E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Postmenopausal women with established osteoporosis and at least two moderate or one severe prevalent fragility fracture. |
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E.1.1.1 | Medical condition in easily understood language |
Postmenopausal women with severe osteoporosis and presence of fracture in spine |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10031288 |
E.1.2 | Term | Osteoporosis with fracture |
E.1.2 | System Organ Class | 100000004859 |
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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 |
The primary objective of this study is to evaluate if teriparatide 20 μg subcutaneously once daily is superior in reducing the incidence of new vertebral fractures during 24 months of therapy, when compared with risedronate 35 mg orally once weekly, in postmenopausal women with prevalent vertebral fragility fractures. |
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E.2.2 | Secondary objectives of the trial |
The key secondary objectives of this study are to evaluate if teriparatide 20 μg/day is superior in reducing the incidence of the following key outcomes during 24 months of therapy, when compared with risedronate 35 mg/week:
1. Incidence of pooled new and worsening vertebral fractures.
2. Incidence of pooled clinical fractures.
3. Incidence of non-vertebral fragility fractures.
4. Incidence of major non-vertebral fragility fractures: hip, radius, humerus, ribs, pelvis and ankle. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] Postmenopausal women ≥ 45 years of age at the time of entry into the trial, whose last menstrual period occurred at least 2 years prior to entry into the trial, and are sufficiently mobile to complete study visits. Women < 55 years of age in whom a bilateral oophorectomy cannot clearly be documented must
have their postmenopausal status confirmed by a serum FSH level > 40 IU/L and serum estradiol level < 20 pg/mL or < 73 pmol/L.
[2] A minimum of 2 moderate (SQ2) or 1 severe (SQ3) vertebral fragility fractures, confirmed by the central reader.
[3] AP lumbar spine or total hip or femoral neck BMD ≥ 1.5 SD below the average BMD for young healthy, non-Hispanic, Caucasian women (T-score ≤ –1.5 SD). Absolute BMD values will be applied to determine patient eligibility.
[4] Without language barrier, cooperative, able to come to the clinic for all follow-up visits; has given informed consent before entering the study and after being informed of the medications and procedures to be used in this study.
[5] In the opinion of the investigator, is willing to be trained and to use the pen injector daily, is able to satisfactorily use a pen-type injection delivery system, or is willing to receive daily subcutaneous injections from a caregiver who has been trained to use the pen injector.
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E.4 | Principal exclusion criteria |
[6] Increased baseline risk of osteosarcoma. This includes patients with Paget’s disease of the bone, previous primary skeletal malignancy, or skeletal exposure to therapeutic irradiation. As elevation of serum alkaline phosphatase activity may indicate the presence of Paget’s disease, an unexplained elevation of this enzyme activity will also be exclusionary.
[7] History of unresolved skeletal diseases that affect bone metabolism, other than osteoporosis, including renal osteodystrophy, osteomalacia, hyperparathyroidism
(uncorrected), hypoparathyroidism, and intestinal
malabsorption.
[8] Abnormally elevated values of serum albumin-corrected calcium levels at baseline, defined as ≥ 10.6 mg/dL (or ≥ 2.65 mmol/L). In cases with borderline non-eligible values (≥ 10.6 and ≤ 10.7 mg/dL), a re-test would be allowed during the screening period.
[9] Abnormally low values of serum albumin- corrected calcium levels at baseline, defined as < 8.0 mg/dL (or < 2.0 mmol/L). In cases with borderline non-eligible values (> 7.8 to < 8.0 mg/dL), a re-test would be allowed during the screening period to allow normalization with vitamin D and calcium supplements before the randomization visit.
[10] Abnormally elevated values of serum intact PTH(1-84) at baseline defined as > 72 pg/mL (or > 7.6 pmol/L).
[11] Severe vitamin D deficiency at baseline defined as 25-hydroxy-vitamin D levels < 9.2 ng/mL (or < 23 nmol/L). In cases with borderline non-eligible values (> 8.0 and < 9.2 ng/mL), a re-test would be allowed during the screening period to allow normalization with vitamin D supplement before the randomization visit.
[12] Abnormal thyroid function not corrected by therapy. Patients with subclinical hyperthyroidism or hypothyroidism, defined as abnormally low or high TSH values respectively, with normal fT4 values are eligible to participate in the study.
[13] History of malignant neoplasms in the 5 years prior to Visit 2, with the exception of superficial basal cell or squamous cell carcinomas of the skin that have been definitively treated. Patients with carcinoma in situ of the uterine cervix treated definitively more than 1 year prior to entry into the study may
be randomized. Patients with multiple myeloma or metastases to bone are excluded.
[14] Active liver disease or clinical jaundice. Significantly impaired hepatic function, defined as AST > 75 U/L or ALT > 75 U/L or GGT > 300 U/L.
[15] Significantly impaired renal function as defined by a calculated endogenous creatinine clearance (ClCr) < 30 mL/min using the following Cockcroft-Gault formula for ClCr.
[16] History of nephrolithiasis or urolithiasis within 1 year prior to Visit 2.
[17] Considered imminent candidates for kyphoplasty or vertebroplasty before Visit 2.
[18] Patients who have been treated with kyphoplasty or vertebroplasty at 3 or more levels before Visit 2, regardless of the time since the last procedure.
[19] Patients who have been treated with kyphoplasty or vertebroplasty within the last 6 months before Visit 2.
[20] Patients with history of osteonecrosis of the jaw or who are, according to the clinical judgment of the investigator, at high risk to develop osteonecrosis of the jaw, including poor oral hygiene, scheduled invasive dental procedures, high doses of bisphosphonates and/or chemotherapy to treat malignancy.
[21] Patients with history of atypical subtrochanteric or diaphyseal femoral fractures, according to the diagnostic criteria of the American Society for Bone and Mineral Research Task Force .
[22] Active or recent history of significant upper gastrointestinal disorders, such as esophageal disorders which delay esophageal transit or emptying (e.g. stricture or achalasia).
[23] Unable to stand or sit in the upright position for at least 30 minutes.
[26] Previous treatment with the following bone active drugs is allowed but treatment must be discontinued at Visit 1 or at the time indicated below:
Oral bisphosphonates (including alendronate, risedronate, ibandronate, etidronate).
SERMs, calcitonin, estrogen (oral, transdermal, or injectable), progestin, estrogen analog, estrogen agonist, estrogen antagonist or tibolone, androgens, strontium ranelate, or active vitamin D3 analogues.
Intravenous zoledronate, if the last dose was administered at least 12 months before Visit 1.
Intravenous ibandronate or pamidronate, if the last dose was administered at least 3 months before Visit 1.
Subcutaneous denosumab, if the last dose was administered at least 6 months before Visit 1.
Fluoride unless given at therapeutic doses (> 20 mg/day) for more than 3 months in the 2 years prior to Visit 1, or for more than a total of 2 years, or at any dosages within the 6 months prior to Visit 2 (previous or current use of fluoridated water or topical dental fluoride treatment is permitted). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of new vertebral fractures |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the 24-month treatment phase |
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E.5.2 | Secondary end point(s) |
Key secondary fracture endpoints :
Incidence of pooled new and worsening vertebral fractures.
Incidence of pooled clinical fractures.
Incidence of non-vertebral fragility fractures.
Incidence of major non-vertebral fragility fractures: hip, radius, humerus, ribs, pelvis, and ankle.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the 24-month treatment phase |
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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 | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
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 | 2 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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 |
Austria |
Belgium |
Brazil |
Canada |
Czech Republic |
Germany |
Greece |
Hungary |
Italy |
Poland |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |