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

• ClinicalTrials.gov Identifier: NCT00106028
• Recruitment Status: Completed
• First Posted: March 21, 2005
• Results First Posted: June 28, 2010
• Last Update Posted: April 22, 2013
• Sponsor: Warner Chilcott
• Information provided by (Responsible Party): Warner Chilcott

Tracking Information

• First Submitted Date: March 18, 2005
• First Posted Date: March 21, 2005
• Results First Submitted Date: April 15, 2009
• Results First Posted Date: June 28, 2010
• Last Update Posted Date: April 22, 2013
• Study Start Date: November 2004
• Actual Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 27, 2011)

Percent Change From Baseline Lumbar Spine Bone Mineral Density (BMD) at Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]

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.

• Original Primary Outcome Measures (submitted: June 23, 2005): The primary objective of the study is to determine the efficacy of risedronate compared to placebo in children 4 to <16 years of age with osteogenesis imperfecta as assessed by percent change from Baseline in lumbar spine bone mineral density at Month 12

Current Secondary Outcome Measures (submitted: July 27, 2011)

• Percent Change From Baseline Lumbar Spine Bone Mineral Density (BMD) at Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  Lumbar Spine Bone Mineral Density (BMD) measured by dual-energy x-ray absorptiometry (DXA)and read by central reader.
• Percent Change From Baseline Lumbar Spine Bone Mineral Density (BMD) at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  Lumbar Spine Bone Mineral Density (BMD) measured by dual-energy x-ray absorptiometry (DXA)and read by central reader.
• Percent Change From Baseline in Total Body BMD at Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  Percent Change from baseline in Total Body Bone Mineral Density (BMD) measured by DXA.
• Percent Change From Baseline in Total Body BMD at Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  Percent Change from baseline in Total Body Bone Mineral Density (BMD) measured by DXA.
• Percent Change From Baseline in Total Body BMD at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  Percent Change from baseline in Total Body Bone Mineral Density (BMD) measured by DXA.
• Percent Change From Baseline in Lumbar Spine BMC (Bone Mineral Content) at Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
• Percent Change From Baseline in Lumbar Spine BMC (Bone Mineral Content) at Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
• Percent Change From Baseline in Lumbar Spine BMC (Bone Mineral Content) at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
• Percent Change From Baseline in Total Body BMC at Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
• Percent Change From Baseline in Total Body BMC at Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
• Percent Change From Baseline in Total Body BMC at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
• Lumbar Spine Z-score - Percent Change From Baseline to Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  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".
• Lumbar Spine Z-score - Percent Change From Baseline to Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  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".
• Lumbar Spine Z-score - Percent Change From Baseline to Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  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".
• Total Body Z-score- Percent Change From Baseline to Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  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".
• Total Body Z-score- Percent Change From Baseline to Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  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".
• Total Body Z-score- Percent Change From Baseline to Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  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".
• Percent Change From Baseline in Lumbar Spine Bone Area at Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  Measured by DXA.
• Percent Change From Baseline in Lumbar Spine Bone Area at Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  Measured by DXA.
• Percent Change From Baseline in Lumbar Spine Bone Area at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  Measured by DXA.
• Percent Change From Baseline in Total Body Bone Area Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
• Percent Change From Baseline in Total Body Bone Area Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
• Percent Change From Baseline in Total Body Bone Area Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
• New Morphometric Vertebral Fracture at Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  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.
• New Morphometric Vertebral Fracture at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  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.
• Categorization by Number of New Morphometric Vertebral Fracture at Month 12, ITT [ Time Frame: Baseline and Month 12 ]
  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.
