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CompletedNCT01221727Updated Aug 7, 2018Results posted

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

A Phase 1 interventional study of Denosumab and Midazolam in Postmenopausal Osteoporosis, sponsored by Amgen. Completed. Open to female participants aged 45 Years to 75 Years. Per ClinicalTrials.gov, last updated 2018-08-07.

Sponsored by Amgen · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
30
Allocation
Randomized
Ages
45 Years to 75 Years
Sex
Female
01

Study summary

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

Read the 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.

02

Conditions studied

  • Postmenopausal Osteoporosis

Keywords

  • Amgen
  • Phase 1
  • Postmenopausal
  • Osteoporosis
03

In context

Osteoporosis

1,640 studies on the registry are indexed under Osteoporosis; 212 are open to participants now.

This study's enrollment of 30 is below the median of 95 across 1,133 interventional studies indexed under Osteoporosis.

Browse Osteoporosis studies →

Lead sponsor

Amgen is the lead sponsor of 1,015 studies on the registry; 49 are open to participants now.

Of its 245 completed or terminated interventional studies of FDA-regulated products, 159 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
45 Years to 75 Years
Sexes eligible
Female
Accepts healthy volunteers
No

Inclusion criteria

  • Between 45 to 75 years of age
  • Postmenopausal women
  • Osteoporosis

Exclusion criteria

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
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
30 participants (actual)

Study arms

  • Other
    Midazolam

    All 27 subjects will receive midazolam.

    Drug: Denosumab

  • Active comparator
    Denosumab

    Eighteen (18) subjects will receive denosumab.

    Drug: Midazolam

Interventions

  • DrugDenosumab

    Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.

    Also known as: AMG 162

  • DrugMidazolam

    All subjects will receive two oral dose administrations of midazolam.

06

What researchers measure

Primary outcomes

  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)

    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

  2. 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

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

  3. 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

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

  4. 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.

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

Secondary outcomes

  1. 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.

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

  2. 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.

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

  3. 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.

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

  4. 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.

    Time frame: Baseline (day 2 pre-dose) to day 16

  5. Summary of Serum C-Telopeptide Concentration

    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

  6. 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.

    Time frame: Baseline (day 2 pre-dose) to day 16

  7. 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.

    Time frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

07

Results

Posted Nov 7, 2013

Participant flow

Participant flow — Overall Study
MilestoneMidazolam With DenosumabMidazolam Only
Started219
Treated198
Completed188
Not completed31
Withdrew: Physician decision20
Withdrew: Withdrawal by subject11

Outcome measures

PrimaryRatio 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.

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Least squares mean · unitless
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)
unitlessMidazolam With Denosumab
AUC (0-t)1.10 (0.94 to 1.29)
AUC (0-inf)1.12 (0.95 to 1.31)
SecondaryRatio 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.

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Least squares mean · unitless
Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
unitlessMidazolam Only
AUC (0-t)0.98 (0.83 to 1.15)
AUC (0-inf)0.98 (0.84 to 1.15)
PrimaryEstimates 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

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Mean · ng*hr/mL
Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group
ng*hr/mLMidazolam With Denosumab
AUC (0-t) Subject: Inter-subject0.19 ± 0.079
AUC (0-t) Residual: Intra-subject0.07 ± 0.025
AUC (0-inf) Subject: Inter-subject0.21 ± 0.085
AUC (0-inf) Residual: Intra-subject0.08 ± 0.027
PrimaryEstimates 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

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Mean · ng/mL
Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group
ng/mLMidazolam With Denosumab
Cmax Subject: Inter-subject0.15 ± 0.064
Cmax Residual: Intra-subject0.07 ± 0.023
SecondaryEstimates 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.

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Mean · ng*hr/mL
Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group
ng*hr/mLMidazolam Only
AUC (0-t) Subject: Inter-subject0.27 ± 0.155
AUC (0-t) Residual: Intra-subject0.03 ± 0.016
AUC (0-inf) Subject: Inter-subject0.31 ± 0.175
AUC (0-inf) Residual: Intra-subject0.03 ± 0.015
SecondaryEstimates 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.

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Mean · ng/mL
Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group
ng/mLMidazolam Only
Cmax Subject: Inter-subject0.23 ± 0.143
Cmax Residual: Intra-subject0.06 ± 0.035
SecondarySummary 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.

