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The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam

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ClinicalTrials.gov Identifier: NCT01221727
Recruitment Status : Completed
First Posted : October 15, 2010
Results First Posted : November 7, 2013
Last Update Posted : August 7, 2018
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Postmenopausal Osteoporosis
Interventions Drug: Denosumab
Drug: Midazolam
Enrollment 30
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Midazolam With Denosumab Midazolam Only
Hide Arm/Group Description 2 mg oral dose of Midazolam on Day 1 and Day 16, 60 mg subcutaneous dose of Denosumab on Day 2 2 mg oral dose of Midazolam on Day 1 and Day 16.
Period Title: Overall Study
Started 21 [1] 9 [1]
Treated 19 [2] 8 [2]
Completed 18 8
Not Completed 3 1
Reason Not Completed
Physician Decision             2             0
Withdrawal by Subject             1             1
[1]
Number of subjects randomized into the study
[2]
Number of subjects received investigational product
Arm/Group Title Midazolam With Denosumab Midazolam Only Total
Hide Arm/Group Description 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. 2 mg oral dose of Midazolam on Day 1 and Day 16. Out of 9 subjects enrolled and randomized, 8 subjects received investigation product. Total of all reporting groups
Overall Number of Baseline Participants 19 8 27
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 19 participants 8 participants 27 participants
64.42  (6.16) 66.25  (5.34) 64.96  (5.89)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 8 participants 27 participants
<65 years 7 3 10
>=65 years and <75 years 12 4 16
>=75 years 0 1 1
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 8 participants 27 participants
Female
19
 100.0%
8
 100.0%
27
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 8 participants 27 participants
Hispanic or Latino
7
  36.8%
4
  50.0%
11
  40.7%
Not Hispanic or Latino
12
  63.2%
4
  50.0%
16
  59.3%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 8 participants 27 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   5.3%
1
  12.5%
2
   7.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   5.3%
1
  12.5%
2
   7.4%
White
17
  89.5%
6
  75.0%
23
  85.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title 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)
Hide Description The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 (serving as a reference point) and day 16 (serving as a test point), and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Unitless
18
Least Squares Mean (90% Confidence Interval)
Unit of Measure: unitless
AUC (0-t)
1.10
(0.94 to 1.29)
AUC (0-inf)
1.12
(0.95 to 1.31)
2.Primary Outcome
Title Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group
Hide Description AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16 , and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Area
18
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
AUC (0-t) Subject: Inter-subject 0.19  (0.079)
AUC (0-t) Residual: Intra-subject 0.07  (0.025)
AUC (0-inf) Subject: Inter-subject 0.21  (0.085)
AUC (0-inf) Residual: Intra-subject 0.08  (0.027)
3.Primary Outcome
Title Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group
Hide Description Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16, and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Concentration
18
Mean (Standard Deviation)
Unit of Measure: ng/mL
Cmax Subject: Inter-subject 0.15  (0.064)
Cmax Residual: Intra-subject 0.07  (0.023)
4.Primary Outcome
Title Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
Hide Description The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 (serving as a reference point) and day 16 (serving as a test point), and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Unitless
18
Least Squares Mean (90% Confidence Interval)
Unit of Measure: unitless
1.11
(0.96 to 1.29)
5.Secondary Outcome
Title Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
Hide Description The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam Only
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Overall Number of Participants Analyzed 8
Overall Number of Units Analyzed
Type of Units Analyzed: Unitless
8
Least Squares Mean (90% Confidence Interval)
Unit of Measure: unitless
AUC (0-t)
0.98
(0.83 to 1.15)
AUC (0-inf)
0.98
(0.84 to 1.15)
6.Secondary Outcome
Title Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group
Hide Description AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability.
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam Only
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Overall Number of Participants Analyzed 8
Overall Number of Units Analyzed
Type of Units Analyzed: Area
8
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
AUC (0-t) Subject: Inter-subject 0.27  (0.155)
AUC (0-t) Residual: Intra-subject 0.03  (0.016)
AUC (0-inf) Subject: Inter-subject 0.31  (0.175)
AUC (0-inf) Residual: Intra-subject 0.03  (0.015)
7.Secondary Outcome
Title Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group
Hide Description Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam Only
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Overall Number of Participants Analyzed 8
Overall Number of Units Analyzed
Type of Units Analyzed: Concentration
8
Mean (Standard Deviation)
Unit of Measure: ng/mL
Cmax Subject: Inter-subject 0.23  (0.143)
Cmax Residual: Intra-subject 0.06  (0.035)
8.Secondary Outcome
Title Summary of Serum Denosumab Concentration
Hide Description 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.
Time Frame Baseline (day 2 pre-dose) to day 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16, and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Concentration
18
Median (Standard Deviation)
Unit of Measure: ng/mL
Day 2 (Pre-dose) 0 [1]   (NA)
Day 16 (0hr) 5820  (1800)
Day 17 (24hr) 5500  (1940)
[1]
All the pre-dose concentration measurements are below LLOQ, and were treated as 0 in the analysis. Therefore, the true standard deviation is not able to be calculated.
