Effects of Denosumab on the Pharmacokinetics of Etanercept

• Sponsor: Amgen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01294397
• Collaborator: (none)
• Enrollment: 19
• Locations: 2
• Arm: 1
• Duration (Months): 58.1
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of the study was to characterize the effects of a single dose of denosumab on the pharmacokinetics (PK) of etanercept in postmenopausal women with low bone mineral density (BMD) and rheumatoid arthritis based on area under the serum concentration-time curve (AUC) and maximum observed serum concentration (Cmax).

Condition or Disease	Intervention/Treatment	Phase
Postmenopausal; Osteopenia; Rheumatoid Arthritis; Osteoporosis	Drug: Etanercept; Drug: Denosumab	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effects of Denosumab on the Pharmacokinetics of Etanercept in Postmenopausal Women With Low Bone Mineral Density and Rheumatoid Arthritis
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Etanercept; Administered by subcutaneous injection once a week; Other Names: Enbrel® ; Drug: Denosumab; Administered by subcutaneous injection; Other Names: Prolia®

Outcome Measures

Primary Outcome Measures

1. Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept [Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.]

   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).

2. Maximum Observed Serum Concentration (Cmax) of Etanercept [Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.]

Secondary Outcome Measures

1. Time to Maximum Serum Concentration (Tmax) of Etanercept [Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.]

2. Serum Denosumab Concentration [Prior to etanercept and denosumab dose administrations, as applicable, on days 8, 22, and 29]

3. Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations [Baseline (Day 8) and Days 22, 29, 85, and 176]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Postmenopausal women (postmenopausal is defined as no vaginal bleeding or spotting for at least 12 months)

• Low bone mineral density (BMD) as determined by screening BMD T-scores of the lumbar spine (L1 to L4), or total evaluable vertebrae (if fewer than L1 to L4), or total hip ≤ -1.0

• Receiving a 50 mg dose of etanercept once weekly ≥ 6 months prior to screening and expected to continue etanercept treatment at this dose and frequency through end of study (EOS)

• If currently taking methotrexate (MTX), receiving a stable dose (7.5 to 20 mg/week) of MTX ≥ 8 weeks prior to screening

• Willing and able to take ≥ 1,000 mg elemental calcium and ≥ 400 IU vitamin D daily upon enrollment

Exclusion Criteria:

• Type 1 diabetes; OR poorly controlled Type 2 diabetes (hemoglobin A1c (HbA1c) > 8.0% at screening; HbA1c ≤ 8.0% within 6 months of screening is acceptable if supporting laboratory documentation is available)

• History of heart failure, coronary artery bypass graft, or cardiac arrhythmia; OR history of acute coronary syndrome

• Comorbid autoimmune disease, demyelinating disease, or hematologic abnormalities

• History of joint replacement in hand and/or wrist; OR history of fused joint in hand and/or wrist

• Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw; OR active dental or jaw condition that requires oral surgery, or non-healed dental/oral surgery; OR planned invasive dental procedure(s) during the course of the study

• Previous exposure to denosumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Duncansville	Pennsylvania	United States	16635
2	Research Site	Dallas	Texas	United States	75231

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01294397
• Other Study ID Numbers: 20101324
• First Posted: Feb 11, 2011
• Last Update Posted: Jun 20, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Amgen: Amgen; Phase 1; Postmenopausal; Osteopenia; Rheumatoid; Bone Mineral Density; Arthritis; Pharmacokinetics; Osteoporosis
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Osteoporosis; Bone Diseases, Metabolic; Denosumab; Etanercept

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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.
Period Title: Overall Study
STARTED	19
COMPLETED	17
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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 Participants	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.1 (6.6)
Sex: Female, Male (Count of Participants)
Female	19 100%
Male	0 0%
Race/Ethnicity, Customized (participants) [Number]
Hispanic/Latino	1 5.3%
Not Hispanic/Latino	18 94.7%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%
Asian	0 0%
Black (or African American)	1 5.3%
Mixed race	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
White	18 94.7%

Outcome Measures

1. Primary Outcome

Title	Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept
Description	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).
Time Frame	Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Outcome Measure Data

Analysis Population Description

Participants with available AUC data

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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.
Measure Participants	17
Etanercept Alone (Day 1)	40.8 (18.8)
Etanercept + Denosumab (Day 22)	40.4 (26.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etanercept + Denosumab
	Comments	Log-transformed AUC0-168 was analyzed with a mixed-effects model with treatment as the fixed effect and subject as the random effect. The mean difference between day 22 and day 1 was expressed as a percentage of the reference (day 1). The mean differences and the 90% CIs were back transformed to produce the ratio (day 22 vs. day 1) of the geometric means and the 90% CIs. If the CI for the ratio was within the standard acceptance range of 0.80 to 1.25, absence of an interaction was concluded.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Ratio of Day 22/Day 1
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.85 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two one-sided tests

