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This is a multi-center, open-label, drug-drug interaction study in postmenopausal women with osteoporosis.
Approximately 27 subjects (Group A: 18; Group B: 9) will receive a 2 mg oral dose of midazolam on day 1 followed by a 24 hour PK collection. Subjects randomized to Group A will receive a single 60 mg subcutaneous (SC) dose of denosumab on day 2 administered in the abdomen. On study day 16, another 2 mg oral dose of midazolam will be administered to all subjects (Groups A and B) followed by a 24 hour PK collection. The primary analysis to determine the effect of denosumab on the PK of midazolam will be based on data from subjects in Group A only.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Midazolam | Other | All 27 subjects will receive midazolam. |
|
| Denosumab | Active Comparator | Eighteen (18) subjects will receive denosumab. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Denosumab | Drug | Eighteen (18) subjects will receive 1 fixed dose administration of denosumab. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
| Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
| Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group | Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
| Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| MD | Amgen | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25505582 | Background | Jang G, Kaufman A, Lee E, Hamilton L, Hutton S, Egbuna O, Padhi D. A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis. Pharmacol Res Perspect. 2014 Apr;2(2):e00033. doi: 10.1002/prp2.33. Epub 2014 Mar 13. |
| Label | URL |
|---|---|
| AmgenTrials clinical trials website | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Midazolam With Denosumab | 2 mg oral dose of Midazolam on Day 1 and Day 16, 60 mg subcutaneous dose of Denosumab on Day 2 |
| FG001 | Midazolam Only | 2 mg oral dose of Midazolam on Day 1 and Day 16. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Midazolam With Denosumab | 2 mg oral dose of Midazolam on Day 1 and Day 16, 60 mg subcutaneous dose of Denosumab on Day 2. Out of 21 subjects enrolled and randomized, 19 subjects received investigation product. |
| BG001 | Midazolam Only |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Least Squares Mean | 90% Confidence Interval | unitless | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | unitless | unitless |
|
47 days
The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Midazolam With Denosumab Group With Midazolam 2mg on Day 1 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA 14.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Amgen Inc. | 866-572-6436 |
| ID | Term |
|---|---|
| D015663 | Osteoporosis, Postmenopausal |
| D010024 | Osteoporosis |
| ID | Term |
|---|---|
| D001851 | Bone Diseases, Metabolic |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D008659 | Metabolic Diseases |
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| ID | Term |
|---|---|
| D000069448 | Denosumab |
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| Midazolam | Drug | All subjects will receive two oral dose administrations of midazolam. |
|
| Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group |
AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability. |
| From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
| Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group | Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
| Summary of Serum Denosumab Concentration | This table summarizes serum Denosumab for Midazolam with Denosumab group. The Lower Limit Of Quantification (LLOQ) is 20 ng/mL. On Day 2 (pre-dose), the true value is below LLOQ, and is treated as 0 in the analysis. | Baseline (day 2 pre-dose) to day 16 |
| Summary of Serum C-Telopeptide Concentration | This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. | Baseline (day 2 pre-dose) to day 16 |
| Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration | This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. | Baseline (day 2 pre-dose) to day 16 |
| Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose |
2 mg oral dose of Midazolam on Day 1 and Day 16. Out of 9 subjects enrolled and randomized, 8 subjects received investigation product.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Age, Customized | Number | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
| Secondary | Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Least Squares Mean | 90% Confidence Interval | unitless | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | unitless | unitless |
|
|
|
| Primary | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group | AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability | The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Mean | Standard Deviation | ng*hr/mL | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | area | area |
|
|
|
| Primary | Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group | Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability | The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Mean | Standard Deviation | ng/mL | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | concentration | concentration |
|
|
|
| Secondary | Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group | AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability. | The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Mean | Standard Deviation | ng*hr/mL | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | area | area |
|
|
|
| Secondary | Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group | Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability. | The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Mean | Standard Deviation | ng/mL | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | concentration | concentration |
|
|
|
| Secondary | Summary of Serum Denosumab Concentration | This table summarizes serum Denosumab for Midazolam with Denosumab group. The Lower Limit Of Quantification (LLOQ) is 20 ng/mL. On Day 2 (pre-dose), the true value is below LLOQ, and is treated as 0 in the analysis. | Serum Denosumab will be collected for subjects in Midazolam with Denosumab group only. The analysis set will contain subjects in Midazolam with Denosumab group who received denosumab administration and for whom serum Denosumab concentrations are determinable when assessed. | Posted | Median | Standard Deviation | ng/mL | Baseline (day 2 pre-dose) to day 16 | concentration | concentration |
|
|
|
| Secondary | Summary of Serum C-Telopeptide Concentration | This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. | Serum CTX will be collected for Midazolam with Denosumab group only. The PD analysis set will contain subjects in Midazolam with Denosumab group who received denosumab administration and for whom serum CTX concentrations are determinable on when assessed. | Posted | Median | Inter-Quartile Range | ng/mL | Baseline (day 2 pre-dose) to day 16 | concentration | concentration |
|
|
|
| Primary | Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | The analysis set will contain all subjects from Midazolam with Denosumab group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Least Squares Mean | 90% Confidence Interval | unitless | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | unitless | unitless |
|
|
|
| Secondary | Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration | This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. | Serum CTX will be collected for Midazolam with Denosumab group only. The PD analysis set will contain subjects in Midazolam with Denosumab group who received denosumab administration and for whom serum CTX concentrations are determinable on when assessed. | Posted | Median | Inter-Quartile Range | percentage | Baseline (day 2 pre-dose) to day 16 | percentage | percentage |
|
|
|
| Secondary | Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) | The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale. | The analysis set will contain all subjects from Midazolam only group for whom the primary endpoint PK parameters (AUC(0-t), AUC(0-inf) and Cmax) can be estimated for both treatment periods. | Posted | Least Squares Mean | 90% Confidence Interval | unitless | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | unitless | unitless |
|
|
|
| 0 |
| 19 |
| 9 |
| 19 |
| EG001 | Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15 | 0 | 18 | 6 | 18 |
| EG002 | Midazolam With Denosumab Group With Midazolam 2mg on Day 16 | 0 | 18 | 10 | 18 |
| EG003 | Midazolam Only Group With Midazolam 2mg on Day 1 | 0 | 8 | 2 | 8 |
| EG004 | Midazolam Only Group With Midazolam 2mg on Day 2-15 | 0 | 8 | 1 | 8 |
| EG005 | Midazolam Only Group With Midazolam 2mg on Day 16 | 0 | 8 | 1 | 8 |
| Nausea | Gastrointestinal disorders | MedDRA 14.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 14.0 | Systematic Assessment |
|
| Chills | General disorders | MedDRA 14.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 14.0 | Systematic Assessment |
|
| Injection site pain | General disorders | MedDRA 14.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 14.0 | Systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | MedDRA 14.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 14.0 | Systematic Assessment |
|
| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA 14.0 | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 14.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA 14.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 14.0 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 14.0 | Systematic Assessment |
|
| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA 14.0 | Systematic Assessment |
|
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, the investigator agrees not to publish any results before the first multi-center publication.
| D009750 |
| Nutritional and Metabolic Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
|
| AUC (0-inf) Residual: Intra-subject |
|
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| AUC (0-inf) Residual: Intra-subject |
|
| Day 17 (24hr) |
|
|