Prostate Cancer
Conditions
Keywords
castrate resistant prostate cancer,, CRPC,, orteronel,, TAK-700
Brief summary
This is a double-blind, placebo-controlled, multiregional Phase1/2 study to characterize the pharmacokinetic and pharmacodynamic responses to orteronel when administered concomitantly with prednisone in Chemotherapy-Naive Participants With Castration-Resistant Prostate Cancer
Detailed description
The drug being tested in this study is called orteronel. Orteronel is being tested to treat adult males who have adenocarcinoma of the prostate. This study will look at the pharmacokinetics (how the drug moves through the body) and pharmacodynamics (how the drug effects the body) in people who take orteronel in addition to prednisone. The study will enroll approximately 144 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the eight treatment groups (4 in Japan, 4 in Ex-Japan) which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). In Japan: Participants were randomized in a ratio of 2:1:2:1 * 200 mg orteronel or Placebo-matching orteronel \[(dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient\] twice daily (BID) + prednisone * 300 mg orteronel, or Placebo-matching orteronel, BID + prednisone Ex-Japan Participants were randomized in a ratio of 2:1:2:1 * 200 mg orteronel or Placebo-matching orteronel, BID in Cycle 1 + prednisone * 400 mg orteronel, or Placebo-matching orteronel ,BID in Cycle 1 + Prednisone Participants initially randomized to placebo received 4 weeks of placebo and then 12 weeks of active treatment with orteronel then entered a follow-up period treatment period. Participants initially randomized to orteronel received 16 weeks of treatment then entered a follow-up treatment period. This multi-centre trial will be conducted worldwide. The overall time to participate in this study is approximately 3.2 years. Participants will make multiple visits to the clinic and a final visit 30 to 40 days after receiving their last dose of study drug for a follow-up assessment.
Interventions
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male participants 18 years or older * Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care * Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma * Prior surgical castration or concurrent use of an agent for medical castration \[e.g. Gonadotropin-releasing hormone (GnRH) analogue\] * Prostate-Specific Antigen (PSA) ≥ 2 ng/mL at screening * Progressive disease based on PSA and/or radiographic criteria
Exclusion criteria
* Prior therapy with orteronel, ketoconazole, aminoglutethimide, or abiraterone. * Known hypersensitivity to compounds related to orteronel, orteronel excipients, prednisone (or commercially available equivalent), or GnRH analogue. * All antiandrogen therapy (including bicalutamide) is excluded within 4 weeks before the first dose of study drug. Any other therapies for prostate cancer, other than GnRH analogue therapy, such as progesterone, medroxyprogesterone, progestins (megesterol), or 5- alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued 2 weeks before the first dose of study drug. * Continuous daily use of oral prednisone (or commercially available equivalent), oral dexamethasone, or other systemic corticosteroids for more than 2 weeks within the 3 months before screening (inhaled, nasal, and local steroids \[e.g., joint injection\] are allowed). * Prior chemotherapy for prostate cancer, with the exception of neoadjuvant/adjuvant therapy as part of initial primary treatment for local disease that was completed 2 or more years before screening. Please note that there are additional inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan | Baseline and Week 4 | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Values for Testosterone | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. |
| Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan | Baseline and Week 4 | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. |
| Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | Baseline and Week 4 | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. |
| Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment | Baseline and Week 12 | Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory. |
| Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | Baseline and Week 4 | A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline. |
| Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Serum Ultra low level quantification of DHEA-S was measured by liquid chromatography and mass spectrometry (LC/MS) at a central laboratory. |
| Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Serum ACTH was measured by immunometric assay at the central laboratory. |
| Absolute Values for Corticosterone | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Serum Corticosterone was measured by high pressure liquid chromatography with mass spectrometry at the central laboratory. |
| Absolute Values for Cortisol | Baseline, Cycle 1 Day 8 and Cycle 2 Day 1 | Serum Cortisol was measured by immunometric assay at the central laboratory. |
| Absolute Values for Prostate-Specific Antigen (PSA) | Baseline and Cycle 2 Day 1 | Serum PSA was measured at the central laboratory. |
| Percentage of Participants With PSA50 After 12 Weeks of Treatment | Baseline and Week 12 | A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline. |
| AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | AUC(0-12) is measure of area under the curve over the dosing interval where the length of the dosing interval is time 0 to 12 hours in this study. |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. |
| AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | Cumulative amount of urine excreted time 0 to 24 hour. |
| Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | Maximum observed steady-state plasma concentration during a dosing interval. |
| Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax at steady state. |
| AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval. |
| Rac: Accumulation Index for Orteronel and M-I Metabolite | Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose | Rac was calculated as the ratio of AUCtau to AUC12hr. |
| Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Cycle 1 Day 8 Predose | Observed predose plasma concentration at steady state. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | From signing of the informed consent form through 30 days after the last dose of study drug, approximately 3.2 years | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding),symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. |
| Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 43 investigative sites in Japan, United States, Greece, Australia, Netherlands, Ireland and United Kingdom from 20 August 2012 to 01 September 2016.
