
Population: PK Analysis Set included 7 patients given BGS649 in Part 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BGS649 (Part 1) | Part 2: Area Under the Concentration-time Curve From Time Zero to Time 't' (AUC0-168) | Week 1 | 114 ng*hr/mL | Standard Deviation 36.9 |
| BGS649 (Part 1) | Part 2: Area Under the Concentration-time Curve From Time Zero to Time 't' (AUC0-168) | Week 4 | 152 ng*hr/mL | Standard Deviation 48.8 |
| BGS649 (Part 1) | Part 2: Area Under the Concentration-time Curve From Time Zero to Time 't' (AUC0-168) | Week 11 | 167 ng*hr/mL | Standard Deviation 21.5 |
Secondary
Part 2: Pharmacokinetics of BGS649: Maximum (Peak) Observed Blood Drug Concentration After Single Dose Administration (Cmax)
PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11.
Time frame: Week 1 to Week 11
Population: PK Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BGS649 (Part 1) | Part 2: Pharmacokinetics of BGS649: Maximum (Peak) Observed Blood Drug Concentration After Single Dose Administration (Cmax) | Week 1 | 2.83 ng/mL | Standard Deviation 0.998 |
| BGS649 (Part 1) | Part 2: Pharmacokinetics of BGS649: Maximum (Peak) Observed Blood Drug Concentration After Single Dose Administration (Cmax) | Week 4 | 1.69 ng/mL | Standard Deviation 0.61 |
| BGS649 (Part 1) | Part 2: Pharmacokinetics of BGS649: Maximum (Peak) Observed Blood Drug Concentration After Single Dose Administration (Cmax) | Week 11 | 1.69 ng/mL | Standard Deviation 0.261 |
Secondary
Part 2: Pharmacokinetics of BGS649: Time to Reach Maximum (Peak) Blood Drug Concentration After Single Dose Administration (Tmax)
PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11.
Time frame: Week 1 to Week 11
Population: PK Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BGS649 (Part 1) | Part 2: Pharmacokinetics of BGS649: Time to Reach Maximum (Peak) Blood Drug Concentration After Single Dose Administration (Tmax) | Week 1 | 1.02 hours | Standard Deviation 0.00339 |
| BGS649 (Part 1) | Part 2: Pharmacokinetics of BGS649: Time to Reach Maximum (Peak) Blood Drug Concentration After Single Dose Administration (Tmax) | Week 4 | 1.01 hours | Standard Deviation 0.0136 |
| BGS649 (Part 1) | Part 2: Pharmacokinetics of BGS649: Time to Reach Maximum (Peak) Blood Drug Concentration After Single Dose Administration (Tmax) | Week 11 | 0.993 hours | Standard Deviation 0.045 |
Secondary
PK of BGS649 Elimination Half-life Associated With the Terminal Slope of a Semi Logarithmic Concentration-time Curve (T1/2)
PK sampling was performed at 0hr (pre-dose), 1 hr, 8 hr, 24 hr, 72 hr, and 168 hr on the following occasions Week 1, Week 4 and week 11.
Time frame: Week 1 to Week 11
Population: PK Analysis Set. Sparse PK sampling (4 samples over 672 h) was included for the PK profile for Week 4; Cmax was included in λz estimation, therefore T1/2 was not reported for all profiles in Week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BGS649 (Part 1) | PK of BGS649 Elimination Half-life Associated With the Terminal Slope of a Semi Logarithmic Concentration-time Curve (T1/2) | Week 1 | 474 hours | Standard Deviation 114 |
| BGS649 (Part 1) | PK of BGS649 Elimination Half-life Associated With the Terminal Slope of a Semi Logarithmic Concentration-time Curve (T1/2) | Week 11 | 489 hours | Standard Deviation 83 |