Osteoporosis, Postmenopausal
Conditions
Brief summary
The objective of this prospective, observational study in Czech Republic and Slovakia is to describe per country the characteristics of women treated with denosumab in routine clinical practice and the clinical management of these patients during the first 2 years of treatment. In addition, the study aims to collect safety data in the real-life clinical practice settings on adverse drug reactions (ADRs) and serious ADRs.
Interventions
BIOLOGICALDenosumab
This is an non-interventional study, therefore denosumab is administered as part of routine care and not for purposes of the study.
Sponsors
One Amgen Center Drive
THOUSAND OAKS
CA
91320-1799
USA
Amgen
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
* Women with a clinical diagnosis of postmenopausal osteoporosis * Decision has been made to treat with denosumab 60 mg once every 6 months * Have received their first injection of denosumab within 8 weeks prior to enrolling in this study. * Appropriate written informed consent has been obtained (as required per local country regulations)
Exclusion criteria
* Participating in ongoing or have participated in previous denosumab clinical trials * Participation in other clinical or device trials in the last 6 months * Contra-indicated for treatment with Prolia® according to the approved applicable local product label. * Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Having Osteoporosis Related Laboratory Examinations | Pre-baseline (before first denosumab injection) and post-baseline | Number of participants having osteoporosis related laboratory examinations pre-treatment with denosumab and during the study. Participants may not have been given denosumab injection when they attended each visit. |
| Number of Denosumab Post-baseline Injections Received by Each Participant | 24 months | — |
| Number of Participants Having Radiologic Bone Assessments | Pre-baseline (before first denosumab injection) and during the study (post-baseline) | Number of participants having radiologic bone assessments pre-treatment with denosumab and during the study. |
| Number of Participants Receiving All Prescriptions and Injections of Denosumab From the Initial Prescribing Physician's Office | 24 months | Number of participants who received all injection(s), including baseline injection, from the initial prescribing site irrespective of total number of injections received on study. |
| Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Baseline (day 1), and at Months 6, 12, 18 and 24 (corresponding to the first, second, third and fourth post-baseline injections respectively) | — |
| Number of Participants Receiving All Prescriptions and Injections of Denosumab | Months 6, 12, 18 and 24 (corresponding to the first, second, third and fourth post-baseline injections respectively) | Number of participants receiving all prescriptions and injections of denosumab whether or not the injections are given at the initial prescribing physician's office. |
| Number of Participants With a Referral by the Prescribing Physician to Other Health Care Providers for Continuation or Follow-up of Care | 24 months | — |
| Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Baseline (day 1) | Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the baseline injection. |
| Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Month 6 | Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the first post-baseline injection. |
| Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Month 12 | Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the second post-baseline injection. |
| Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Month 18 | Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the third post-baseline injection. |
| Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Month 24 | Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the fourth post-baseline injection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious ADRs to Denosumab | 24 months | Serious adverse events that were considered related to denosumab were classified as serious adverse drug reactions (SADRs). A serious adverse event (SAE) is any AE that also: • is fatal • is life threatening (places the patient at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is an other significant medical hazard that does not meet any of the above criteria. |
| Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | 24 months | Adverse events (AEs) that were considered related to denosumab as evaluated by the investigator were classified as adverse drug reactions (ADRs). |
Countries
Czechia, Slovakia
Participant flow
Recruitment details
The study was conducted at various study centers in the Czech Republic and Slovakia. The recruitment period was from 26 June 2012 to 15 May 2013.