Pre-assignment details
Male participants with a diagnosis of adenocarcinoma of the prostate were enrolled in the study. In Japan, participants were randomized to 200 mg orteronel, Placebo, 300 mg orteronel, or Placebo, BID, in a ratio of 2:1:2:1; ex-Japan participants were randomized to 200 mg orteronel, Placebo, 400 mg orteronel, or Placebo, BID, in a ratio of 2:1:2:1.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Orteronel 200 mg (Japan) Orteronel placebo-matching tablets, orally, twice daily (BID) in Cycle 1 (28 days) followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily continuously throughout the study. | 11 |
| Orteronel 200 mg (Japan) Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 22 |
| Placebo + Orteronel 300 mg (Japan) Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 followed by orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 10 |
| Orteronel 300 mg (Japan) Orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 22 |
| Placebo + Orteronel 200 mg (Ex-Japan) Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles outside of Japan (Ex-Japan) for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 11 |
| Orteronel 200 mg (Ex-Japan) Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 25 |
| Placebo + Orteronel 400 mg (Ex-Japan) Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 followed by orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 12 |
| Orteronel 400 mg (Ex-Japan) Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study. | 24 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 13 | 7 | 7 |
| Overall Study | Progressive Disease | 11 | 9 | 19 | 20 |
| Overall Study | Reason not Specified | 10 | 7 | 5 | 5 |
| Overall Study | Symptomatic Deterioration | 1 | 0 | 2 | 0 |
| Overall Study | Unsatisfactory Therapeutic Response | 7 | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo + Orteronel 200 mg (Japan) | Orteronel 200 mg (Japan) | Placebo + Orteronel 300 mg (Japan) | Orteronel 300 mg (Japan) | Placebo + Orteronel 200 mg (Ex-Japan) | Orteronel 200 mg (Ex-Japan) | Placebo + Orteronel 400 mg (Ex-Japan) | Orteronel 400 mg (Ex-Japan) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 72.1 years | 68.5 years | 70.1 years | 71.5 years | 69.6 years | 69.9 years | 73.3 years | 69.4 years | 70.6 years |
| Body Mass Index (BMI) | 25.05 kg/m^2 | 25.21 kg/m^2 | 24.43 kg/m^2 | 23.73 kg/m^2 | 29.85 kg/m^2 | 29.61 kg/m^2 | 28.37 kg/m^2 | 29.40 kg/m^2 | 26.96 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 10 Participants | 22 Participants | 11 Participants | 25 Participants | 12 Participants | 23 Participants | 136 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 161.94 cm | 167.10 cm | 163.92 cm | 164.71 cm | 170.41 cm | 174.79 cm | 176.70 cm | 174.74 cm | 169.29 cm |
| Race/Ethnicity, Customized Asian - Japanese | 11 participants | 22 participants | 10 participants | 22 participants | 0 participants | 0 participants | 0 participants | 0 participants | 65 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 0 participants | 0 participants | 0 participants | 0 participants | 11 participants | 25 participants | 11 participants | 23 participants | 70 participants |
| Region of Enrollment Australia | 0 participants | 0 participants | 0 participants | 0 participants | 3 participants | 1 participants | 2 participants | 2 participants | 8 participants |
| Region of Enrollment Greece | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 4 participants | 1 participants | 3 participants | 10 participants |
| Region of Enrollment Ireland | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 5 participants | 3 participants | 3 participants | 13 participants |
| Region of Enrollment Japan | 11 participants | 22 participants | 10 participants | 22 participants | 0 participants | 0 participants | 0 participants | 0 participants | 65 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 6 participants | 1 participants | 5 participants | 13 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 9 participants | 4 participants | 10 participants | 25 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 22 Participants | 10 Participants | 22 Participants | 11 Participants | 25 Participants | 12 Participants | 24 Participants | 137 Participants |
| Weight | 65.82 kg | 70.32 kg | 65.75 kg | 64.49 kg | 87.34 kg | 90.39 kg | 88.23 kg | 89.85 kg | 77.77 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 44 / 44 | 33 / 33 | 32 / 32 | 35 / 36 | 36 / 36 |
| serious Total, serious adverse events | 10 / 44 | 8 / 33 | 18 / 32 | 16 / 36 | 12 / 36 |
Outcome results
Primary
Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan
Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
Time frame: Baseline and Week 4
