| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal osteoporosis |
| osteoporosi post menopausale |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10031285 |
| E.1.2 | Term | Osteoporosis postmenopausal |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| For the overall study period (12-month double-blind alendronate [ALN]- controlled study period followed by the open-label ALN study period) • To assess the effect of AMG 785 treatment for 12 months followed by ALN treatment compared with ALN treatment alone on the subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) in women with PMO • To assess the effect of AMG 785 treatment for 12 months followed by ALN treatment compared with ALN treatment alone on the subject incidence of new vertebral fracture in women with PMO |
Per tutto il periodo dello studio (12 mesi in doppio cieco controllato da alendronato [ALN] seguito da un
periodo in aperto con ALN)
• Valutare l’effetto del trattamento con AMG 785 per 12 mesi seguito dal trattamento con ALN
rispetto al solo trattamento con ALN sull’incidenza nei soggetti di fratture cliniche (frattura non
vertebrale e frattura vertebrale clinica) in donne affette da PMO
• Valutare l’effetto del trattamento con AMG 785 per 12 mesi seguito dal trattamento con ALN
rispetto al solo trattamento con ALN sull’incidenza nei soggetti di nuove fratture vertebrali in donne
affette da PMO |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the effect of AMG 785 treatment for 12 months followed by ALN treatment compared with ALN treatment alone on: • Subject incidence of fractures (all fractures [nonvertebral fractures and new vertebral fractures], new or worsening vertebral fracture, nonvertebral fracture, major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip], hip fracture, and multiple new or worsening vertebral fracture) • Percent changes in Dual energy X-ray Absorptiometry (DXA) bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck To assess the effect of AMG 785 treatment for 12 months compared with ALN treatment on: • Subject incidence of fractures (clinical fracture [nonvertebral fracture and clinical vertebral fracture], new vertebral fracture, all fractures [nonvertebral fractures and new vertebral fractures]) |
| Per tutto il periodo dello studio (12 mesi in doppio cieco controllato da ALN seguito da un periodo in aperto con ALN) Valutare l’effetto del trattamento con AMG 785 per 12 mesi seguito dal trattamento con ALN rispetto al solo trattamento con ALN su: • Incidenza delle fratture nei soggetti (tutte le fratture [fratture non vertebrali e nuove fratture vertebrali], frattura vertebrale nuova o peggioramento di frattura pregressa, frattura non vertebrale, frattura non vertebrale grave [bacino, femore distale, tibia prossimale, costole, omero prossimale, avambraccio e anca], frattura dell’anca e fratture multiple vertebrale nuove o peggioramento di frattura vertebrale preesistente) • Variazioni percentuali della densità minerale ossea (BMD) della colonna lombare, dell’anca totale e del collo femorale mediante assorbimetria a raggi X a doppia energia (DXA) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
OTHER SUBSTUDIES:
Italy won't take part to the substudy on biomarkers of bone turnover, imaging and pharmacokinetics
|
ALTRI SOTTOSTUDI:
Si precisa che l’Italia non parteciperà al sottostudio secondario, previsto dal protocollo, relativo a biomarcatori/marcatori del turnover osseo (BTM), imaging e farmacocinetica (PK).
|
|
| E.3 | Principal inclusion criteria |
| 4.1.1 Ambulatory postmenopausal women, age ≥ 60 to ≤ 90 years at randomization 4.1.2 BMD T-score ≤ -2.50 at the total hip or femoral neck and at least one moderate (SQ2) or severe (SQ3) vertebral fracture, as assessed by the central imaging vendor at the time of screening, based on DXA scans and lateral spine x-rays. 4.1.3 At least one hip is evaluable by DXA, as assessed by the principal investigator 4.1.4 Subject has provided informed consent |
| 4.1.1 Ambulatory postmenopausal women, age ≥ 60 to ≤ 90 years at randomization 4.1.2 BMD T-score ≤ -2.50 at the total hip or femoral neck and at least one moderate (SQ2) or severe (SQ3) vertebral fracture, as assessed by the central imaging vendor at the time of screening, based on DXA scans and lateral spine x-rays. 4.1.3 At least one hip is evaluable by DXA, as assessed by the principal investigator 4.1.4 Subject has provided informed consent |
|
| E.4 | Principal exclusion criteria |
