Multiple Sclerosis, Osteoporosis
Conditions
Keywords
Multiple Sclerosis, Osteoporosis, Zoledronic Acid
Brief summary
This study is designed to evaluate the efficacy and safety of zoledronic acid 5 mg intravenous (i.v.) relative to placebo in Multiple Sclerosis (MS) patients with osteoporosis and to support the optimal use of zoledronic acid for this indication. Primary objective is the change of Bone Mineral Density (BMD) at lumbar spine (L1-L4) and total hip region assessed by T-Score at month 12 relative to screening as measured by Dual X-ray Absorptiometry (DXA). This double-blind period will be followed by a 52-week open-label treatment phase to assess long-term efficacy and safety of zoledronic acid in these patients.
Interventions
DRUGZoledronic Acid
Zoledronic acid 5 mg once a year via intravenous infusion
DRUGPlacebo
Placebo to zoledronic acid once a year via intravenous infusion
DIETARY_SUPPLEMENTCalcium and Vitamin D combination
Calcium 500 mg and Vitamin D 400 IU combined tablet, taken orally twice a day
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: * Written informed consent to participate in the trial * Definite diagnosis of Multiple Sclerosis (MS) as defined by 2005 revised McDonald criteria * MS-subtype: Relapsing-remitting MS (RRMS), Secondary progressive MS (SPMS), Primary progressive MS (PPMS) * Expanded Disability Status Scale (Kurtzke's scale; EDSS) score between 2.5 to 6.5 (including both) * Bone mineral density (BMD) T-score of less or equal to -2.0 and more 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 Dual X-Ray Absorptiometry (DXA)-scan (\< or = 3 months) * Sufficient ability to read, write and communicate comprehensibly and comply to study procedures * No immunomodulatory treatment for MS within the last 30 days or stable and well tolerated therapy with any beta-interferon formulation, or glatirameracetate or fingolimod for at least 30 days immediately prior to baseline
Exclusion criteria
* Contraindications against Calcium and Vitamin D and zoledronic acid according to the summary product characteristics * More than one osteoporotic fracture * Concomitant medication with influence on bone mineral density (eg. enzyme- inducing antiepileptics like Carbamazepin, Phenytoin, Phenobarbital, Primidon) * Any neurological disorder other than MS which is known to affect bone mineral density (e.g. muscular dystrophy, severe paresis for other reasons than MS, degenerative nervous disorder, stroke) * Women who are pregnant or breast feeding, or menstruating and capable of becoming pregnant. * Baseline renal insufficiency * 25-OH vitamin D level \< 10 ng/ml at screening * Serum calcium levels \> 2.75 mmol/l (11.0 mg/dL) or \< 2.00 mmol/L (8.0 mg/dL) at screening * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Mineral Density of the Lumbar Spine at 12 Months | Screening (day -21 to -1) and month 12 | Change in bone mineral density (BMD) of the lumbar spine was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 12. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Change in Bone Mineral Density of the Total Hip Region at 12 Months | Screening (day -21 to -1) and month 12 | Change in bone mineral density (BMD) of the total hip region was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 12. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Mineral Density of the Total Hip at 6 Months | Screening (day -21 to -1) and month 6 | Change in bone mineral density (BMD) of the total hip was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 6. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Change in Bone Mineral Density of the Femoral Neck at 12 Months | Screening (day -21 to -1) and month 12 | Change in bone mineral density (BMD) of the femoral neck was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 12. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Change in Bone Mineral Density of the Lumbar Spine at 24 Months | Screening (day -21 to -1) and month 24 | Change in bone mineral density (BMD) of the lumbar spine was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 24. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Change in Bone Mineral Density of the Lumbar Spine at 6 Months | Screening (day -21 to -1) and month 6 | Change in bone mineral density (BMD) of the lumbar spine was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 6. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Change in Bone Mineral Density of the Femoral Neck at 24 Months | Screening (day -21 to -1) and month 24 | Change in bone mineral density (BMD) of the femoral neck was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 24. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Course of Disease in Multiple Sclerosis Patients | Screening (day -21 to -1) and month 12 | The course of disease in Multiple Sclerosis (MS) patients was measured comparing results from the Expanded Disability Status Scale (EDSS) from screening and month 12. EDSS is a scale, ranging from 0 (normal) to 10 (death due to MS) for assessing neurologic impairment in MS. It is based on a weighting scheme of eight functional systems. The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel&Bladder, Cerebral and Other functions. EDSS was assessed by the treating neurologist. |
| Adverse Events and Serious Adverse Events Comparison of Treatment Groups | 24 months | Adverse Events and Serious Adverse events are reported in the safety section. |
