E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
osteoporosis in patients with multiple sclerosis |
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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 | 10049088 |
E.1.2 | Term | Osteopenia |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 | 10031282 |
E.1.2 | Term | Osteoporosis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
To demonstrate that zoledronic acid has superior efficacy compared with placebo on the percent change of bone mineral density (BMD) as assessed by the T-score at lumbar spine and total hip region at month 12 relative to screening as measured by Dual X-ray Absorptiometry (DXA) in MS patients suffering from osteoporosis. |
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E.2.2 | Secondary objectives of the trial |
To further explore efficacy of zoledronic acid the following secondary outcomes will be evaluated
•change from baseline to month 6 of BMD at lumbar spine,total hip, and femoral neck as measured by DXA
•change from baseline to month 12 of BMD at femoral neck as measured by DXA
•change from baseline to end of study of BMD at lumbar spine, total hip, and femoral neck as measured by DXA
•To evaluate the effect of zoledronic acid vs. placebo on the course of disease in MS-
patients; the Expanded Disability Status Scale (EDSS) will be used at month 12
•To evaluate the effect of zoledronic acid vs. placebo on the number of new clinically evident fractures at month 12 and at the end of the additional 1 year open label phase
•To evaluate safety and tolerability of zoledronic acid versus placebo in MS-patients
•To evaluate safety and tolerability of zoledronic acid in MS patients at the end of the additional 1 year open label phase
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Written informed consent to participate in the trial
2) Males and Females between 18 and 75 years of age
3) Definite diagnosis of multiple sclerosis as defined by 2005 revised McDonald criteria (Appendix 3)
4) MS-subtype: RRMS, SPMS, PPMS
5) EDSS score between 2.5 to 6.5 (including)
6) No immunomodulatory treatment for MS within the last 30 days or stable and well tolerated therapy with any beta-interferon formulation, glatirameracetate or fingolimod for at least 30 days immediately prior to baseline.
7) BMD T-score of less or equal to -2.0 but not less or equal to -4.0 at the lumbar spine (L1-L4 with at least 2 evaluable vertebrae) and/or total hip region and/or femoral neck in recent DXA-scan (≤ 3 months). The DXA-scans for all assessments need to be performed with the same DXA-machine.
8) Previous participation in CZOL446HDE39
9) 25-OH vitamin D level greater or equal to 15 ng/ml
10) Sufficient ability to read, write and communicate comprehensibly and comply to study procedures
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E.4 | Principal exclusion criteria |
1) Contraindications against Calcium and Vitamin D according to the summary product characteristics
2) Contraindications against zoledronic acid according to the summary of product characteristics
3) Hypersensitivity to bisphosphonates, Calcium and Vitamin D or to drugs with similar chemical structures
4) More than one osteoporotic fracture
5) Severe disability or any clinical impairment that can prevent the patient to meet all study requirements
6) Concomitant medication with influence on bone mineral density (eg. enzyme-inducing antiepileptics like Carbamazepin, Phenytoin, Phenobarbital, Primidon)
7) Any neurological disorder other than MS which is known to affect bone mineral density (e.g. muscular dystrophy, severe paresis due to other reasons than MS, degenerative nervous disorder, stroke)
8) Any bone disorder other than osteoporosis known to affect bone mineral density (e.g. paget´s disease, osteogenesis imperfecta, multiple myeloma)
9) Study personnel or first degree relatives of investigator(s) must not be included in the study.
10) Women who are
- pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mlU/ml)).
- menstruating and capable of becoming pregnant* and not practicing two medically approved methods of contraception (Pearl Index < 1**) during and up to at least one year after the end of treatment. A negative pregnancy test (serum) for all women is required with sufficient lead time before inclusion.
*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH level > 40 mlU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy
**examples of particularly reliable methods with Pearl Index (PI) < 1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe:
• Combination pill with estrogen and gestagen (no minipill, PI=0.1-0.9)
• Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.)
• Contraceptive patch (EVRA®, PI=0.72 uncorr.; 0.9 corr.)
• Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14)
• Progestin-containing contraceptives (Implanon®, PI=0-0.08)
• Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
• Intra-uterine progestine device (Mirena®, PI=0.16)
11) Baseline renal insufficiency (calculated creatinine clearance less than 35.0 mL/min); Urine dipstick greater than or equal to 2+ protein at Visit 1 without evidence of contamination or bacteriuria (may be repeated one time at least a week apart if there is suspicion of contamination).
12) Pre-existing hypocalcemia ≤ 2.0 mmol/L (8.0 mg/dL) not adequately treated by intake of calcium and vitamin D before baseline
13) Use of testosterone therapy within one year prior to randomization
14) Use of systemic corticosteroids (oral or i.v.) in the last year with more than 7.5 mg/day prednisolone (or equivalent) continuously for more than four weeks.
NOTE: Use of corticosteroids in forms such as topical creams, nasal or inhaled formulations or those injected locally (eg. intra-articularly, ocular, intrsthecal) or pulsed therapy for MS-relapses are NOT exclusionary.
15) Prior exposure to anabolic steroids or growth hormone within 6 months prior to randomization
16) Treatment with any investigational drug(s) and/or devices within 30 days prior to randomization.
17) Treatment with any other immunomodulatory drug(s) than beta-interferon formulations within 3 months prior to randomization.
18) Active history of iritis, uveitis or episcleritis
19) History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases with the exception of localized basal cell carcinoma of the skin.
20) Any disease of the spine that would preclude the proper acquisition of the spine DXA-scans (L1-L4) e.g., implantable devices, scoliosis, ankylosing spondylitis. Patients with less than 2 evaluable vertebrae in the region of interest (ROI) L1-L4 will not be considered eligible for this study.
21) Spine (L1-L4) and bilateral hip surgery, that interfere with the DXA measurements (e.g. bilateral hip replacement)
22) History of nephrocalcinosis
23) Any kind of tooth extraction during the last 3 months or surgery of the jaw during the last 6 month before inclusion in the study
24) Any kind of jaw bone disease or infection, that may necessitate oral surgery during the course of the study
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E.5 End points |
E.5.1 | Primary end point(s) |
The co-primary endpoints are the change in bone mineral density as measured by the T-score from the DXA of lumbar spine and total hip total region (baseline to week 53). The DXA is a widely used measure of bone mineral density. |
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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 | Yes |
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 | 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) | No |
E.8.2.2 | Placebo | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |