A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804

Study Overview
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Brief Summary
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The purpose of this study is to select a suitable dose of BPS804 by measuring the strength/quality of bone using a special type of CT scanner. Participants will be treated for 12 months and followed up for a further 12 months.

Detailed Description
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This study was previously posted by Mereo Biopharma and was transferred to Ultragenyx in February 2021.

Official Title
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A Phase 2b, Multicentre, Multinational, Double-blind, Dose-finding Study, Incorporating an Open Label Substudy, in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With Setrusumab (BPS804)

Conditions
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Osteogenesis Imperfecta, Type I, Osteogenesis Imperfecta Type III, Osteogenesis Imperfecta Type IV

Intervention / Treatment
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* Drug: setrusumab
* Dietary Supplement: Calcium
* Dietary Supplement: Vitamin D
* Drug: zoledronic acid (optional)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a clinical diagnosis of OI Type I, III or IV with a confirmed defect in the COL1A1/COL1A2 genes, as confirmed by genetic testing One or more fractures in the past 5 years Capable of giving signed consent Exclusion Criteria: History of skeletal malignancies or other bone diseases (other than OI) History of neural foraminal stenosis (except if due to scoliosis) History of myocardial infarction, angina pectoris, ischaemic stroke or transient ischaemic attack History of endocrine or thyroid/parathyroid conditions that could affect bone metabolism Treatment with bisphosphonates within 3 months of randomisation Treatment with teraparatide, denosumab or other anabolic/anti-reabsorptive medications within 6 months of randomisation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: Double-blind, Dose-finding Study, incorporating an open-label substudy
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Setrusumab 20 mg/kg (Blinded)<br>Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. | Drug: setrusumab<br>* Intravenous infusion<br>* Other names: BPS804;Dietary Supplement: Calcium<br>* tablets<br>Dietary Supplement: Vitamin D<br>* capsules<br>Drug: zoledronic acid (optional)<br>* Following completion of the study treatment (Month 12) participants can receive an optional single dose of zoledronic acid. Participants can receive an optional further dose of zoledronic acid at Month 18 at the discretion of their treating physician.<br>|
| Experimental: Setrusumab 8 mg/kg (Blinded)<br>Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. | Drug: setrusumab<br>* Intravenous infusion<br>* Other names: BPS804;Dietary Supplement: Calcium<br>* tablets<br>Dietary Supplement: Vitamin D<br>* capsules<br>Drug: zoledronic acid (optional)<br>* Following completion of the study treatment (Month 12) participants can receive an optional single dose of zoledronic acid. Participants can receive an optional further dose of zoledronic acid at Month 18 at the discretion of their treating physician.<br>|
| Experimental: Setrusumab 2 mg/kg (Blinded)<br>Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. | Drug: setrusumab<br>* Intravenous infusion<br>* Other names: BPS804;Dietary Supplement: Calcium<br>* tablets<br>Dietary Supplement: Vitamin D<br>* capsules<br>Drug: zoledronic acid (optional)<br>* Following completion of the study treatment (Month 12) participants can receive an optional single dose of zoledronic acid. Participants can receive an optional further dose of zoledronic acid at Month 18 at the discretion of their treating physician.<br>|
| Experimental: Setrusumab 20 mg/kg (Open-Label)<br>Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. | Drug: setrusumab<br>* Intravenous infusion<br>* Other names: BPS804;Dietary Supplement: Calcium<br>* tablets<br>Dietary Supplement: Vitamin D<br>* capsules<br>Drug: zoledronic acid (optional)<br>* Following completion of the study treatment (Month 12) participants can receive an optional single dose of zoledronic acid. Participants can receive an optional further dose of zoledronic acid at Month 18 at the discretion of their treating physician.<br>|
| Placebo Comparator: Placebo<br>Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. | Dietary Supplement: Calcium<br>* tablets<br>Dietary Supplement: Vitamin D<br>* capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12 | Assessed by high resolution peripheral quantitative computed tomography (HRpQCT). HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presents the ratio of the means between the visit and Baseline from analysis of covariance (ANCOVA). | Baseline, Month 12 (end of treatment [EOT]) | 
| Change From Baseline in Radial Bone Strength (Failure Load) at Month 12 | Assessed by finite element analysis (FEA) of models generated from HRpQCT images of the distal radius. | Baseline, Month 12 (EOT) | 
| Change From Baseline in Radial Bone Strength (Stiffness) at Month 12 | Assessed by FEA of models generated from HRpQCT images of the distal radius. | Baseline, Month 12 (EOT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set | Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. | Baseline, Months 6, 12 (EOT), 18, 24 | 
| Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm | Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. | Baseline, Months 6, 12 (EOT) | 
| Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set | Assessed by FEA of models generated from HRpQCT images of the distal radius. | Baseline, Months 6, 12 (EOT), 18, 24 | 
| Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm | Assessed by FEA of models generated from HRpQCT images of the distal radius. | Baseline, Months 6, 12 (EOT) | 
| Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set | Assessed by FEA of models generated from HRpQCT images of the distal radius. | Baseline, Months 6, 12 (EOT), 18, 24 | 
| Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm | Assessed by FEA of models generated from HRpQCT images of the distal radius. | Baseline, Months 6, 12 (EOT) | 
| Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12 | Fracture assessment, confirmed by central radiographic reading, was carried out for peripheral including all major long bones, minor bone (digits, ribs) and vertebral fractures. Fractures without clinical symptoms, detected only by means of radiographic investigations, were not included in the analysis. | Month 12 (EOT) | 
| Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6 | BMD was evaluated by dual-energy x-ray absorptiometry (DXA). T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD. | Baseline, Month 6 | 
| Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6 | BMD was evaluated by DXA. | Baseline, Month 6 | 
| Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12 | BMD was evaluated by DXA. T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD. | Baseline, Month 12 (EOT) | 
| Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12 | BMD was evaluated by DXA. | Baseline, Month 12 (EOT) | 
| Change From Baseline in Total vBMD (Radial and Tibial) Over Time | Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. | Baseline, Months 6, 12 (EOT), 18, and 24 | 
| Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time | Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. | Baseline, Months 6, 12 (EOT), 18, and 24 | 
| Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set |  | Baseline, Month 6, Month 12 (EOT) | 
| Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12 | Lean and fat body mass was evaluated using whole body DXA (including the head). | Baseline, Months 6, 12 (EOT) | 
| Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12 |  | Baseline, Months 1, 3, 6, 9, 12 (EOT) | 
| Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12 |  | Baseline, Months 1, 3, 6, 9, 12 (EOT) | 
| Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12 | The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Physical Component Summary ranges from 0 to 100, where higher scores reflect better physical functioning. | Baseline, Months 6, 12 (EOT) | 
| Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12 | The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Mental Component Summary ranges from 0 to 100, where higher scores reflect better mental health functioning. | Baseline, Months 6, 12 (EOT) | 
| Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12 | The EQ-5D-5L is a standardised measure of health status comprised of a descriptive system of 5 health-related quality of life states (i.e., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) of overall health. Each dimension is rated on a 5-point response scale indicating severity of problems, where 1 is no problems and 5 is extreme problems. The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1 (1 being perfect health). | Baseline, Months 6 and 12 (EOT) | 
| Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12 | The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The total score is calculated on a 0-100 scale, where higher scores indicate a greater (negative) impact on quality of life. | Baseline, Months 6, 12 (EOT) | 
| Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12 | The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Pain subscale ranges from 0 to 10, with higher value representing worse pain. | Baseline, Months 6, 12 (EOT) | 
| Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12 | The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Activities subscale ranges from 0 to 100, with higher value representing increased difficulty. | Baseline, Months 6, 12 (EOT) | 
| Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14 | Serum samples were screened for antibodies binding to setrusumab using a validated assay method by or under the supervision of the sponsor. | up to Month 14 | 
| Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death | An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; is another important medical event. The intensity for each AE was graded as mild, moderate or severe, according to the investigator's judgement. An event was considered related to study drug if there were a reasonable possibility of a relationship, according to the investigator's clinical judgment. A TEAE was defined as an event occurring or worsening on or after the first dose of study medication. | Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteogenesis Imperfecta, Brittle Bone Disease