Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children

Children with Osteogenesis Imperfecta (OI) have bone pain, low bone mass and fractures. There are no approved drugs for the treatment of OI in children, even though some intravenous (IV) bisphosphonates are used off-label in some countries. In a single dose, pharmacokinetic study, data showed that risedronate was well tolerated in 28 children with OI. This three year study will test the safety and efficacy of risedronate in the treatment of children with OI. For the first year, patients will be randomized to the risedronate and placebo groups in a 2:1 ratio. For the second and third years of the study, all patients will receive risedronate.

Study Overview

• Status: Completed
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Drug: Placebo; Drug: risedronate sodium (Actonel)

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Perth, Australia
    • Princess Margaret Hospital for Children
  • New South Wales
    • Westmead, New South Wales, Australia
      • The Children's Hospital at Westmead
• Belgium
  • Bruxelles, Belgium
    • Cliniques Universitaires Saint Luc
• Chile
  • Santiago, Chile
    • Pontificia Universidad Catolica de Chile
• Czech Republic
  • Plzen, Czech Republic
    • Osteocentrum, II. Interní klinika, Fakultní nemocnice Plzeň-Bory
• Finland
  • Helsinki, Finland
    • Hospital for Children and Adolescents
• Germany
  • Koln, Germany
    • Klinikum und Poliklinik für Kinderheilkunde der Universität zu Köln
• Hungary
  • Budapest, Hungary
    • 2nd Department of Pediatrics, Semmelwies University, Faculty of Medicine
• Italy
  • Valeggio sul Mincio, Italy
    • Rheumatologic Rehabilitation Unit of the University of Verona
• Poland
  • Warzawa-Międzylesie, Poland
    • Zaklad Biochemii i Medycyny Doswiadczalnej (Biochemisty Dept, Institute "Monument-Children Health Centre"
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa
      • Little Company of Mary Hospital
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Deu
• United Kingdom
  • Bristol, United Kingdom
    • Bristol Royal Hospital for Children,
  • Glasgow, United Kingdom, G3 8SJ
    • Royal Hospital for Sick Children
  • Sheffield, United Kingdom, S210 2TH
    • Sheffield Children's Hospital
• United States
  • Florida
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • University of Nebraska Medical Center, Children's Hospital
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
  • Ohio
    • Dayton, Ohio, United States, 45409
      • Wright State University BioMedical Imaging Laboratory and Miami Valley Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• OI diagnosis
• increased risk of fracture: either has a history of at least 1 radiographically confirmed, non-traumatic or low impact fracture plus low bone mineral density (BMD) or has very low BMD with or without a history of fractures.

Exclusion Criteria:

• Any bisphosphonate use within one year of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Daily; placebo tablet, once a day for one year then for two years open label risedronate	Drug: Placebo; placebo tablet once a day for one year followed by risedronate once a day for two years
Experimental: Risedronate Daily; risedronate tablet, once a day for one year then for two years open label risedronate once a day	Drug: risedronate sodium (Actonel); risedronate tablet once a day for one year followed by risedronate once a day for two years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline Lumbar Spine Bone Mineral Density (BMD) at Month 12, ITT Population	Lumbar Spine Bone Mineral Density (BMD) measured by dual-energy x-ray absorptiometry (DXA)and read by central reader. Duplicate scans obtained at screening and Month 12.	Baseline and Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline Lumbar Spine Bone Mineral Density (BMD) at Month 24, ITT Population	Lumbar Spine Bone Mineral Density (BMD) measured by dual-energy x-ray absorptiometry (DXA)and read by central reader.	Baseline and Month 24
Percent Change From Baseline Lumbar Spine Bone Mineral Density (BMD) at Month 36, ITT Population	Lumbar Spine Bone Mineral Density (BMD) measured by dual-energy x-ray absorptiometry (DXA)and read by central reader.	Baseline and Month 36
Percent Change From Baseline in Total Body BMD at Month 12, ITT Population	Percent Change from baseline in Total Body Bone Mineral Density (BMD) measured by DXA.	Baseline and Month 12
Percent Change From Baseline in Total Body BMD at Month 24, ITT Population	Percent Change from baseline in Total Body Bone Mineral Density (BMD) measured by DXA.	Baseline and Month 24
Percent Change From Baseline in Total Body BMD at Month 36, ITT Population	Percent Change from baseline in Total Body Bone Mineral Density (BMD) measured by DXA.	Baseline and Month 36
Percent Change From Baseline in Lumbar Spine BMC (Bone Mineral Content) at Month 12, ITT Population		Baseline and Month 12
Percent Change From Baseline in Lumbar Spine BMC (Bone Mineral Content) at Month 24, ITT Population		Baseline and Month 24
Percent Change From Baseline in Lumbar Spine BMC (Bone Mineral Content) at Month 36, ITT Population		Baseline and Month 36
Percent Change From Baseline in Total Body BMC at Month 12, ITT Population		Baseline and Month 12
Percent Change From Baseline in Total Body BMC at Month 24, ITT Population		Baseline and Month 24
Percent Change From Baseline in Total Body BMC at Month 36, ITT Population		Baseline and Month 36
Lumbar Spine Z-score - Percent Change From Baseline to Month 12, ITT Population	Lumbar Spine Z-score - number of standard deviations a patient's BMD differs from the average BMD of their age, sex, and ethnicity. Positive scores indicate BMD above the mean; Positive values are "best values" and negative values are "worst values".	Baseline and Month 12
Lumbar Spine Z-score - Percent Change From Baseline to Month 24, ITT Population	Lumbar Spine Z-score - number of standard deviations a patient's BMD differs from the average BMD of their age, sex, and ethnicity. Positive scores indicate BMD above the mean; Positive values are "best values" and negative values are "worst values".	Baseline and Month 24
Lumbar Spine Z-score - Percent Change From Baseline to Month 36, ITT Population	Lumbar Spine Z-score - number of standard deviations a patient's BMD differs from the average BMD of their age, sex, and ethnicity. Positive scores indicate BMD above the mean; Positive values are "best values" and negative values are "worst values".	Baseline and Month 36
Total Body Z-score- Percent Change From Baseline to Month 12, ITT Population	Total Body Z-score - number of standard deviations a patient's BMD differs from the average BMD of their age, sex, and ethnicity. Positive scores indicate BMD above the mean; Positive values are "best values" and negative values are "worst values".	Baseline and Month 12
Total Body Z-score- Percent Change From Baseline to Month 24, ITT Population	Total Body Z-score - number of standard deviations a patient's BMD differs from the average BMD of their age, sex, and ethnicity. Positive scores indicate BMD above the mean; Positive values are "best values" and negative values are "worst values".	Baseline and Month 24
Total Body Z-score- Percent Change From Baseline to Month 36, ITT Population	Total Body Z-score - number of standard deviations a patient's BMD differs from the average BMD of their age, sex, and ethnicity. Positive scores indicate BMD above the mean; Positive values are "best values" and negative values are "worst values".	Baseline and Month 36
Percent Change From Baseline in Lumbar Spine Bone Area at Month 12, ITT Population	Measured by DXA.	Baseline and Month 12
Percent Change From Baseline in Lumbar Spine Bone Area at Month 24, ITT Population	Measured by DXA.	Baseline and Month 24
Percent Change From Baseline in Lumbar Spine Bone Area at Month 36, ITT Population	Measured by DXA.	Baseline and Month 36
Percent Change From Baseline in Total Body Bone Area Month 12, ITT Population		Baseline and Month 12
Percent Change From Baseline in Total Body Bone Area Month 24, ITT Population		Baseline and Month 24
Percent Change From Baseline in Total Body Bone Area Month 36, ITT Population		Baseline and Month 36
New Morphometric Vertebral Fracture at Month 12, ITT Population	Morphometric Vertebral Fracture measured by semi-quantitative (SQ) analysis of x-rays using the Genant scoring system at endpoint. (Ref: Genant 1993). SQ-Scores range from 0 (no fracture) to 3 (severe fracture). New fracture = SQ score is 0 at baseline and >0 at the specified end visit.	Baseline and Month 12