• Categorization by Number of New Morphometric Vertebral Fracture at Month 36, ITT [ Time Frame: Baseline and Month 36 ]
  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.
• Incidence New Vertebral Fractures by SQ (Semi-Quantitative) Score, Patients Aged 4-9 Years, Month 12, ITT Population [ Time Frame: Month 12 ]
  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.
• Incidence New Vertebral Fractures by SQ Score, Patients Aged 10-15 Years, Month 12, ITT Population [ Time Frame: Month 12 ]
  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.
• Probability of Fracture in 12 Months (Kaplan-Meier Cumulative Incidence), ITT Population [ Time Frame: Time to First Event (days) up to 12 Months ]
  Long bones include radius, ulna, humerus, tibia, fibula, femur, upper limb and lower limb fracture.
• Number of Clinical Fractures, Month 12, ITT Population [ Time Frame: 12 Months ]
  Long bones include radius, ulna, humerus, tibia, fibula, femur, upper limb and lower limb fracture.
• Serum BAP - Percent Change From Baseline to Month 12, ITT Population [ Time Frame: Baseline and 12 Months ]
  Serum Bone Alkaline Phosphatase (BAP - bone formation marker). Negative percent changes indicate response to treatment.
• Serum BAP - Percent Change From Baseline to Month 24, ITT Population [ Time Frame: Baseline and 24 Months ]
  Serum Bone Alkaline Phosphatase (BAP - bone formation marker). Negative percent changes indicate response to treatment.
• Serum BAP - Percent Change From Baseline to Month 36, ITT Population [ Time Frame: Baseline and 36 Months ]
  Serum Bone Alkaline Phosphatase (BAP - bone formation marker). Negative percent changes indicate response to treatment.
• Urine NTX/Cr - Percent Change From Baseline at Month 12, ITT Population [ Time Frame: Baseline and Endpoint / Month 12 ]
  Urine type-I collagen N-telopeptide/creatinine (NTX/Cr; bone resorption marker). Negative percent changes indicate response to treatment.
• Urine NTX/Cr - Percent Change From Baseline at Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  Urine type-I collagen N-telopeptide/creatinine (NTX/Cr; bone resorption marker). Negative percent changes indicate response to treatment.
• Urine NTX/Cr - Percent Change From Baseline at Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  Urine type-I collagen N-telopeptide/creatinine (NTX/Cr; bone resorption marker). Negative percent changes indicate response to treatment.
• Wong-Baker FACES Pain Rating Scale - Change From Baseline to Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  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.
• Bone Age (Years), Change From Baseline to Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  Bone Age determined by visual assessment of hand / wrist radiographs.
• Bone Age (Years), Change From Baseline to Month 24, ITT Population [ Time Frame: Baseline and Month 24 ]
  Bone Age determined by visual assessment of hand / wrist radiographs.
• Bone Age (Years), Change From Baseline to Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  Bone Age determined by visual assessment of hand / wrist radiographs.
• Annualized Growth Velocity - Change From Baseline to Month 12, ITT Population [ Time Frame: Baseline and Month 12 ]
  Annualized Growth Velocity [= bone age change from baseline x (365.25/time in days between baseline and the bone age measurement)]
• Annualized Growth Velocity - Change From Baseline to Month 36, ITT Population [ Time Frame: Baseline and Month 36 ]
  Annualized Growth Velocity [= bone age change from baseline x (365.25/time in days between baseline and the bone age measurement)]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
• Official Title: Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Osteogenesis Imperfecta

Intervention

• Drug: risedronate sodium (Actonel)
  risedronate tablet once a day for one year followed by risedronate once a day for two years
• Drug: Placebo
  placebo tablet once a day for one year followed by risedronate once a day for two years

Study Arms

• Placebo Comparator: Placebo Daily
  placebo tablet, once a day for one year then for two years open label risedronate
  Intervention: Drug: Placebo
• Experimental: Risedronate Daily
  risedronate tablet, once a day for one year then for two years open label risedronate once a day
  Intervention: Drug: risedronate sodium (Actonel)

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 19, 2010): 143
• Original Enrollment (submitted: June 23, 2005): 124
• Actual Study Completion Date: March 2010
• Actual Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 15 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Chile, Czech Republic, Finland, Germany, Hungary, Italy, Poland, South Africa, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT00106028
• Other Study ID Numbers: 2003100; HMR4003I/3001
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Warner Chilcott
• Original Responsible Party: Not Provided
• Current Study Sponsor: Warner Chilcott
• Original Study Sponsor: Procter and Gamble
• Collaborators: Not Provided

Investigators

• Study Director: Dietrich H Wenderoth, MD; Procter and Gamble

• PRS Account: Warner Chilcott
• Verification Date: April 2013