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Japan) | Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan | 86.0 percentage of participants |
| Orteronel 300 mg (Japan) | Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan | 100.0 percentage of participants |
p-value: 0.1078Fisher Exact
Secondary
Absolute Values for Adrenocorticotropic Hormone (ACTH)
Serum ACTH was measured by immunometric assay at the central laboratory.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 1 Day 8 | 3.1 pmol/L | Standard Deviation 2.68 |
| Placebo (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline | 5.0 pmol/L | Standard Deviation 1.66 |
| Placebo (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 2 Day 1 | 1.7 pmol/L | Standard Deviation 1.19 |
| Orteronel 300 mg (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 1 Day 8 | 2.3 pmol/L | Standard Deviation 1.55 |
| Orteronel 300 mg (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline | 5.5 pmol/L | Standard Deviation 2.54 |
| Orteronel 300 mg (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 2 Day 1 | 1.7 pmol/L | Standard Deviation 1.08 |
| Orteronel 300 mg (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 1 Day 8 | 3.0 pmol/L | Standard Deviation 2.7 |
| Orteronel 300 mg (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline | 8.3 pmol/L | Standard Deviation 4.98 |
| Orteronel 300 mg (Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 2 Day 1 | 2.7 pmol/L | Standard Deviation 2.17 |
| Placebo (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 1 Day 8 | 3.1 pmol/L | Standard Deviation 2.62 |
| Placebo (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline | 4.7 pmol/L | Standard Deviation 2.06 |
| Placebo (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 2 Day 1 | 3.0 pmol/L | Standard Deviation 1.73 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 1 Day 8 | 3.8 pmol/L | Standard Deviation 3.04 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline | 6.0 pmol/L | Standard Deviation 4.05 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 2 Day 1 | 3.7 pmol/L | Standard Deviation 4.38 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Baseline | 6.4 pmol/L | Standard Deviation 4.04 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 2 Day 1 | 3.6 pmol/L | Standard Deviation 2.26 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Adrenocorticotropic Hormone (ACTH) | Cycle 1 Day 8 | 3.2 pmol/L | Standard Deviation 2.56 |
Secondary
Absolute Values for Corticosterone
Serum Corticosterone was measured by high pressure liquid chromatography with mass spectrometry at the central laboratory.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Absolute Values for Corticosterone | Cycle 1 Day 8 | 1.530 nmol/L | Standard Deviation 1.6404 |
| Placebo (Japan) | Absolute Values for Corticosterone | Baseline | 5.946 nmol/L | Standard Deviation 3.4433 |
| Placebo (Japan) | Absolute Values for Corticosterone | Cycle 2 Day 1 | 0.758 nmol/L | Standard Deviation 0.5108 |
| Orteronel 300 mg (Japan) | Absolute Values for Corticosterone | Cycle 1 Day 8 | 11.067 nmol/L | Standard Deviation 14.422 |
| Orteronel 300 mg (Japan) | Absolute Values for Corticosterone | Baseline | 6.515 nmol/L | Standard Deviation 4.8246 |
| Orteronel 300 mg (Japan) | Absolute Values for Corticosterone | Cycle 2 Day 1 | 11.108 nmol/L | Standard Deviation 9.0708 |
| Orteronel 300 mg (Japan) | Absolute Values for Corticosterone | Cycle 1 Day 8 | 9.709 nmol/L | Standard Deviation 13.4538 |
| Orteronel 300 mg (Japan) | Absolute Values for Corticosterone | Baseline | 7.768 nmol/L | Standard Deviation 6.8625 |
| Orteronel 300 mg (Japan) | Absolute Values for Corticosterone | Cycle 2 Day 1 | 14.654 nmol/L | Standard Deviation 9.2064 |
| Placebo (Ex-Japan) | Absolute Values for Corticosterone | Cycle 1 Day 8 | 5.598 nmol/L | Standard Deviation 7.1366 |
| Placebo (Ex-Japan) | Absolute Values for Corticosterone | Baseline | 6.317 nmol/L | Standard Deviation 4.1467 |
| Placebo (Ex-Japan) | Absolute Values for Corticosterone | Cycle 2 Day 1 | 4.321 nmol/L | Standard Deviation 6.4063 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Corticosterone | Cycle 1 Day 8 | 48.668 nmol/L | Standard Deviation 66.3904 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Corticosterone | Baseline | 10.030 nmol/L | Standard Deviation 7.7341 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Corticosterone | Cycle 2 Day 1 | 29.929 nmol/L | Standard Deviation 35.5565 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Corticosterone | Baseline | 17.975 nmol/L | Standard Deviation 35.0695 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Corticosterone | Cycle 2 Day 1 | 47.204 nmol/L | Standard Deviation 53.4566 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Corticosterone | Cycle 1 Day 8 | 60.301 nmol/L | Standard Deviation 77.5434 |
