Effects of Denosumab on the Pharmacokinetics of Etanercept

Phase 1

Terminated

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).

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Etanercept + Denosumab	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.
Etanercept + Denosumab	Etanercept	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.

Primary Outcome Measures

Name	Time	Method
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.
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).

Secondary Outcome Measures

Name	Time	Method
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.
Serum Denosumab Concentration	Prior to etanercept and denosumab dose administrations, as applicable, on days 8, 22, and 29
Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations	Baseline (Day 8) and Days 22, 29, 85, and 176