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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01221727
• Collaborator: (none)
• Enrollment: 30
• Arms: 2
• Duration (Months): 8

Study Details

Study Description

Brief Summary

This is a multi-center, open-label, drug-drug interaction study in postmenopausal women with osteoporosis.

Condition or Disease	Intervention/Treatment	Phase
Postmenopausal Osteoporosis	Drug: Denosumab; Drug: Midazolam	Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam, a Cytochrome P450 3A4/P-gp (CYP3A4) Substrate, in Postmenopausal Osteoporotic Women
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Other: Midazolam All 27 subjects will receive midazolam.	Drug: Denosumab; Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.; Other Names: AMG 162
Active Comparator: Denosumab Eighteen (18) subjects will receive denosumab.	Drug: Midazolam; All subjects will receive two oral dose administrations of midazolam.

Outcome Measures

Primary Outcome Measures

1. 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) [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

2. Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability

3. Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability

4. Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

Secondary Outcome Measures

1. Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

2. Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability.

3. Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.

4. Summary of Serum Denosumab Concentration [Baseline (day 2 pre-dose) to day 16]

   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.

5. Summary of Serum C-Telopeptide Concentration [Baseline (day 2 pre-dose) to day 16]

   This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.

6. Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration [Baseline (day 2 pre-dose) to day 16]

   This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.

7. Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) [From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose]

   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Between 45 to 75 years of age

• Postmenopausal women

• Osteoporosis

Exclusion Criteria:

• Use of any known inhibitors of cytochrome P450 3A4/P-gp (CYP3A4) within 14 days or 5 half lives, whichever is longer; or grapefruit juice or grapefruit containing products within 7 days prior to investigational product administration

• Use of any known CYP3A4 inducers within 30 days or 5 half-lives, whichever is longer, prior to investigational product administration

• Use of any herbal medicine with a known impact on CYP3A4 (eg, St. John's wort) within 30 days prior to investigational product administration

• Current use of medications prescribed for osteoporosis treatment

• Use of midazolam within 14 days prior to investigational product administration

• Influenza or other vaccination within 28 days of screening

• Previous exposure to denosumab

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• 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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01221727
• Other Study ID Numbers: 20101131
• First Posted: Oct 15, 2010
• Last Update Posted: Aug 7, 2018
• Last Verified: Sep 1, 2015

• Keywords provided by Amgen: Amgen; Phase 1; Postmenopausal; Osteoporosis
• Additional relevant MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal; Denosumab; Midazolam

Study Results

Participant Flow

Arm/Group Title	Midazolam With Denosumab	Midazolam Only
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	9
Treated	19	8
COMPLETED	18	8
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Midazolam With Denosumab	Midazolam Only	Total
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 Participants	19	8	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.42 (6.16)	66.25 (5.34)	64.96 (5.89)
Age, Customized (Number) [Number]
<65 years	7 36.8%	3 37.5%	10 37%
>=65 years and <75 years	12 63.2%	4 50%	16 59.3%
>=75 years	0 0%	1 12.5%	1 3.7%
Sex: Female, Male (Count of Participants)
Female	19 100%	8 100%	27 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 36.8%	4 50%	11 40.7%
Not Hispanic or Latino	12 63.2%	4 50%	16 59.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	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%
Black or African American	1 5.3%	1 12.5%	2 7.4%
White	17 89.5%	6 75%	23 85.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

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)
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

Outcome Measure Data

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
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
Measure Participants	18
Measure unitless	18
AUC (0-t)	1.10
AUC (0-inf)	1.12

2. Secondary Outcome

Title	Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
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

Outcome Measure Data

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
Arm/Group Description	Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Measure Participants	8
Measure unitless	8
AUC (0-t)	0.98
AUC (0-inf)	0.98

3. Primary Outcome

Title	Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group
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

Outcome Measure Data

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
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
Measure Participants	18
Measure area	18
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)

4. Primary Outcome

Title	Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group
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