Secondary
Absolute Values for Cortisol
Serum Cortisol was measured by immunometric assay at the central laboratory.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Absolute Values for Cortisol | Cycle 1 Day 8 | 82.3 nmol/L | Standard Deviation 46.16 |
| Placebo (Japan) | Absolute Values for Cortisol | Baseline | 366.5 nmol/L | Standard Deviation 116.69 |
| Placebo (Japan) | Absolute Values for Cortisol | Cycle 2 Day 1 | 53.9 nmol/L | Standard Deviation 24.92 |
| Orteronel 300 mg (Japan) | Absolute Values for Cortisol | Cycle 1 Day 8 | 49.5 nmol/L | Standard Deviation 25.53 |
| Orteronel 300 mg (Japan) | Absolute Values for Cortisol | Baseline | 371.3 nmol/L | Standard Deviation 119.38 |
| Orteronel 300 mg (Japan) | Absolute Values for Cortisol | Cycle 2 Day 1 | 49.2 nmol/L | Standard Deviation 21.71 |
| Orteronel 300 mg (Japan) | Absolute Values for Cortisol | Cycle 1 Day 8 | 55.5 nmol/L | Standard Deviation 55.97 |
| Orteronel 300 mg (Japan) | Absolute Values for Cortisol | Baseline | 383.4 nmol/L | Standard Deviation 125.98 |
| Orteronel 300 mg (Japan) | Absolute Values for Cortisol | Cycle 2 Day 1 | 54.3 nmol/L | Standard Deviation 39.93 |
| Placebo (Ex-Japan) | Absolute Values for Cortisol | Cycle 1 Day 8 | 175.8 nmol/L | Standard Deviation 107.82 |
| Placebo (Ex-Japan) | Absolute Values for Cortisol | Baseline | 384.8 nmol/L | Standard Deviation 117.14 |
| Placebo (Ex-Japan) | Absolute Values for Cortisol | Cycle 2 Day 1 | 149.6 nmol/L | Standard Deviation 122.91 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Cortisol | Cycle 1 Day 8 | 100.9 nmol/L | Standard Deviation 87.38 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Cortisol | Baseline | 449.0 nmol/L | Standard Deviation 131.54 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Cortisol | Cycle 2 Day 1 | 97.2 nmol/L | Standard Deviation 85.66 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Cortisol | Baseline | 446.8 nmol/L | Standard Deviation 193.09 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Cortisol | Cycle 2 Day 1 | 109.1 nmol/L | Standard Deviation 83.19 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Cortisol | Cycle 1 Day 8 | 122.0 nmol/L | Standard Deviation 88.7 |
Secondary
Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S)
Serum Ultra low level quantification of DHEA-S was measured by liquid chromatography and mass spectrometry (LC/MS) at a central laboratory.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 1 Day 8 | 414.9 nmol/L | Standard Deviation 392.63 |
| Placebo (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline | 1928.0 nmol/L | Standard Deviation 1306.59 |
| Placebo (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 2 Day 1 | 268.9 nmol/L | Standard Deviation 357.32 |
| Orteronel 300 mg (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 1 Day 8 | 63.4 nmol/L | Standard Deviation 55.11 |
| Orteronel 300 mg (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline | 2529.0 nmol/L | Standard Deviation 1309.39 |
| Orteronel 300 mg (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 2 Day 1 | 14.5 nmol/L | Standard Deviation 21.83 |
| Orteronel 300 mg (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 1 Day 8 | 71.8 nmol/L | Standard Deviation 80.23 |
| Orteronel 300 mg (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline | 2340.9 nmol/L | Standard Deviation 1606.36 |
| Orteronel 300 mg (Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 2 Day 1 | 36.3 nmol/L | Standard Deviation 123.48 |
| Placebo (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 1 Day 8 | 973.8 nmol/L | Standard Deviation 1677.95 |
| Placebo (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline | 2601.7 nmol/L | Standard Deviation 3009.41 |
| Placebo (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 2 Day 1 | 815.7 nmol/L | Standard Deviation 1918.88 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 1 Day 8 | 116.9 nmol/L | Standard Deviation 161.01 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline | 1783.0 nmol/L | Standard Deviation 1554.76 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 2 Day 1 | 21.5 nmol/L | Standard Deviation 25.68 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline | 2155.7 nmol/L | Standard Deviation 1591.51 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 2 Day 1 | 180.6 nmol/L | Standard Deviation 527.03 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S) | Cycle 1 Day 8 | 226.6 nmol/L | Standard Deviation 328.7 |
Secondary
Absolute Values for Prostate-Specific Antigen (PSA)
Serum PSA was measured at the central laboratory.