Participants by arm
| Arm | Count |
|---|---|
| Czech Republic Patients in the Czech Republic with postmenopausal osteoporosis who received at least 1 injection of denosumab 60 mg administered subcutaneously every 6 months as part of their routine clinical care. | 300 |
| Slovakia Patients in Slovakia with postmenopausal osteoporosis who received at least 1 injection of denosumab 60 mg administered subcutaneously every 6 months as part of their routine clinical care. | 300 |
| Total | 600 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 2 |
| Overall Study | Lost to Follow-up | 6 | 6 |
| Overall Study | Other | 8 | 9 |
| Overall Study | Withdrawal by Subject | 16 | 4 |
Baseline characteristics
| Characteristic | Slovakia | Total | Czech Republic |
|---|---|---|---|
| Age at Menopause | 48.3 years STANDARD_DEVIATION 5.2 | 48.3 years STANDARD_DEVIATION 5.4 | 48.3 years STANDARD_DEVIATION 5.6 |
| Age, Continuous | 64.3 years STANDARD_DEVIATION 8.6 | 66.7 years STANDARD_DEVIATION 9 | 69.0 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 300 Participants | 600 Participants | 300 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Time Since Postmenopausal Osteoarthritis Diagnosis | 3.0 years STANDARD_DEVIATION 4.1 | 4.1 years STANDARD_DEVIATION 4.8 | 5.3 years STANDARD_DEVIATION 5.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 300 | 0 / 300 |
| serious Total, serious adverse events | 0 / 300 | 1 / 300 |
Outcome results
Primary
Number of Denosumab Post-baseline Injections Received by Each Participant
Time frame: 24 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Denosumab Post-baseline Injections Received by Each Participant | One post-baseline injection | 7 participants |
| Czech Republic | Number of Denosumab Post-baseline Injections Received by Each Participant | Three post-baseline injections | 16 participants |
| Czech Republic | Number of Denosumab Post-baseline Injections Received by Each Participant | Two post-baseline injections | 14 participants |
| Czech Republic | Number of Denosumab Post-baseline Injections Received by Each Participant | Four post-baseline injections | 246 participants |
| Czech Republic | Number of Denosumab Post-baseline Injections Received by Each Participant | No post-baseline injections | 17 participants |
| Slovakia | Number of Denosumab Post-baseline Injections Received by Each Participant | Four post-baseline injections | 243 participants |
| Slovakia | Number of Denosumab Post-baseline Injections Received by Each Participant | No post-baseline injections | 7 participants |
| Slovakia | Number of Denosumab Post-baseline Injections Received by Each Participant | One post-baseline injection | 10 participants |
| Slovakia | Number of Denosumab Post-baseline Injections Received by Each Participant | Two post-baseline injections | 7 participants |
| Slovakia | Number of Denosumab Post-baseline Injections Received by Each Participant | Three post-baseline injections | 33 participants |
Primary
Number of Participants Having Osteoporosis Related Laboratory Examinations
Number of participants having osteoporosis related laboratory examinations pre-treatment with denosumab and during the study. Participants may not have been given denosumab injection when they attended each visit.
Time frame: Pre-baseline (before first denosumab injection) and post-baseline
Population: Full analysis set; n = participants with visits at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants Having Osteoporosis Related Laboratory Examinations | First post-baseline injection (n = 285, 294) | 148 participants |
| Czech Republic | Number of Participants Having Osteoporosis Related Laboratory Examinations | Third post-baseline injection (n = 270, 280) | 163 participants |
| Czech Republic | Number of Participants Having Osteoporosis Related Laboratory Examinations | Second post-baseline injection (n = 280, 286) | 162 participants |
| Czech Republic | Number of Participants Having Osteoporosis Related Laboratory Examinations | Fourth post-baseline injection (n = 262, 263) | 174 participants |
| Czech Republic | Number of Participants Having Osteoporosis Related Laboratory Examinations | Baseline injection (n = 300, 300) | 230 participants |
| Slovakia | Number of Participants Having Osteoporosis Related Laboratory Examinations | Fourth post-baseline injection (n = 262, 263) | 223 participants |
| Slovakia | Number of Participants Having Osteoporosis Related Laboratory Examinations | Baseline injection (n = 300, 300) | 260 participants |
| Slovakia | Number of Participants Having Osteoporosis Related Laboratory Examinations | First post-baseline injection (n = 285, 294) | 207 participants |
| Slovakia | Number of Participants Having Osteoporosis Related Laboratory Examinations | Second post-baseline injection (n = 280, 286) | 224 participants |
| Slovakia | Number of Participants Having Osteoporosis Related Laboratory Examinations | Third post-baseline injection (n = 270, 280) | 226 participants |
Primary
Number of Participants Having Radiologic Bone Assessments
Number of participants having radiologic bone assessments pre-treatment with denosumab and during the study.