9.Secondary Outcome
Title Summary of Serum C-Telopeptide Concentration
Hide Description This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
Time Frame Baseline (day 2 pre-dose) to day 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16, and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Concentration
18
Median (Inter-Quartile Range)
Unit of Measure: ng/mL
Baseline (day 2 pre-dose)
0.4655
(0.3390 to 0.6290)
Day 16
0.0606
(0.0483 to 0.0662)
Change from baseline to Day 16
-0.4079
(-0.5752 to -0.2712)
10.Secondary Outcome
Title Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration
Hide Description This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
Time Frame Baseline (day 2 pre-dose) to day 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam With Denosumab
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16, and 60 mg subcutaneous dose of Denosumab on day 2
Overall Number of Participants Analyzed 18
Overall Number of Units Analyzed
Type of Units Analyzed: Percentage
18
Median (Inter-Quartile Range)
Unit of Measure: percentage
-87.52
(-91.45 to -80.01)
11.Secondary Outcome
Title Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
Hide Description The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Time Frame From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Midazolam Only
Hide Arm/Group Description:
Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Overall Number of Participants Analyzed 8
Overall Number of Units Analyzed
Type of Units Analyzed: Unitless
8
Least Squares Mean (90% Confidence Interval)
Unit of Measure: unitless
1.05
(0.82 to 1.33)
Time Frame 47 days
Adverse Event Reporting Description The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
 
Arm/Group Title Midazolam With Denosumab Group With Midazolam 2mg on Day 1 Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15 Midazolam With Denosumab Group With Midazolam 2mg on Day 16 Midazolam Only Group With Midazolam 2mg on Day 1 Midazolam Only Group With Midazolam 2mg on Day 2-15 Midazolam Only Group With Midazolam 2mg on Day 16
Hide Arm/Group Description [Not Specified] [Not Specified] [Not Specified] [Not Specified] [Not Specified] [Not Specified]
All-Cause Mortality
Midazolam With Denosumab Group With Midazolam 2mg on Day 1 Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15 Midazolam With Denosumab Group With Midazolam 2mg on Day 16 Midazolam Only Group With Midazolam 2mg on Day 1 Midazolam Only Group With Midazolam 2mg on Day 2-15 Midazolam Only Group With Midazolam 2mg on Day 16
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Midazolam With Denosumab Group With Midazolam 2mg on Day 1 Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15 Midazolam With Denosumab Group With Midazolam 2mg on Day 16 Midazolam Only Group With Midazolam 2mg on Day 1 Midazolam Only Group With Midazolam 2mg on Day 2-15 Midazolam Only Group With Midazolam 2mg on Day 16
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/19 (0.00%)   0/18 (0.00%)   0/18 (0.00%)   0/8 (0.00%)   0/8 (0.00%)   0/8 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Midazolam With Denosumab Group With Midazolam 2mg on Day 1 Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15 Midazolam With Denosumab Group With Midazolam 2mg on Day 16 Midazolam Only Group With Midazolam 2mg on Day 1 Midazolam Only Group With Midazolam 2mg on Day 2-15 Midazolam Only Group With Midazolam 2mg on Day 16
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/19 (47.37%)   6/18 (33.33%)   10/18 (55.56%)   2/8 (25.00%)   1/8 (12.50%)   1/8 (12.50%) 
Gastrointestinal disorders             
Constipation  1  0/19 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/8 (0.00%) 
Nausea  1  1/19 (5.26%)  1/18 (5.56%)  1/18 (5.56%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Vomiting  1  1/19 (5.26%)  0/18 (0.00%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
General disorders             
Chills  1  0/19 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Fatigue  1  1/19 (5.26%)  0/18 (0.00%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Injection site pain  1  0/19 (0.00%)  2/18 (11.11%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Infections and infestations             
Nasopharyngitis  1  0/19 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Injury, poisoning and procedural complications             
Laceration  1  1/19 (5.26%)  0/18 (0.00%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia  1  0/19 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Musculoskeletal stiffness  1  1/19 (5.26%)  0/18 (0.00%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Neck pain  1  0/19 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Nervous system disorders             
Dizziness  1  1/19 (5.26%)  0/18 (0.00%)  2/18 (11.11%)  0/8 (0.00%)  0/8 (0.00%)  1/8 (12.50%) 
Headache  1  1/19 (5.26%)  0/18 (0.00%)  3/18 (16.67%)  1/8 (12.50%)  0/8 (0.00%)  0/8 (0.00%) 
Presyncope  1  1/19 (5.26%)  0/18 (0.00%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Somnolence  1  7/19 (36.84%)  0/18 (0.00%)  7/18 (38.89%)  2/8 (25.00%)  0/8 (0.00%)  0/8 (0.00%) 
Renal and urinary disorders             
Pollakiuria  1  1/19 (5.26%)  0/18 (0.00%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  0/19 (0.00%)  0/18 (0.00%)  1/18 (5.56%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Oropharyngeal pain  1  0/19 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Skin and subcutaneous tissue disorders             
Ecchymosis  1  0/19 (0.00%)  1/18 (5.56%)  0/18 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01221727     History of Changes
Other Study ID Numbers: 20101131
First Submitted: October 14, 2010
First Posted: October 15, 2010
Results First Submitted: February 13, 2013
Results First Posted: November 7, 2013
Last Update Posted: August 7, 2018