| Change in Bone Mineral Density of the Total Hip Region at 24 Months | Screening (day -21 to -1) and month 24 | Change in bone mineral density (BMD) of the total hip region was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 24. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
| Change in Bone Mineral Density of the Femoral Neck at 6 Months | Screening (day -21 to -1) and month 6 | Change in bone mineral density (BMD) of the femoral neck was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 6. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone. |
Countries
Germany
Participant flow
Recruitment details
168 participants were planned to be randomized. 29 participants were randomized in a 2:1 ratio (zoledronic acid : placebo); no participants completed the study. One participant withdrew consent and the study was terminated.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Participants received zoledronic acid infusion in addition to calcium and vitamin D | 21 |
| Placebo Participants received placebo to zoledronic acid infusion in addition to calcium and vitamin D | 8 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study was terminated | 20 | 8 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Zoledronic Acid | Placebo | Total |
|---|---|---|---|
| Age Continuous | 60.1 years STANDARD_DEVIATION 8 | 56.0 years STANDARD_DEVIATION 8.2 | 59.0 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 16 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 21 | 5 / 8 |
| serious Total, serious adverse events | 2 / 21 | 0 / 8 |
Outcome results
Primary
Change in Bone Mineral Density of the Lumbar Spine at 12 Months
Change in bone mineral density (BMD) of the lumbar spine was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 12. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 12
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Primary
Change in Bone Mineral Density of the Total Hip Region at 12 Months
Change in bone mineral density (BMD) of the total hip region was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 12. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 12
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Adverse Events and Serious Adverse Events Comparison of Treatment Groups
Adverse Events and Serious Adverse events are reported in the safety section.
Time frame: 24 months
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done. The sample size was not powered for comparison between groups; however, all AEs are reported in the safety section.
Secondary
Change in Bone Mineral Density of the Femoral Neck at 12 Months
Change in bone mineral density (BMD) of the femoral neck was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 12. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 12
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Change in Bone Mineral Density of the Femoral Neck at 24 Months
Change in bone mineral density (BMD) of the femoral neck was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 24. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 24
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Change in Bone Mineral Density of the Femoral Neck at 6 Months
Change in bone mineral density (BMD) of the femoral neck was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 6. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 6
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Change in Bone Mineral Density of the Lumbar Spine at 24 Months
Change in bone mineral density (BMD) of the lumbar spine was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 24. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 24
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Change in Bone Mineral Density of the Lumbar Spine at 6 Months
Change in bone mineral density (BMD) of the lumbar spine was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 6. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 6
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Change in Bone Mineral Density of the Total Hip at 6 Months
Change in bone mineral density (BMD) of the total hip was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 6. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 6
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Change in Bone Mineral Density of the Total Hip Region at 24 Months
Change in bone mineral density (BMD) of the total hip region was measured using Dual X-ray Absorptiometry (DXA) at screening and at month 24. A DXA scanner is a device that uses x-ray beams to measure the amount of minerals in the bone.
Time frame: Screening (day -21 to -1) and month 24
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.
Secondary
Course of Disease in Multiple Sclerosis Patients
The course of disease in Multiple Sclerosis (MS) patients was measured comparing results from the Expanded Disability Status Scale (EDSS) from screening and month 12. EDSS is a scale, ranging from 0 (normal) to 10 (death due to MS) for assessing neurologic impairment in MS. It is based on a weighting scheme of eight functional systems. The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel&Bladder, Cerebral and Other functions. EDSS was assessed by the treating neurologist.
Time frame: Screening (day -21 to -1) and month 12
Population: A total of 168 randomized participants were needed to have a power of 93% % to detect a significant difference in lumbar spine BMD. This study randomized 29 participants of the planned 168; hence, the planned analysis was not done.