| 4.2.1 Strontium, fluoride (for osteoporosis), odanacatib (MK-0822): at any time 4.2.2 Intravenous (IV) bisphosphonates: dose received within 5 years prior to randomization 4.2.3 Oral bisphosphonates: • More than 3 years of cumulative use • Any dose received within 6 months prior to randomization More than 1 month of cumulative use between 6 and 12 months prior to randomization 4.2.4 Denosumab: dose received within 18 months prior to randomization 4.2.5 Teriparatide or any PTH analogs: dose received within 12 months prior to randomization 4.2.6 Systemic oral or transdermal estrogen, SERMs, or calcitonin: more than 1 month of cumulative use within 6 months prior to randomization 4.2.7 Androgen deprivation or hormonal ablation therapy: more than 1 month of cumulative use within 6 months prior to randomization 4.2.8 Tibolone or cinacalcet: dose received within 3 months prior to randomization 4.2.9 Systemic glucocorticosteroids: ≥ 5 mg prednisone equivalent per day for more than 10 days within 3 months prior to randomization 4.2.10 History of metabolic or bone disease (except osteoporosis) that may interfere with the interpretation of the results, such as Paget's disease, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, Cushing's disease, hyperprolactinemia, and malabsorption syndrome 4.2.11 History of solid organ or bone marrow transplants 4.2.12 Vitamin D insufficiency (defined as 25 (OH) vitamin D levels < 20 ng/mL as assessed by the central laboratory. Vitamin D repletion will be permitted and subjects may be rescreened once 4.2.13 Current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside the normal range, as assessed by the central laboratory 4.2.14 Current, uncontrolled hyper- or hypothyroidism, defined as thyroidstimulating hormone outside of the normal range, per subject report or chart review 4.2.15 Current, uncontrolled hyper- or hypoparathyroidism, defined as PTH outside the normal range, per subject report or chart review 4.2.16 Possible diagnosis of multiple myeloma or related myeloproliferative disorder, as assessed by serum protein electrophoresis performed by the local laboratory 4.2.17 Exclusion criteria related to contraindications or possible signs of intolerance to ALN; contraindications and potential signs of intolerance for ALN therapy include: • Hypocalcemia (as defined in 4.2.13) • Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia • Inability to stand or sit upright for at least 30 minutes • Hypersensitivity to ALN or other constituents of ALN tablets • Increased risk of aspiration • Pregnancy and lactation • Other contraindications to ALN based on the country-specific product insert applicable to the specific study center • Significantly impaired renal function (as assessed by the central laboratory based on a derived creatinine clearance of < 35 mL/min using the Modification of Diet in Renal Disease. The estimated glomerular filtration rate is calculated as follows: estimated glomerular filtration rate (mL/min/1.73m2) = 175 x [Serum creatinine (mg/dL)]-1.154 x [Age]-0.203 x [0.742 if subject is female] x [1.210 if subject is black]. 4.2.18 General • Subject is currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s) • Subject has previously entered this study or has previously participated in a study with a sclerostin antibody product • Other investigational procedures are excluded • Malignancy except non-melanoma skin cancers, cervical or breast XML File Identifier: tGn+dfDjPJ4ntWh8RmhnMMjLt4E= Page 18/30 ductal carcinoma in situ within the last 5 years |
| 4.2.1 Strontium, fluoride (for osteoporosis), odanacatib (MK-0822): at any time 4.2.2 Intravenous (IV) bisphosphonates: dose received within 5 years prior to randomization 4.2.3 Oral bisphosphonates: • More than 3 years of cumulative use • Any dose received within 6 months prior to randomization More than 1 month of cumulative use between 6 and 12 months prior to randomization 4.2.4 Denosumab: dose received within 18 months prior to randomization 4.2.5 Teriparatide or any PTH analogs: dose received within 12 months prior to randomization 4.2.6 Systemic oral or transdermal estrogen, SERMs, or calcitonin: more than 1 month of cumulative use within 6 months prior to randomization 4.2.7 Androgen deprivation or hormonal ablation therapy: more than 1 month of cumulative use within 6 months prior to randomization 4.2.8 Tibolone or cinacalcet: dose received within 3 months prior to randomization 4.2.9 Systemic glucocorticosteroids: ≥ 5 mg prednisone equivalent per day for more than 10 days within 3 months prior to randomization 4.2.10 History of metabolic or bone disease (except osteoporosis) that may interfere with the interpretation of the results, such as Paget's disease, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, Cushing's disease, hyperprolactinemia, and malabsorption syndrome 4.2.11 History of solid organ or bone marrow transplants 4.2.12 Vitamin D insufficiency (defined as 25 (OH) vitamin D levels < 20 ng/mL as assessed by the central laboratory. Vitamin D repletion will be permitted and subjects may be rescreened once 4.2.13 Current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside the normal range, as assessed by the central laboratory 4.2.14 Current, uncontrolled hyper- or hypothyroidism, defined as thyroidstimulating hormone outside of the normal range, per subject report or chart review 4.2.15 Current, uncontrolled hyper- or hypoparathyroidism, defined as PTH outside the normal range, per subject report or chart review 4.2.16 Possible diagnosis of multiple myeloma or related myeloproliferative disorder, as assessed by serum protein electrophoresis performed by the local laboratory 4.2.17 Exclusion criteria related to contraindications or possible signs of intolerance to ALN; contraindications and potential signs of intolerance for ALN therapy include: • Hypocalcemia (as defined in 4.2.13) • Abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia • Inability to stand or sit upright for at least 30 minutes • Hypersensitivity to ALN or other constituents of ALN tablets • Increased risk of aspiration • Pregnancy and lactation • Other contraindications to ALN based on the country-specific product insert applicable to the specific study center • Significantly impaired renal function (as assessed by the central laboratory based on a derived creatinine clearance of < 35 mL/min using the Modification of Diet in Renal Disease. The estimated glomerular filtration rate is calculated as follows: estimated glomerular filtration rate (mL/min/1.73m2) = 175 x [Serum creatinine (mg/dL)]-1.154 x [Age]-0.203 x [0.742 if subject is female] x [1.210 if subject is black]. 