| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 main objective of this study is to compare the bone formation activity, measured by the mineralization surface (MS%BS), in iliac crest bone biopsies from postmenopausal women with osteoporosis following 6 months of treatment with teriparatide 20 µg/day plus elemental calcium and Vitamin D, to that following strontium ranelate 2 g/day plus elemental calcium and Vitamin D. |
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| E.2.2 | Secondary objectives of the trial |
·Other dynamic histomorphometric parameters of bone formation and resorption.
·Structural (static) parameters of cortical and trabecular bone.
·Biochemical markers of bone turnover including markers of bone formation: serum aminoterminal propeptide of type I procollagen [P1NP], bone-specific alkaline phosphatase [BSAP], and bone resorption: serum type I collagen degradation fragments (ß-CTx).
·Safety as determined by absence of primary mineralization defects, woven bone, and other histological anomalies, and other histological anomalies, and clinical adverse events reports.
An additional exploratory objective of this study will be:
·To examine the relationship between biochemical markers at 1, 3 and 6 months and the histomorphometric parameters following 6 months of therapy with teriparatide or strontium ranelate. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Ambulatory, postmenopausal women aged 45 to 90 years inclusive at the time of entry into the trial, whose last menstrual period or bilateral oophorectomy occurred at least 5 years prior to entry into the trial. Women below the age of 55 years in whom a bilateral oophorectomy cannot clearly be documented must have their postmenopausal status confirmed by a serum FSH level ≥30 IU/L and serum estradiol level ≤20 pg/ml or ≤73 pmol/L.
[2] Free of severe or chronically disabling conditions other than osteoporosis.
[3] Able to use a pen-type injection delivery system satisfactorily in the opinion of the investigator and willing to be trained on and use the pen-injector on a daily basis.
[4] Without language barrier, cooperative, expected to return for all follow-up procedures, and have given informed consent after being informed of the risks, medications, and procedures to be used in the study.
[5] Posterior-anterior lumbar spine (L-1 through L-4) BMD and/or femoral neck BMD and/or total hip BMD measurement at least 2.5 standard deviations (SD) below the average bone mass for young women (T-score equal or below to -2.5 standard deviations).
The lumbar spine and hip BMD assessment and the determination of the patient’s eligibility for entry into the screening phase will be made by the individual investigator. Any lumbar vertebra that cannot be analyzed due to artifacts, severe crush fracture, osteophytes, or other abnormalities, should be excluded from the analysis. A minimum of two lumbar vertebrae in the L-1 through L-4 region must be evaluable by DXA if this is the only anatomical site where the BMD cut-off level <-2.5 SD is demonstrated. A DXA assessment performed within three months prior to Visit 1 may be acceptable for patient´s eligibility.
[6] Normal or clinically insignificant abnormal laboratory values (as defined by the investigator) including serum calcium, PTH(1-84), alkaline phosphatase.
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| E.4 | Principal exclusion criteria |
[7]History of unresolved skeletal diseases that affect bone metabolism other than postmenopausal osteoporosis including Paget's disease, renal osteodystrophy, osteomalacia, any secondary causes of osteoporosis, hyperparathyroidism (uncorrected), and intestinal malabsorption.
[8]In the opinion of the investigator, have any medical or anatomical condition that potentially could put the patient at additional risk of an adverse event due to the biopsy procedure (for example, coagulation abnormality, anticoagulant medication, extreme obesity, etc).
[9]Have undergone two previous transiliac bone biopsies (one in each iliac crest). Patients with one previous transiliac bone biopsy are eligible provided that the new sample is obtained from the contralateral iliac crest.
[10]History of malignant neoplasms in the 5 years prior to Visit 1, with the exception of superficial basal cell carcinoma or squamous cell carcinoma of the skin that has 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.
[11]Increased baseline risk of osteosarcoma; this includes subjects with Paget’s disease of the bone, previous primary skeletal malignancy, or skeletal exposure to therapeutic irradiation, i.e. prior external beam or implant radiation therapy. As an elevation of serum skeletal alkaline phosphatase activity may indicate the presence of Paget’s disease, an unexplained elevation of this enzyme activity will also be exclusionary.
[12]Abnormal thyroid function not corrected by therapy. Normal thyroid function may be documented by a normal TSH during the screening phase or a combination of clinical and biochemical parameters which, in the judgment of the investigator and the Lilly Clinical Research Physician, sufficiently establishes the presence of normal thyroid function.
[13]Active liver disease or clinical jaundice.
[14]Significantly impaired renal function as defined by either of the following criteria:Serum creatinine that, in the opinion of the investigator, indicates significant renal impairment / Measured or calculated endogenous creatinine clearance <30 mL/min using the Cockcroft-Gault formula for creatinine clearance
[15]Women who do not qualify for therapy according to the prescribing information for strontium ranelate, including patients with increased risk or past history of venous thromboembolism, and phenylketonuria.
[16]History of excessive consumption of alcohol or abuse of drugs in the 1 year prior to Visit 2 in the opinion of the investigator.
[17]Poor medical or psychiatric risk for treatment with an investigational drug in the opinion of the investigator.
[18]Current or past treatment with any bisphosphonate, parathyroid hormone or its analogs, androgens or other anabolic steroids or therapeutic doses of fluorides at any time prior to Visit 2.
Past treatment (more than 12 months before Visit 2) with a selective estrogen receptor modulator (SERM), nasal or injectable calcitonin, oral, transdermal, or injectable estrogens, progestins, estrogen analogs, estrogen agonists, estrogen antagonists or tibolone is allowed. Previous or current use of fluoridated water or topical dental fluoride treatments are permitted.
[19]Treatment with Vitamin D >50,000 IU/week, or with any dose of calcitriol or Vitamin D analogs or agonists in the 6 months prior to Visit 2.
[20]Treatment with systemic corticosteroids in the last month prior to Visit 2 or for more than 14 days in the 1 year prior to Visit 2. Ophthalmic, otic, topical, orally inhaled, nasally inhaled, or intra-articular corticosteroid therapy may be used without these restrictions. However, orally inhaled or nasally inhaled corticosteroids in doses >840 mg/day beclomethasone dipropionate or equivalent for more than 14 days in the last year prior to randomization will be disqualifying.
[21]Treatment in the 6 months prior to Visit 2 with any other drug believed by the investigator to significantly affect bone metabolism.
[22]Known allergy to teriparatide, any diluents or excipients of teriparatide, or to any other form of PTH or PTH analog. Known or suspected incompatibility or hypersensitivity to strontium ranelate.
[23]Allergy or other i tolerance to tetracycline that would preclude its administration in conjunction with the bone biopsy procedures. If the patient is not allergic to all tetracyclines, then this exclusion may be waived by the sponsor and a different tetracycline to which the patient is not allergic may be used.
[24]Prior participation in any other clinical trial studying teriparatide or strontium ranelate or prior treatment with PTH, PTH analog or strontium ranelate. Previous withdrawal from this study or withdrawal from any other studies which involved teriparatide or strontium ranelate.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy end point is measurement of Mineralization surface (MS%BS) evaluated in double tetracycline stained bone biopsies.
Mineralization surface (MS%BS) reflects the percentage of cancellous surface that is being actively mineralized, i.e. the proportion of the cancellous surface covered by newly formed osteoid. The most accurate calculation of MS%BS is dividing the area of double-label surfaces plus one-half the area of single-label surfaces by the total bone surface area.
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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 | 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 | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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