Outcome Measure Data

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
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
Measure Participants	18
Measure concentration	18
Cmax Subject: Inter-subject	0.15 (0.064)
Cmax Residual: Intra-subject	0.07 (0.023)

5. Secondary Outcome

Title	Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group
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

Outcome Measure Data

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
Arm/Group Description	Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Measure Participants	8
Measure area	8
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)

6. Secondary Outcome

Title	Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group
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

Outcome Measure Data

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
Arm/Group Description	Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Measure Participants	8
Measure concentration	8
Cmax Subject: Inter-subject	0.23 (0.143)
Cmax Residual: Intra-subject	0.06 (0.035)

7. Secondary Outcome

Title	Summary of Serum Denosumab Concentration
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

Outcome Measure Data

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
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
Measure Participants	18
Measure concentration	18
Day 2 (Pre-dose)	0 (NA)
Day 16 (0hr)	5820 (1800)
Day 17 (24hr)	5500 (1940)

8. Secondary Outcome

Title	Summary of Serum C-Telopeptide Concentration
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

Outcome Measure Data

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
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
Measure Participants	18
Measure concentration	18
Baseline (day 2 pre-dose)	0.4655 (0.0698)
Day 16	0.0606 (0.0030)
Change from baseline to Day 16	-0.4079 (0.0702)

9. Primary Outcome

Title	Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
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

Outcome Measure Data

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
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
Measure Participants	18
Measure unitless	18
Least Squares Mean (90% Confidence Interval) [unitless]	1.11

10. Secondary Outcome

Title	Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration
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

Outcome Measure Data

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
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
Measure Participants	18
Measure percentage	18
Median (Inter-Quartile Range) [percentage]	-87.52

11. Secondary Outcome

Title	Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
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

Outcome Measure Data

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
Arm/Group Description	Subjects received 2 mg oral dose of Midazolam on day 1 and day 16
Measure Participants	8
Measure unitless	8
Least Squares Mean (90% Confidence Interval) [unitless]	1.05

Adverse Events

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
Arm/Group Description
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/19 (47.4%)		6/18 (33.3%)		10/18 (55.6%)		2/8 (25%)		1/8 (12.5%)		1/8 (12.5%)
Gastrointestinal disorders
Constipation	0/19 (0%)		1/18 (5.6%)		0/18 (0%)		0/8 (0%)		1/8 (12.5%)		0/8 (0%)
Nausea	1/19 (5.3%)		1/18 (5.6%)		1/18 (5.6%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Vomiting	1/19 (5.3%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
General disorders
Chills	0/19 (0%)		1/18 (5.6%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Fatigue	1/19 (5.3%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Injection site pain	0/19 (0%)		2/18 (11.1%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Infections and infestations
Nasopharyngitis	0/19 (0%)		0/18 (0%)		1/18 (5.6%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Injury, poisoning and procedural complications
Laceration	1/19 (5.3%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/19 (0%)		1/18 (5.6%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Musculoskeletal stiffness	1/19 (5.3%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Neck pain	0/19 (0%)		0/18 (0%)		1/18 (5.6%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Nervous system disorders
Dizziness	1/19 (5.3%)		0/18 (0%)		2/18 (11.1%)		0/8 (0%)		0/8 (0%)		1/8 (12.5%)
Headache	1/19 (5.3%)		0/18 (0%)		3/18 (16.7%)		1/8 (12.5%)		0/8 (0%)		0/8 (0%)
Presyncope	1/19 (5.3%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Somnolence	7/19 (36.8%)		0/18 (0%)		7/18 (38.9%)		2/8 (25%)		0/8 (0%)		0/8 (0%)
Renal and urinary disorders
Pollakiuria	1/19 (5.3%)		0/18 (0%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/19 (0%)		0/18 (0%)		1/18 (5.6%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Oropharyngeal pain	0/19 (0%)		1/18 (5.6%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Ecchymosis	0/19 (0%)		1/18 (5.6%)		0/18 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.