Time frame: Baseline and Cycle 2 Day 1
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Baseline | 37.588 ng/mL | Standard Deviation 48.9413 |
| Placebo (Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Cycle 2 Day 1 | 24.325 ng/mL | Standard Deviation 46.9725 |
| Orteronel 300 mg (Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Baseline | 27.227 ng/mL | Standard Deviation 24.8821 |
| Orteronel 300 mg (Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Cycle 2 Day 1 | 18.005 ng/mL | Standard Deviation 16.9858 |
| Orteronel 300 mg (Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Baseline | 97.504 ng/mL | Standard Deviation 293.9496 |
| Orteronel 300 mg (Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Cycle 2 Day 1 | 38.892 ng/mL | Standard Deviation 95.0124 |
| Placebo (Ex-Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Baseline | 133.238 ng/mL | Standard Deviation 189.9345 |
| Placebo (Ex-Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Cycle 2 Day 1 | 152.940 ng/mL | Standard Deviation 261.9735 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Baseline | 165.992 ng/mL | Standard Deviation 368.5016 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Cycle 2 Day 1 | 117.257 ng/mL | Standard Deviation 286.187 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Baseline | 100.237 ng/mL | Standard Deviation 210.5675 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Prostate-Specific Antigen (PSA) | Cycle 2 Day 1 | 56.437 ng/mL | Standard Deviation 97.1621 |
Secondary
Absolute Values for Testosterone
Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Absolute Values for Testosterone | Cycle 1 Day 8 | 1.957 ng/dL | Standard Deviation 2.2843 |
| Placebo (Japan) | Absolute Values for Testosterone | Baseline | 9.749 ng/dL | Standard Deviation 3.846 |
| Placebo (Japan) | Absolute Values for Testosterone | Cycle 2 Day 1 | 1.096 ng/dL | Standard Deviation 0.7751 |
| Orteronel 300 mg (Japan) | Absolute Values for Testosterone | Cycle 1 Day 8 | 0.213 ng/dL | Standard Deviation 0.0449 |
| Orteronel 300 mg (Japan) | Absolute Values for Testosterone | Baseline | 9.079 ng/dL | Standard Deviation 4.4581 |
| Orteronel 300 mg (Japan) | Absolute Values for Testosterone | Cycle 2 Day 1 | 0.203 ng/dL | Standard Deviation 0.0145 |
| Orteronel 300 mg (Japan) | Absolute Values for Testosterone | Cycle 1 Day 8 | 0.251 ng/dL | Standard Deviation 0.1727 |
| Orteronel 300 mg (Japan) | Absolute Values for Testosterone | Baseline | 10.148 ng/dL | Standard Deviation 4.6504 |
| Orteronel 300 mg (Japan) | Absolute Values for Testosterone | Cycle 2 Day 1 | 0.270 ng/dL | Standard Deviation 0.2311 |
| Placebo (Ex-Japan) | Absolute Values for Testosterone | Baseline | 9.173 ng/dL | Standard Deviation 5.6123 |
| Placebo (Ex-Japan) | Absolute Values for Testosterone | Cycle 1 Day 8 | 3.509 ng/dL | Standard Deviation 4.3471 |
| Placebo (Ex-Japan) | Absolute Values for Testosterone | Cycle 2 Day 1 | 3.095 ng/dL | Standard Deviation 3.7254 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Testosterone | Cycle 1 Day 8 | 0.345 ng/dL | Standard Deviation 0.277 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Testosterone | Baseline | 9.263 ng/dL | Standard Deviation 5.6572 |
| Orteronel 200 mg (Ex-Japan) | Absolute Values for Testosterone | Cycle 2 Day 1 | 0.266 ng/dL | Standard Deviation 0.1837 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Testosterone | Baseline | 14.588 ng/dL | Standard Deviation 13.9833 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Testosterone | Cycle 2 Day 1 | 11.720 ng/dL | Standard Deviation 45.1753 |
| Orteronel 400 mg (Ex-Japan) | Absolute Values for Testosterone | Cycle 1 Day 8 | 6.658 ng/dL | Standard Deviation 20.4347 |
Secondary
AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite
Cumulative amount of urine excreted time 0 to 24 hour.
Time frame: Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel | 115.0 mg | Geometric Coefficient of Variation 26 |
| Placebo (Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 39.6 mg | Geometric Coefficient of Variation 31.5 |
| Orteronel 300 mg (Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 62.5 mg | Geometric Coefficient of Variation 26.6 |
| Orteronel 300 mg (Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel | 164.0 mg | Geometric Coefficient of Variation 26.2 |
| Orteronel 300 mg (Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel | 95.3 mg | Geometric Coefficient of Variation 31.9 |
| Orteronel 300 mg (Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 30.0 mg | Geometric Coefficient of Variation 40.1 |
| Placebo (Ex-Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel | 161.0 mg | Geometric Coefficient of Variation 41.4 |
| Placebo (Ex-Japan) | AE (0-24) Cumulative Amount of Drug Excreted Into the Urine for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 52.8 mg | Geometric Coefficient of Variation 46.4 |
Secondary
AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite
AUC(0-12) is measure of area under the curve over the dosing interval where the length of the dosing interval is time 0 to 12 hours in this study.
Time frame: Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel | 8810 h*ng/mL | Geometric Coefficient of Variation 16.4 |
| Placebo (Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 2130 h*ng/mL | Geometric Coefficient of Variation 28.3 |
| Orteronel 300 mg (Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 3290 h*ng/mL | Geometric Coefficient of Variation 33.8 |
| Orteronel 300 mg (Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel | 12800 h*ng/mL | Geometric Coefficient of Variation 31.2 |
| Orteronel 300 mg (Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel | 7830 h*ng/mL | Geometric Coefficient of Variation 51.1 |
| Orteronel 300 mg (Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 1570 h*ng/mL | Geometric Coefficient of Variation 65.5 |
| Placebo (Ex-Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel | 10200 h*ng/mL | Geometric Coefficient of Variation 41.4 |
| Placebo (Ex-Japan) | AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 2080 h*ng/mL | Geometric Coefficient of Variation 44.8 |
Secondary
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite
Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.
Time frame: Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel | 13300 h*ng/mL | Geometric Coefficient of Variation 20.4 |
| Placebo (Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 4840 h*ng/mL | Geometric Coefficient of Variation 35 |
| Orteronel 300 mg (Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 7460 h*ng/mL | Geometric Coefficient of Variation 46.3 |
| Orteronel 300 mg (Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel | 20400 h*ng/mL | Geometric Coefficient of Variation 36.1 |
| Orteronel 300 mg (Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel | 12600 h*ng/mL | Geometric Coefficient of Variation 36.2 |
| Orteronel 300 mg (Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 4340 h*ng/mL | Geometric Coefficient of Variation 69.4 |
| Placebo (Ex-Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel | 20000 h*ng/mL | Geometric Coefficient of Variation 55 |
| Placebo (Ex-Japan) | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 6590 h*ng/mL | Geometric Coefficient of Variation 78 |
Secondary
Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel | 1520 ng/mL | Geometric Coefficient of Variation 23.9 |
| Placebo (Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 272 ng/mL | Geometric Coefficient of Variation 33.1 |
| Orteronel 300 mg (Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 422 ng/mL | Geometric Coefficient of Variation 37 |
| Orteronel 300 mg (Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel | 2210 ng/mL | Geometric Coefficient of Variation 33.9 |
| Orteronel 300 mg (Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel | 1300 ng/mL | Geometric Coefficient of Variation 59.7 |
| Orteronel 300 mg (Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 199 ng/mL | Geometric Coefficient of Variation 61.9 |
| Placebo (Ex-Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel | 1610 ng/mL | Geometric Coefficient of Variation 50.3 |
| Placebo (Ex-Japan) | Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 261 ng/mL | Geometric Coefficient of Variation 47.2 |
Secondary
Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite
Maximum observed steady-state plasma concentration during a dosing interval.