Time frame:
Baseline (day 2 pre-dose) to day 16
Reported as:
Median · ng/mL
Summary of Serum Denosumab Concentration
ng/mLMidazolam With Denosumab
Day 2 (Pre-dose)0 ± NA
Day 16 (0hr)5820 ± 1800
Day 17 (24hr)5500 ± 1940
SecondarySummary of Serum C-Telopeptide Concentration

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
Reported as:
Median · ng/mL
Summary of Serum C-Telopeptide Concentration
ng/mLMidazolam With Denosumab
Baseline (day 2 pre-dose)0.4655 ± 0.0698
Day 160.0606 ± 0.0030
Change from baseline to Day 16-0.4079 ± 0.0702
PrimaryRatio 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.

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Least squares mean · unitless
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
unitlessMidazolam With Denosumab
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)1.11 (0.96 to 1.29)
SecondarySummary 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.

Time frame:
Baseline (day 2 pre-dose) to day 16
Reported as:
Median · percentage
Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration
percentageMidazolam With Denosumab
Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration-87.52 (-91.45 to -80.01)
SecondaryRatio 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.

Time frame:
From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Reported as:
Least squares mean · unitless
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
unitlessMidazolam Only
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)1.05 (0.82 to 1.33)

Adverse events

Collected over 47 days. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Midazolam With Denosumab Group With Midazolam 2mg on Day 1—0/19 (0%)9/19 (47.4%)
Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15—0/18 (0%)6/18 (33.3%)
Midazolam With Denosumab Group With Midazolam 2mg on Day 16—0/18 (0%)10/18 (55.6%)
Midazolam Only Group With Midazolam 2mg on Day 1—0/8 (0%)2/8 (25%)
Midazolam Only Group With Midazolam 2mg on Day 2-15—0/8 (0%)1/8 (12.5%)
Midazolam Only Group With Midazolam 2mg on Day 16—0/8 (0%)1/8 (12.5%)
Most frequent other events
Showing 10 of 19
Most frequent other events
EventMidazolam With Denosumab Group With Midazolam 2mg on Day 1Midazolam With Denosumab Group With Denosumab 60mg on Day 2-15Midazolam With Denosumab Group With Midazolam 2mg on Day 16Midazolam Only Group With Midazolam 2mg on Day 1Midazolam Only Group With Midazolam 2mg on Day 2-15Midazolam Only Group With Midazolam 2mg on Day 16
SomnolenceNervous system disorders7/190/187/182/80/80/8
HeadacheNervous system disorders1/190/183/181/80/80/8
ConstipationGastrointestinal disorders0/191/180/180/81/80/8
DizzinessNervous system disorders1/190/182/180/80/81/8
Injection site painGeneral disorders0/192/180/180/80/80/8
NauseaGastrointestinal disorders1/191/181/180/80/80/8
ChillsGeneral disorders0/191/180/180/80/80/8
NasopharyngitisInfections and infestations0/190/181/180/80/80/8
ArthralgiaMusculoskeletal and connective tissue disorders0/191/180/180/80/80/8
Neck painMusculoskeletal and connective tissue disorders0/190/181/180/80/80/8

Baseline characteristics

Age, Continuous
Age, Continuous(years)Midazolam With DenosumabMidazolam OnlyTotal
Mean64.42 ± 6.1666.25 ± 5.3464.96 ± 5.89
Age, Customized
Age, Customized(Participants)Midazolam With DenosumabMidazolam OnlyTotal
<65 years7310
>=65 years and <75 years12416
>=75 years011
Sex: Female, Male
Sex: Female, Male(Participants)Midazolam With DenosumabMidazolam OnlyTotal
Female19827
Male000
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Midazolam With DenosumabMidazolam OnlyTotal
Hispanic or Latino7411
Not Hispanic or Latino12416
Unknown or Not Reported000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Midazolam With DenosumabMidazolam OnlyTotal
American Indian or Alaska Native000
Asian112
Native Hawaiian or Other Pacific Islander000
Black or African American112
White17623
More than one race000
Unknown or Not Reported000
08

Study locations

No study locations are listed for this record.

09

References and documents

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. PubMed 25505582 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 7, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01221727
Lead sponsor
Amgen
Responsible party
Sponsor
First posted
Oct 15, 2010
Start date
Nov 2010
Primary completion
Jul 2011
Completion
Jul 2011
Results posted
Nov 7, 2013
Last update
Aug 7, 2018

Study contacts

MD
study director · Amgen

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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