Zoledronic Acid in MS-patients With Osteoporosis (EXALT)

A 1-year, Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy of Zoledronic Acid 5 mg (Aclasta®) on Bone Mineral Density in Patients With Multiple Sclerosis Followed by a 1-year Open-label Treatment Phase

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.

Study Overview

• Status: Terminated
• Conditions: Multiple Sclerosis; Osteoporosis
• Intervention / Treatment: Drug: Zoledronic Acid; Dietary supplement: Calcium and Vitamin D combination; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Bamberg, Germany
    • Novartis Investigative Site
  • Berlin, Germany
    • Novartis Investigative Site
  • Bochum, Germany
    • Novartis Investigative Site
  • Hamburg, Germany
    • Novartis Investigative Site
  • Heidelberg, Germany
    • Novartis Investigative Site
  • Kassel, Germany
    • Novartis Investigative Site
  • Leipzig, Germany
    • Novartis Investigative Site
  • Leverkusen, Germany
    • Novartis Investigative Site
  • Ludwigshafen, Germany
    • Novartis Investigative Site
  • Magdeburg, Germany
    • Novartis Investigative Site
  • Muenchen, Germany
    • Novartis Investigative Site
  • Numbrecht, Germany
    • Novartis Investigative Site
  • Oldenburg, Germany
    • Novartis Investigative Site
  • Siegen, Germany
    • Novartis Investigative Site
  • Stade, Germany
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Zoledronic Acid; Participants received zoledronic acid infusion in addition to calcium and vitamin D	Drug: Zoledronic Acid; Zoledronic acid 5 mg once a year via intravenous infusion; Dietary supplement: Calcium and Vitamin D combination; Calcium 500 mg and Vitamin D 400 IU combined tablet, taken orally twice a day
PLACEBO_COMPARATOR: Placebo; Participants received placebo to zoledronic acid infusion in addition to calcium and vitamin D	Dietary supplement: Calcium and Vitamin D combination; Calcium 500 mg and Vitamin D 400 IU combined tablet, taken orally twice a day; Drug: Placebo; Placebo to zoledronic acid once a year via intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Screening (day -21 to -1) and month 12
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.	Screening (day -21 to -1) and month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Screening (day -21 to -1) and month 6
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.	Screening (day -21 to -1) and month 6
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.	Screening (day -21 to -1) and month 6
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.	Screening (day -21 to -1) and month 12
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.	Screening (day -21 to -1) and month 24
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.	Screening (day -21 to -1) and month 24
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.	Screening (day -21 to -1) and month 24
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.	Screening (day -21 to -1) and month 12
Adverse Events and Serious Adverse Events Comparison of Treatment Groups	Adverse Events and Serious Adverse events are reported in the safety section.	24 months

Collaborators and Investigators

• Sponsor: Novartis

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): June 1, 2012
• Study Completion (ACTUAL): June 1, 2012

Study Registration Dates

• First Submitted: July 19, 2010
• First Submitted That Met QC Criteria: July 19, 2010
• First Posted (ESTIMATE): July 20, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): November 26, 2013
• Last Update Submitted That Met QC Criteria: October 24, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Osteoporosis; Zoledronic Acid
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Multiple Sclerosis; Sclerosis; Osteoporosis; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Calcium; Zoledronic Acid
• Other Study ID Numbers: CZOL446HDE40; 2009-011888-37 (EUDRACT_NUMBER)