2. Primary Outcome

Title	Maximum Observed Serum Concentration (Cmax) of Etanercept
Time Frame	Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Outcome Measure Data

Analysis Population Description

Participants with available Cmax data

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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.
Measure Participants	19
Etanercept Alone - Day 1 (n=19)	8.71 (5.47)
Etanercept + Denosumab - Day 22 (n=18)	8.25 (5.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Etanercept + Denosumab
	Comments	Log-transformed Cmax was analyzed with a mixed-effects model with treatment as the fixed effect and subject as the random effect. The mean difference between day 22 and day 1 was expressed as a percentage of the reference (day 1). The mean differences and the 90% CIs were back transformed to produce the ratio (day 22 vs. day 1) of the geometric means and the 90% CIs. If the CI for the ratio was within the standard acceptance range of 0.80 to 1.25, absence of an interaction was concluded.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Ratio of Day 22/Day 1
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 90%; 0.81 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two one-sided tests

3. Secondary Outcome

Title	Time to Maximum Serum Concentration (Tmax) of Etanercept
Time Frame	Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose.

Outcome Measure Data

Analysis Population Description

Participants with available Tmax data

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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.
Measure Participants	19
Etanercept Alone - Day 1 (n=19)	3.0
Etanercept + Denosumab - Day 22 (n=18)	2.0

4. Secondary Outcome

Title	Serum Denosumab Concentration
Time Frame	Prior to etanercept and denosumab dose administrations, as applicable, on days 8, 22, and 29

Outcome Measure Data

Analysis Population Description

Participants with available data

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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.
Measure Participants	19
Day 8 (n=19)	0.00 (0.00)
Day 22 (n=18)	5.30 (1.35)
Day 29 (n=18)	4.85 (1.35)

5. Secondary Outcome

Title	Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations
Time Frame	Baseline (Day 8) and Days 22, 29, 85, and 176

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Etanercept + Denosumab
Arm/Group Description	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.
Measure Participants	19
Day 22 (n = 18)	-32.3
Day 29 (n = 18)	-32.3
Day 85 (n = 17)	-26.2
Day 176/End of Study (n = 19)	-25.1

Adverse Events

Time Frame	From first dose of etenercept in the run-in period (day -28) until end of study (day 176).
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Etanercept 50 mg Day - 28 - Day 7		Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS		All Subjects On-study
Arm/Group Description	Participants received etanercept 50 mg subcutaneously once weekly. Adverse events are reported from day -28 until day 7.		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).		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.
All Cause Mortality
	Etanercept 50 mg Day - 28 - Day 7		Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS		All Subjects On-study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Etanercept 50 mg Day - 28 - Day 7		Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS		All Subjects On-study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Etanercept 50 mg Day - 28 - Day 7		Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS		All Subjects On-study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/19 (68.4%)		2/19 (10.5%)		13/19 (68.4%)
Eye disorders
Eye haemorrhage	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Gastrointestinal disorders
Diarrhoea	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Haemorrhoidal haemorrhage	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
General disorders
Injection site erythema	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Injection site pruritus	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Nodule	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Immune system disorders
Seasonal allergy	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Infections and infestations
Bronchitis	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Conjunctivitis	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Herpes zoster	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Upper respiratory tract infection	3/19 (15.8%)		0/19 (0%)		3/19 (15.8%)
Urinary tract infection	2/19 (10.5%)		0/19 (0%)		2/19 (10.5%)
Injury, poisoning and procedural complications
Ankle fracture	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Arthropod sting	0/19 (0%)		1/19 (5.3%)		1/19 (5.3%)
Tooth fracture	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Wound dehiscence	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Nervous system disorders
Headache	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Nasal congestion	0/19 (0%)		1/19 (5.3%)		1/19 (5.3%)
Oropharyngeal pain	2/19 (10.5%)		0/19 (0%)		2/19 (10.5%)
Sinus congestion	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Erythema	2/19 (10.5%)		0/19 (0%)		2/19 (10.5%)
Rash	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)
Surgical and medical procedures
Fracture treatment	1/19 (5.3%)		0/19 (0%)		1/19 (5.3%)

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 multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.