Osteopenia, Osteoporosis, Postmenopausal, Rheumatoid Arthritis
Conditions
Keywords
Amgen, Phase 1, Postmenopausal, Osteopenia, Rheumatoid, Bone Mineral Density, Arthritis, Pharmacokinetics, Osteoporosis
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).
Interventions
DRUGEtanercept
Administered by subcutaneous injection once a week
DRUGDenosumab
Administered by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 80 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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
| Measure | Time frame |
|---|---|
| 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 |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative Decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Etanercept + Denosumab |
|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 6.6 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants |
| Race/Ethnicity, Customized Black (or African American) | 1 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 1 participants |
| Race/Ethnicity, Customized Mixed race | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 18 participants |
| Race/Ethnicity, Customized White | 18 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 19 | 2 / 19 | 13 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 | 0 / 19 |
Outcome results
Primary
Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept
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.
Population: Participants with available AUC data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Etanercept + 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 |
| Etanercept + Denosumab | 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 |
Comparison: 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.90% CI: [0.85, 1.08]
Primary
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.
Population: Participants with available Cmax data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Etanercept + Denosumab | Maximum Observed Serum Concentration (Cmax) of Etanercept | Etanercept Alone - Day 1 (n=19) | 8.71 μg/mL | Standard Deviation 5.47 |
| Etanercept + Denosumab | Maximum Observed Serum Concentration (Cmax) of Etanercept | Etanercept + Denosumab - Day 22 (n=18) | 8.25 μg/mL | Standard Deviation 5.57 |
Comparison: 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.90% CI: [0.81, 1.05]
Secondary
Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations
Time frame: 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)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Etanercept + Denosumab | Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations | Day 22 (n = 18) | -32.3 percent change |
| Etanercept + Denosumab | Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations | Day 29 (n = 18) | -32.3 percent change |
| Etanercept + Denosumab | Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations | Day 85 (n = 17) | -26.2 percent change |
| Etanercept + Denosumab | Percent Change From Baseline in Serum C-telopeptide (sCTx) Concentrations | Day 176/End of Study (n = 19) | -25.1 percent change |
Secondary
Serum Denosumab Concentration
Time frame: Prior to etanercept and denosumab dose administrations, as applicable, on days 8, 22, and 29
Population: Participants with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Etanercept + Denosumab | Serum Denosumab Concentration | Day 8 (n=19) | 0.00 μg/mL | Standard Deviation 0 |
| Etanercept + Denosumab | Serum Denosumab Concentration | Day 22 (n=18) | 5.30 μg/mL | Standard Deviation 1.35 |
| Etanercept + Denosumab | Serum Denosumab Concentration | Day 29 (n=18) | 4.85 μg/mL | Standard Deviation 1.35 |
Secondary
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.
Population: Participants with available Tmax data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Etanercept + Denosumab | Time to Maximum Serum Concentration (Tmax) of Etanercept | Etanercept + Denosumab - Day 22 (n=18) | 2.0 days |
| Etanercept + Denosumab | Time to Maximum Serum Concentration (Tmax) of Etanercept | Etanercept Alone - Day 1 (n=19) | 3.0 days |