New Morphometric Vertebral Fracture at Month 36, ITT Population	Morphometric Vertebral Fracture measured by SQ analysis of x-rays using the Genant scoring system. (Ref: Genant 1993). SQ-Scores range from 0 (no fracture) to 3 (severe fracture). New fracture = SQ score is 0 at baseline and >0 at the specified end visit.	Baseline and Month 36
Categorization by Number of New Morphometric Vertebral Fracture at Month 12, ITT	Patients with 1 or more New Morphometric Vertebral Fracture as measured by SQ analysis of x-rays using the Genant scoring system (Ref: Genant 1993). SQ-Scores range from 0 (no fracture) to 3 (severe fracture). Incidence = SQ score is 0 at baseline and >0 at post-baseline.	Baseline and Month 12
Categorization by Number of New Morphometric Vertebral Fracture at Month 36, ITT	Patients with 1 or more New Morphometric Vertebral Fracture as measured by SQ analysis of x-rays using the Genant scoring system (Ref: Genant 1993). SQ-Scores range from 0 (no fracture) to 3 (severe fracture). Incidence = SQ score is 0 at baseline and >0 at post-baseline.	Baseline and Month 36
Incidence New Vertebral Fractures by SQ (Semi-Quantitative) Score, Patients Aged 4-9 Years, Month 12, ITT Population	Patients aged 4-9 years with new morphometric vertebral fractures as measured by SQ analysis of x-rays using the Genant scoring system at Month 12 +/- 14 days. (Ref: Genant 1993). SQ Score mild - 0/no fracture to Grade 1, Moderate to Severe - change from 0/no fracture to Grade 2-3.	Month 12
Incidence New Vertebral Fractures by SQ Score, Patients Aged 10-15 Years, Month 12, ITT Population	Patients aged 10-15 years with new morphometric vertebral fractures as measured by SQ analysis of x-rays using the Genant scoring system at Month 12 +/- 14 days. (Ref: Genant 1993). SQ Score mild - 0/no fracture to Grade 1, Moderate to Severe - change from 0/no fracture to Grade 2-3.	Month 12
Probability of Fracture in 12 Months (Kaplan-Meier Cumulative Incidence), ITT Population	Long bones include radius, ulna, humerus, tibia, fibula, femur, upper limb and lower limb fracture.	Time to First Event (days) up to 12 Months
Number of Clinical Fractures, Month 12, ITT Population	Long bones include radius, ulna, humerus, tibia, fibula, femur, upper limb and lower limb fracture.	12 Months
Serum BAP - Percent Change From Baseline to Month 12, ITT Population	Serum Bone Alkaline Phosphatase (BAP - bone formation marker). Negative percent changes indicate response to treatment.	Baseline and 12 Months
Serum BAP - Percent Change From Baseline to Month 24, ITT Population	Serum Bone Alkaline Phosphatase (BAP - bone formation marker). Negative percent changes indicate response to treatment.	Baseline and 24 Months
Serum BAP - Percent Change From Baseline to Month 36, ITT Population	Serum Bone Alkaline Phosphatase (BAP - bone formation marker). Negative percent changes indicate response to treatment.	Baseline and 36 Months
Urine NTX/Cr - Percent Change From Baseline at Month 12, ITT Population	Urine type-I collagen N-telopeptide/creatinine (NTX/Cr; bone resorption marker). Negative percent changes indicate response to treatment.	Baseline and Endpoint / Month 12
Urine NTX/Cr - Percent Change From Baseline at Month 24, ITT Population	Urine type-I collagen N-telopeptide/creatinine (NTX/Cr; bone resorption marker). Negative percent changes indicate response to treatment.	Baseline and Month 24
Urine NTX/Cr - Percent Change From Baseline at Month 36, ITT Population	Urine type-I collagen N-telopeptide/creatinine (NTX/Cr; bone resorption marker). Negative percent changes indicate response to treatment.	Baseline and Month 36
Wong-Baker FACES Pain Rating Scale - Change From Baseline to Month 12, ITT Population	Wong-Baker FACES Pain Rating Scale (pain assessment scale using facial expressions, translated into a range from 0= no pain [smiling face] to 10= worst pain possible [distorted face with tears]; negative values indicate decrease in pain). Reference: Wong DL et al.	Baseline and Month 12
Bone Age (Years), Change From Baseline to Month 12, ITT Population	Bone Age determined by visual assessment of hand / wrist radiographs.	Baseline and Month 12
Bone Age (Years), Change From Baseline to Month 24, ITT Population	Bone Age determined by visual assessment of hand / wrist radiographs.	Baseline and Month 24
Bone Age (Years), Change From Baseline to Month 36, ITT Population	Bone Age determined by visual assessment of hand / wrist radiographs.	Baseline and Month 36
Annualized Growth Velocity - Change From Baseline to Month 12, ITT Population	Annualized Growth Velocity [= bone age change from baseline x (365.25/time in days between baseline and the bone age measurement)]	Baseline and Month 12
Annualized Growth Velocity - Change From Baseline to Month 36, ITT Population	Annualized Growth Velocity [= bone age change from baseline x (365.25/time in days between baseline and the bone age measurement)]	Baseline and Month 36

Collaborators and Investigators

• Sponsor: Warner Chilcott
• Investigators: Study Director: Dietrich H Wenderoth, MD, Procter and Gamble

Publications and helpful links

General Publications

• Bishop N, Adami S, Ahmed SF, Anton J, Arundel P, Burren CP, Devogelaer JP, Hangartner T, Hosszu E, Lane JM, Lorenc R, Makitie O, Munns CF, Paredes A, Pavlov H, Plotkin H, Raggio CL, Reyes ML, Schoenau E, Semler O, Sillence DO, Steiner RD. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Oct 26;382(9902):1424-32. doi: 10.1016/S0140-6736(13)61091-0. Epub 2013 Aug 6.

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: March 18, 2005
• First Submitted That Met QC Criteria: March 18, 2005
• First Posted (Estimate): March 21, 2005

Study Record Updates

• Last Update Posted (Estimate): April 22, 2013
• Last Update Submitted That Met QC Criteria: April 15, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Primary disease: Osteogenesis Imperfecta
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Risedronic Acid
• Other Study ID Numbers: 2003100; HMR4003I/3001