Time frame: Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel | 2180 ng/mL | Geometric Coefficient of Variation 22.4 |
| Placebo (Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 565 ng/mL | Geometric Coefficient of Variation 32.4 |
| Orteronel 300 mg (Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 864 ng/mL | Geometric Coefficient of Variation 39.5 |
| Orteronel 300 mg (Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel | 3210 ng/mL | Geometric Coefficient of Variation 31.5 |
| Orteronel 300 mg (Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel | 1840 ng/mL | Geometric Coefficient of Variation 37.1 |
| Orteronel 300 mg (Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 485 ng/mL | Geometric Coefficient of Variation 75.4 |
| Placebo (Ex-Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel | 3100 ng/mL | Geometric Coefficient of Variation 45 |
| Placebo (Ex-Japan) | Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite | Orteronel Metabolite M-I | 761 ng/mL | Geometric Coefficient of Variation 81.3 |
Secondary
Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite
Observed predose plasma concentration at steady state.
Time frame: Cycle 1 Day 8 Predose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel | 710 ng/mL | Geometric Coefficient of Variation 28.1 |
| Placebo (Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel Metbolite M-I | 291 ng/mL | Geometric Coefficient of Variation 47.1 |
| Orteronel 300 mg (Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel Metbolite M-I | 444 ng/mL | Geometric Coefficient of Variation 66.7 |
| Orteronel 300 mg (Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel | 1060 ng/mL | Geometric Coefficient of Variation 63.7 |
| Orteronel 300 mg (Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel | 807 ng/mL | Geometric Coefficient of Variation 45.4 |
| Orteronel 300 mg (Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel Metbolite M-I | 314 ng/mL | Geometric Coefficient of Variation 68.6 |
| Placebo (Ex-Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel | 899 ng/mL | Geometric Coefficient of Variation 59.8 |
| Placebo (Ex-Japan) | Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite | Orteronel Metbolite M-I | 417 ng/mL | Geometric Coefficient of Variation 58 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding),symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time frame: From signing of the informed consent form through 30 days after the last dose of study drug, approximately 3.2 years
Population: Safety Population included all randomized participants who received at least one dose of study drug. Adverse events are summarized as per the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 7 participants |
| Placebo (Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 0 participants |
| Orteronel 300 mg (Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 33 participants |
| Orteronel 300 mg (Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 8 participants |
| Orteronel 300 mg (Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 32 participants |
| Orteronel 300 mg (Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 18 participants |
| Placebo (Ex-Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 18 participants |
| Placebo (Ex-Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 1 participants |
| Orteronel 200 mg (Ex-Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 36 participants |
| Orteronel 200 mg (Ex-Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 16 participants |
| Orteronel 400 mg (Ex-Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 36 participants |
| Orteronel 400 mg (Ex-Japan) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 12 participants |
Secondary
Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment
A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline.
Time frame: Baseline and Week 4
Population: Participants from the Pharmacodynamics-evaluable population, defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement, with data available after 4 Weeks of Treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Japan) | Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | 48.0 percentage of participants |
| Orteronel 300 mg (Japan) | Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | 50.0 percentage of participants |
| Orteronel 300 mg (Japan) | Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | 41.0 percentage of participants |
| Placebo (Ex-Japan) | Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | 17.0 percentage of participants |
| Orteronel 200 mg (Ex-Japan) | Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | 48.0 percentage of participants |
| Orteronel 400 mg (Ex-Japan) | Percentage of Participants With Prostate-Specific Antigen Reduction ≥ 50% (PSA50) After 4 Weeks of Treatment | 46.0 percentage of participants |
Secondary
Percentage of Participants With PSA50 After 12 Weeks of Treatment
A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline.
