Trial Outcomes & Findings for Effects of Denosumab on the Pharmacokinetics of Etanercept (NCT NCT01294397)

Last Updated: 2017-06-20

Results Overview

The AUC0-168 of etanercept was measured when administered alone (assessed from day 1) and after administration with denosumab (assessed from day 22, 14 days after denosumab dosing, close to the time of the maximum observed denosumab serum concentration and corresponding to a time approximately 1 week after maximal pharmacodynamic (PD) effects of denosumab are attained).

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

19 participants

Primary outcome timeframe

Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Results posted on

2017-06-20

Participant Flow

This study was conducted at 2 centers in the United States. The first participant enrolled on 07 March 2011; the last participant was enrolled on 15 June 2015.

Following determination of eligibility at screening, 19 participants were enrolled into a 4-week run-in period of etanercept 50 mg subcutaneous once-weekly injection to ensure steady-state.

Participant milestones

Participant milestones
Measure	Etanercept + Denosumab Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Overall Study STARTED	19
Overall Study COMPLETED	17
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Etanercept + Denosumab Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Overall Study Withdrawal by Subject	1
Overall Study Administrative Decision	1

Baseline Characteristics

Effects of Denosumab on the Pharmacokinetics of Etanercept

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Etanercept + Denosumab n=19 Participants Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Age, Continuous	63.1 years STANDARD_DEVIATION 6.6 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic/Latino	1 participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic/Latino	18 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants
Race/Ethnicity, Customized Asian	0 participants n=5 Participants
Race/Ethnicity, Customized Black (or African American)	1 participants n=5 Participants
Race/Ethnicity, Customized Mixed race	0 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants n=5 Participants
Race/Ethnicity, Customized White	18 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Population: Participants with available AUC data

Outcome measures

Outcome measures
Measure	Etanercept + Denosumab n=17 Participants Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept Etanercept Alone (Day 1)	40.8 day*μg/mL Standard Deviation 18.8
Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept Etanercept + Denosumab (Day 22)	40.4 day*μg/mL Standard Deviation 26.6

PRIMARY outcome

Timeframe: Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Population: Participants with available Cmax data

Outcome measures

Outcome measures
Measure	Etanercept + Denosumab n=19 Participants Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Maximum Observed Serum Concentration (Cmax) of Etanercept Etanercept Alone - Day 1 (n=19)	8.71 μg/mL Standard Deviation 5.47
Maximum Observed Serum Concentration (Cmax) of Etanercept Etanercept + Denosumab - Day 22 (n=18)	8.25 μg/mL Standard Deviation 5.57

SECONDARY outcome

Timeframe: Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Population: Participants with available Tmax data

Outcome measures

Outcome measures
Measure	Etanercept + Denosumab n=19 Participants Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Time to Maximum Serum Concentration (Tmax) of Etanercept Etanercept Alone - Day 1 (n=19)	3.0 days Interval 0.99 to 4.9
Time to Maximum Serum Concentration (Tmax) of Etanercept Etanercept + Denosumab - Day 22 (n=18)	2.0 days Interval 0.93 to 4.9

SECONDARY outcome

Timeframe: Prior to etanercept and denosumab dose administrations, as applicable, on days 8, 22, and 29

Population: Participants with available data

Outcome measures

Outcome measures
Measure	Etanercept + Denosumab n=19 Participants Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Serum Denosumab Concentration Day 29 (n=18)	4.85 μg/mL Standard Deviation 1.35
Serum Denosumab Concentration Day 8 (n=19)	0.00 μg/mL Standard Deviation 0.00
Serum Denosumab Concentration Day 22 (n=18)	5.30 μg/mL Standard Deviation 1.35

SECONDARY outcome

Timeframe: Baseline (Day 8) and Days 22, 29, 85, and 176

Population: Participants with available data at baseline (19) and each time point (indicated by n)

Outcome measures

Outcome measures
Measure	Etanercept + Denosumab n=19 Participants Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab.
Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations Day 22 (n = 18)	-32.3 percent change Interval -58.7 to 0.0
Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations Day 29 (n = 18)	-32.3 percent change Interval -60.9 to 0.0
Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations Day 85 (n = 17)	-26.2 percent change Interval -60.9 to 0.0
Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations Day 176/End of Study (n = 19)	-25.1 percent change Interval -60.4 to 0.0

Adverse Events

Etanercept 50 mg Day - 28 - Day 7

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

All Subjects On-study

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee 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 multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Etanercept 50 mg Day - 28 - Day 7 n=19 participants at risk Participants received etanercept 50 mg subcutaneously once weekly. Adverse events are reported from day -28 until day 7.	Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS n=19 participants at risk Participants received etanercept 50 mg subcutaneously once weekly. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab. Adverse events are reported from day 8 to end of study (day 176).	All Subjects On-study n=19 participants at risk Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, participants were administered a single 60 mg subcutaneous injection of denosumab. Adverse events are reported from day -28 up to day 176.
Eye disorders Eye haemorrhage	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Gastrointestinal disorders Diarrhoea	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Gastrointestinal disorders Haemorrhoidal haemorrhage	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
General disorders Injection site erythema	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
General disorders Injection site pruritus	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
General disorders Nodule	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Immune system disorders Seasonal allergy	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Bronchitis	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Conjunctivitis	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Herpes zoster	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Upper respiratory tract infection	15.8% 3/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	15.8% 3/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Urinary tract infection	10.5% 2/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	10.5% 2/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Injury, poisoning and procedural complications Ankle fracture	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Injury, poisoning and procedural complications Arthropod sting	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Injury, poisoning and procedural complications Tooth fracture	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Injury, poisoning and procedural complications Wound dehiscence	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Nervous system disorders Headache	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Respiratory, thoracic and mediastinal disorders Cough	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	10.5% 2/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	10.5% 2/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Respiratory, thoracic and mediastinal disorders Sinus congestion	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Skin and subcutaneous tissue disorders Erythema	10.5% 2/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	10.5% 2/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Skin and subcutaneous tissue disorders Rash	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Surgical and medical procedures Fracture treatment	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	5.3% 1/19 • From first dose of etenercept in the run-in period (day -28) until end of study (day 176). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.