Time frame: Pre-baseline (before first denosumab injection) and during the study (post-baseline)
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants Having Radiologic Bone Assessments | Pre-baseline | 297 participants |
| Czech Republic | Number of Participants Having Radiologic Bone Assessments | Post-baseline | 253 participants |
| Slovakia | Number of Participants Having Radiologic Bone Assessments | Pre-baseline | 299 participants |
| Slovakia | Number of Participants Having Radiologic Bone Assessments | Post-baseline | 216 participants |
Primary
Number of Participants Receiving All Prescriptions and Injections of Denosumab
Number of participants receiving all prescriptions and injections of denosumab whether or not the injections are given at the initial prescribing physician's office.
Time frame: Months 6, 12, 18 and 24 (corresponding to the first, second, third and fourth post-baseline injections respectively)
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants Receiving All Prescriptions and Injections of Denosumab | First post-baseline injection | 283 participants |
| Czech Republic | Number of Participants Receiving All Prescriptions and Injections of Denosumab | Second post-baseline injection | 276 participants |
| Czech Republic | Number of Participants Receiving All Prescriptions and Injections of Denosumab | Third post-baseline injection | 262 participants |
| Czech Republic | Number of Participants Receiving All Prescriptions and Injections of Denosumab | Fourth post-baseline injection | 246 participants |
| Slovakia | Number of Participants Receiving All Prescriptions and Injections of Denosumab | Fourth post-baseline injection | 243 participants |
| Slovakia | Number of Participants Receiving All Prescriptions and Injections of Denosumab | First post-baseline injection | 293 participants |
| Slovakia | Number of Participants Receiving All Prescriptions and Injections of Denosumab | Third post-baseline injection | 276 participants |
| Slovakia | Number of Participants Receiving All Prescriptions and Injections of Denosumab | Second post-baseline injection | 283 participants |
Primary
Number of Participants Receiving All Prescriptions and Injections of Denosumab From the Initial Prescribing Physician's Office
Number of participants who received all injection(s), including baseline injection, from the initial prescribing site irrespective of total number of injections received on study.
Time frame: 24 months
Population: Full analysis set (all enrolled patients who provided informed consent and received at least one injection)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Czech Republic | Number of Participants Receiving All Prescriptions and Injections of Denosumab From the Initial Prescribing Physician's Office | 295 participants |
| Slovakia | Number of Participants Receiving All Prescriptions and Injections of Denosumab From the Initial Prescribing Physician's Office | 296 participants |
Primary
Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection
Time frame: Baseline (day 1), and at Months 6, 12, 18 and 24 (corresponding to the first, second, third and fourth post-baseline injections respectively)
Population: Full analysis set; n = the number of participants who received the corresponding injection
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | First post-baseline injection (n = 283, 293) | 282 participants |
| Czech Republic | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Third post-baseline injection (n = 262, 276) | 260 participants |
| Czech Republic | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Second post-baseline injection (n = 276, 283) | 275 participants |
| Czech Republic | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Fourth post-baseline injection (n = 246, 243) | 245 participants |
| Czech Republic | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Baseline injection (n = 300, 300) | 300 participants |
| Slovakia | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Fourth post-baseline injection (n = 246, 243) | 240 participants |
| Slovakia | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Baseline injection (n = 300, 300) | 298 participants |
| Slovakia | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | First post-baseline injection (n = 283, 293) | 291 participants |
| Slovakia | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Second post-baseline injection (n = 276, 283) | 282 participants |
| Slovakia | Number of Participants Receiving an Individual Prescription and Injection of Denosumab From the Initial Prescribing Physician Office by Each Individual Injection | Third post-baseline injection (n = 262, 276) | 274 participants |
Primary
Number of Participants With a Referral by the Prescribing Physician to Other Health Care Providers for Continuation or Follow-up of Care
Time frame: 24 months
Population: Full analysis set participants who discontinued the study prematurely
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants With a Referral by the Prescribing Physician to Other Health Care Providers for Continuation or Follow-up of Care | Referred to other health care providers (total) | 0 participants |
| Czech Republic | Number of Participants With a Referral by the Prescribing Physician to Other Health Care Providers for Continuation or Follow-up of Care | Referred to rheumatologist | 0 participants |
| Slovakia | Number of Participants With a Referral by the Prescribing Physician to Other Health Care Providers for Continuation or Follow-up of Care | Referred to other health care providers (total) | 2 participants |
| Slovakia | Number of Participants With a Referral by the Prescribing Physician to Other Health Care Providers for Continuation or Follow-up of Care | Referred to rheumatologist | 2 participants |
Primary
Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection
Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the baseline injection.