Time frame: Baseline and Week 12
Population: Participants from the Pharmacodynamics-evaluable population, defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement, with data available after 12 Weeks of Treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Japan) | Percentage of Participants With PSA50 After 12 Weeks of Treatment | 55.0 percentage of participants |
| Orteronel 300 mg (Japan) | Percentage of Participants With PSA50 After 12 Weeks of Treatment | 47.0 percentage of participants |
| Orteronel 300 mg (Japan) | Percentage of Participants With PSA50 After 12 Weeks of Treatment | 56.0 percentage of participants |
| Placebo (Ex-Japan) | Percentage of Participants With PSA50 After 12 Weeks of Treatment | 44.0 percentage of participants |
Secondary
Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan
Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
Time frame: Baseline and Week 4
Population: Pharmacodynamics-evaluable population was defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Japan) | Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan | 48.0 percentage of participants |
| Orteronel 300 mg (Japan) | Percentage of Participants With Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan | 79.0 percentage of participants |
p-value: 0.035595% CI: [0.9895, 18.7606]Fisher Exact
Secondary
Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment
Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
Time frame: Baseline and Week 12
Population: Participants from the Pharmacodynamics-evaluable population, defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement, with data available after 12 Weeks of Treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Japan) | Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment | -95.804 percent change | Standard Deviation 5.3367 |
| Orteronel 300 mg (Japan) | Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment | -95.703 percent change | Standard Deviation 5.7468 |
| Orteronel 300 mg (Japan) | Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment | -91.311 percent change | Standard Deviation 17.5217 |
| Placebo (Ex-Japan) | Percent Change From Baseline in Serum Testosterone Level After 12 Weeks of Treatment | -14.442 percent change | Standard Deviation 406.3116 |
Secondary
Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment
Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
Time frame: Baseline and Week 4
Population: Participants from the Pharmacodynamics-evaluable population, defined as participants with a baseline and at least 1 post-baseline pharmacodynamics measurement, with data available after 4 Weeks of Treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Japan) | Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | -87.666 percent change | Standard Deviation 10.425 |
| Orteronel 300 mg (Japan) | Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | -97.245 percent change | Standard Deviation 1.2548 |
| Orteronel 300 mg (Japan) | Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | -96.812 percent change | Standard Deviation 2.7055 |
| Placebo (Ex-Japan) | Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | -63.702 percent change | Standard Deviation 43.3941 |
| Orteronel 200 mg (Ex-Japan) | Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | -86.268 percent change | Standard Deviation 37.2015 |
| Orteronel 400 mg (Ex-Japan) | Percent Change From Baseline in Serum Testosterone Level After 4 Weeks of Treatment | -53.954 percent change | Standard Deviation 118.805 |
Secondary
Rac: Accumulation Index for Orteronel and M-I Metabolite
Rac was calculated as the ratio of AUCtau to AUC12hr.
Time frame: Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel | 1.51 ratio | Geometric Coefficient of Variation 9.1 |
| Placebo (Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 2.27 ratio | Geometric Coefficient of Variation 17.5 |
| Orteronel 300 mg (Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 2.26 ratio | Geometric Coefficient of Variation 43 |
| Orteronel 300 mg (Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel | 1.59 ratio | Geometric Coefficient of Variation 46.6 |
| Orteronel 300 mg (Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel | 1.62 ratio | Geometric Coefficient of Variation 39.3 |
| Orteronel 300 mg (Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 2.76 ratio | Geometric Coefficient of Variation 45 |
| Placebo (Ex-Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel | 1.97 ratio | Geometric Coefficient of Variation 90.5 |
| Placebo (Ex-Japan) | Rac: Accumulation Index for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 3.17 ratio | Geometric Coefficient of Variation 77.7 |
Secondary
Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite
Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax at steady state.
Time frame: Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo (Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel | 2.05 hours |
| Placebo (Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 3.08 hours |
| Orteronel 300 mg (Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 4.78 hours |
| Orteronel 300 mg (Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel | 2.96 hours |
| Orteronel 300 mg (Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel | 2.00 hours |
| Orteronel 300 mg (Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 3.00 hours |
| Placebo (Ex-Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel | 1.98 hours |
| Placebo (Ex-Japan) | Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax), Equal to Time (Hours) to Cmax at Steady State for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 3.00 hours |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Time frame: Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
Population: Pharmacokinetic Population included all randomized participants who received orteronel in Cycle 1.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo (Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel | 2.97 hours |
| Placebo (Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 5.00 hours |
| Orteronel 300 mg (Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 4.98 hours |
| Orteronel 300 mg (Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel | 2.43 hours |
| Orteronel 300 mg (Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel | 2.00 hours |
| Orteronel 300 mg (Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 5.05 hours |
| Placebo (Ex-Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel | 1.92 hours |
| Placebo (Ex-Japan) | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Orteronel Metabolite M-I | 4.98 hours |