4.2.18 General • Subject is currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s) • Subject has previously entered this study or has previously participated in a study with a sclerostin antibody product • Other investigational procedures are excluded • Malignancy except non-melanoma skin cancers, cervical or breast XML File Identifier: tGn+dfDjPJ4ntWh8RmhnMMjLt4E= Page 18/30 ductal carcinoma in situ within the last 5 years |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
During the overall study period (12-month double-blind ALN-controlled
study period followed by the open label ALN study period)
• Subject incidence of clinical fracture (nonvertebral fracture and clinical
vertebral fracture) at primary analysis
• Subject incidence of new vertebral fracture through Month 24 |
| Durante tutto il periodo dello studio (12 mesi in doppio cieco controllato da ALN seguito da un periodo in aperto con ALN) • Incidenza nei soggetti di fratture cliniche (frattura non vertebrale e frattura vertebrale clinica) all’analisi primaria • Incidenza nei soggetti di nuove fratture vertebrali fino al Mese 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| During the overall study period (12-month double-blind ALN-controlled study period followed by the open-label ALN study period) • Subject incidence of nonvertebral fracture at primary analysis • Subject incidence of all fractures (nonvertebral fracture and new vertebral fracture) at primary analysis • Subject incidence of new or worsening vertebral fracture through Month 24 • Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip) at primary analysis • Subject incidence of hip fracture at primary analysis • Subject incidence of multiple new or worsening vertebral fractures through Month 24 • Percent change from baseline in BMD at the lumbar spine, total hip, and femoral neck at Months 24 and 36 During the 12-month double-blind ALN-controlled study period • Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) through Month 12 • Subject incidence of new vertebral fracture through Month 12 • Subject incidence of all fractures (nonvertebral fracture and new vertebral fracture) through Month 12 • Percent change from baseline in BMD at the lumbar spine, total hip and femoral neck at Month 12 |
| Durante tutto il periodo dello studio (12 mesi in doppio cieco controllato da ALN seguito da un periodo in aperto con ALN) • Incidenza all’analisi primaria di fratture non vertebrali nei soggetti • Incidenza all’analisi primaria di tutte le fratture (frattura non vertebrale e nuova frattura vertebrale) nei soggetti • Incidenza nei soggetti di fratture vertebrali nuove o peggioramento di fratture vertebrali preesistenti fino al Mese 24 • Incidenza nei soggetti di fratture non vertebrali gravi (bacino, femore distale, tibia prossimale, costole, omero prossimale, avambraccio e anca) all’analisi primaria • Incidenza nei soggetti di fratture dell’anca all’analisi primaria • Incidenza nei soggetti di fratture vertebrali nuove o peggiorate multiple fino al Mese 24 • Variazioni percentuali dal baseline di BMD sulla spina lombare, l’anca totale e il collo femorale ai Mesi 24 e 36 Durante il periodo dello studio di 12 mesi in doppio cieco controllato da ALN • Incidenza nei soggetti di fratture cliniche (frattura non vertebrale e frattura vertebrale clinica) fino al Mese 12 • Incidenza nei soggetti di nuove fratture vertebrali fino al Mese 12 • Incidenza nei soggetti di tutte le fratture (frattura non vertebrale e nuova frattura vertebrale) fino al Mese 12 • Variazioni percentuali della BMD rispetto al basale nella colonna lombare, l’anca totale e il collo femorale al Mese 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Month 12 and 24 |
| mesi 12 e 24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Mexico |
| New Zealand |
| Peru |
| South Africa |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study (primary completion and end of trial) is defined as the
time when clinical fracture events (nonvertebral fracture or clinical
vertebral fracture) have been confirmed for at least 330 subjects but
not before all subjects have had the opportunity to complete the Month
24 visit. |
Fine di studio è definita come il
momento in cui gli eventi clinici di frattura non vertebrale (o clinica
fratture vertebrali) sono stati confermati in almeno 330 soggetti. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 35 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 35 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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