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

Study Overview
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Brief Summary
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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.

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

Conditions
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Osteogenesis Imperfecta

Intervention / Treatment
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* Drug: risedronate sodium (Actonel)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary disease: Osteogenesis Imperfecta