Time frame: Baseline (day 1)
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Prescribing Physician | 54 participants |
| Czech Republic | Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Other Physician | 19 participants |
| Czech Republic | Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Nurse | 227 participants |
| Slovakia | Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Prescribing Physician | 84 participants |
| Slovakia | Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Other Physician | 21 participants |
| Slovakia | Types of Health Care Providers Administering an Individual Injection of Denosumab at the Baseline Injection | Nurse | 195 participants |
Primary
Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection
Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the first post-baseline injection.
Time frame: Month 6
Population: Full analysis set participants who received a first post-baseline injection (i.e. at month 6)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Prescribing Physician | 70 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Other Physician | 8 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Nurse | 205 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Prescribing Physician | 109 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Other Physician | 0 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the First Post-baseline Injection | Nurse | 184 participants |
Primary
Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection
Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the fourth post-baseline injection.
Time frame: Month 24
Population: Full analysis set participants who received a fourth post-baseline injection (i.e. at month 24)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Prescribing Physician | 76 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Other Physician | 0 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Nurse | 170 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Prescribing Physician | 93 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Other Physician | 6 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Fourth Post-baseline Injection | Nurse | 144 participants |
Primary
Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection
Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the second post-baseline injection.
Time frame: Month 12
Population: Full analysis set participants who received a second post-baseline injection (i.e. at month 12)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Prescribing Physician | 75 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Other Physician | 0 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Nurse | 201 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Prescribing Physician | 104 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Other Physician | 0 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Second Post-baseline Injection | Nurse | 179 participants |
Primary
Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection
Types of health care providers administering an individual injection of denosumab inside or outside the initial prescribing office at the third post-baseline injection.
Time frame: Month 18
Population: Full analysis set participants who received a third post-baseline injection (i.e. at month 18)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Prescribing Physician | 69 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Other Physician | 4 participants |
| Czech Republic | Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Nurse | 189 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Prescribing Physician | 113 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Other Physician | 1 participants |
| Slovakia | Types of Health Care Providers Administering Denosumab at the Third Post-baseline Injection | Nurse | 162 participants |
Secondary
Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab
Adverse events (AEs) that were considered related to denosumab as evaluated by the investigator were classified as adverse drug reactions (ADRs).
Time frame: 24 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | All adverse drug reactions | 4 participants |
| Czech Republic | Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | ADRs leading to discontinuation of denosumab | 2 participants |
| Czech Republic | Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | Fatal adverse drug reactions | 0 participants |
| Slovakia | Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | All adverse drug reactions | 12 participants |
| Slovakia | Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | ADRs leading to discontinuation of denosumab | 5 participants |
| Slovakia | Number of Participants With Adverse Drug Reactions (ADRs) to Denosumab | Fatal adverse drug reactions | 0 participants |
Secondary
Number of Participants With Serious ADRs to Denosumab
Serious adverse events that were considered related to denosumab were classified as serious adverse drug reactions (SADRs). A serious adverse event (SAE) is any AE that also: • is fatal • is life threatening (places the patient at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is an other significant medical hazard that does not meet any of the above criteria.
Time frame: 24 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Czech Republic | Number of Participants With Serious ADRs to Denosumab | All serious adverse drug reactions | 0 participants |
| Czech Republic | Number of Participants With Serious ADRs to Denosumab | SADRs leading to discontinuation of denosumab | 0 participants |
| Czech Republic | Number of Participants With Serious ADRs to Denosumab | Fatal serious ADRs | 0 participants |
| Slovakia | Number of Participants With Serious ADRs to Denosumab | All serious adverse drug reactions | 1 participants |
| Slovakia | Number of Participants With Serious ADRs to Denosumab | SADRs leading to discontinuation of denosumab | 0 participants |
| Slovakia | Number of Participants With Serious ADRs to Denosumab | Fatal serious ADRs | 0 participants |