Study to Assess Dose, Efficacy and Safety of Setrusumab in Participants With Osteogenesis Imperfecta

Study Overview
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Brief Summary
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The primary objectives of the study are to identify a setrusumab dosing strategy in participants with OI and to evaluate the effect of setrusumab vs placebo on reduction in fracture rate.

Detailed Description
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Participants in Phase 2 will be randomized 1:1 to receive low dose or high dose setrusumab. Participants will continue receiving their assigned dose until the selected dosing strategy is determined for the remainder of the study. Phase 2 participants will receive setrusumab at the selected dosing strategy in the open-label treatment extension period. Phase 3 participants will be randomized 2:1 to receive setrusumab or placebo. Phase 3 participants will transition to an open-label treatment extension period after the Phase 3 primary analysis is complete, or once a participant has completed 24 months of treatment in the double-blind period, whichever is sooner. Participants in the Phase 2 and Phase 3 treatment extension periods will receive open-label setrusumab treatment for at least 12 months, with the ability to extend until commercial availability in their respective country.

Official Title
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An Operationally Seamless, Randomized Phase 2/3 Study Consisting of a Phase 2 Single-Blind, Dose-Evaluation Phase and a Phase 3 Double-Blind, Placebo-Controlled Phase to Assess the Efficacy and Safety of Setrusumab in Subjects With Osteogenesis Imperfecta

Conditions
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Osteogenesis Imperfecta

Intervention / Treatment
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* Biological: Setrusumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of OI Types I, III, or IV as confirmed by identification of genetic mutation in collagen, type I, alpha 1 (COL1A1) or collagen, type I, alpha 2 (COLA2) ≥ 1 fracture in the past 12 months, ≥ 2 fractures in the past 24 months or ≥ 1 tibia, femur or humerus fracture in the past 24 months Serum 25 hydroxyvitamin D ≥ 20 ng/mL at the Screening Visit. If levels are below 20 ng/mL the subject may be rescreened after a minimum of 14 days of supplementation as directed by their treating physician Willing to not receive bisphosphonate therapy during the study From the period following informed consent to 60 days after the last dose of the study drug, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not to father a child or donate sperm Willing and able to provide informed consent for subjects greater than or equal to 18 years of age, or provide assent (if possible) and have a legally authorized representative provide informed consent, after the nature of the study has been explained and prior to any research-related procedures Willing to provide access to medical records for the collection of radiographic data, fracture data, growth data, and disease history Must, in the opinion of the Investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule, and comply with the assessments Exclusion Criteria: For Phase 2 Only: A history of bone surgery within the previous 6 months prior to Screening or planned bone surgery for the first 3 months of the study History of skeletal malignancies or bone metastases at any time History of neural foraminal stenosis (except if due to scoliosis) Clinical manifestations of Chiari malformation or basilar invagination. Presence of any other neurologic disease that has been unstable within past 2 years requires review by the Medical Monitor History of or uncontrolled concomitant diseases such as hypo/hyperparathyroidism, Paget's disease, abnormal thyroid function, thyroid disease or other endocrine disorders or conditions that could affect bone metabolism such as Stage IV/V renal disease Rickets or any skeletal condition (other than OI) leading to long-bone deformities and/or increased risk of fractures History of stroke, myocardial infarction, transient ischemic attack or angina. Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limits after a ≥ 4 hour fast Estimated glomerular filtration rate ≤ 29 mL/min/1.73 m2 Prior treatment with the following: Bisphosphonate use prior to Screening that is a minimum of 3 months or the length of the dosing interval up to 6 months Teriparatide, growth hormone, or other bone anabolic or anti-resorptive medications within 6 months of Screening Denosumab within 24 months of Screening Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence of such abuse as indicated by the laboratory results during the Screening assessments Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results Known hypersensitivity to setrusumab or excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects History of external radiation therapy Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time during the study Use of any investigational product or investigational medical device within 4 weeks or 5 half-lives of investigational drug (whichever is longer) prior to Screening, or during the study (per discretion of the Investigator in consultation with the Medical Monitor) Concurrent participation in another clinical study without prior approval from the Investigator in consultation with the Medical Monitor

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 25 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Setrusumab -> Open-Label (OL) Setrusumab Selected Dose<br>Single-blind setrusumab low dose during phase 2 followed by open-label setrusumab selected dose During treatment and treatment extension periods, participants will receive daily supplementation with calcium and vitamin D as directed by the treating physician | Biological: Setrusumab<br>* A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion<br>* Other names: UX143;|
| Experimental: High Dose Setrusumab -> OL Setrusumab Selected Dose<br>Single-blind setrusumab high dose during phase 2 followed by open-label setrusumab During treatment and treatment extension periods, participants will receive daily supplementation with calcium and vitamin D as directed by the treating physician | Biological: Setrusumab<br>* A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion<br>* Other names: UX143;|
| Experimental: Setrusumab Selected Dose -> OL Setrusumab Selected Dose<br>Double-blind setrusumab selected dose during phase 3 followed by open-label setrusumab During treatment and treatment extension periods, participants will receive daily supplementation with calcium and vitamin D as directed by the treating physician | Biological: Setrusumab<br>* A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion<br>* Other names: UX143;|
| Placebo Comparator: Placebo -> OL Setrusumab Selected Dose<br>Double-blind placebo during phase 3 followed by open-label setrusumab During treatment and treatment extension periods, participants will receive daily supplementation with calcium and vitamin D as directed by the treating physician | Biological: Setrusumab<br>* A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion<br>* Other names: UX143;Other: Placebo<br>* A 5% dextrose/glucose solution administered QM via IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Percent Change in Serum Amino-terminal Propeptide of Type 1 Procollagen (P1NP) from Baseline at Month 1 |  | Baseline, Month 1 | 
| Phase 3: Annualized Rate of all Radiographically-confirmed Fractures, Excluding Morphometric Vertebral Fractures, During the Double-blind Treatment Period |  | Up to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Serum Setrusumab Concentration |  | From Predose up to Month 24 | 
| Phase 2: Baseline-Corrected Area Under the Effect Curve (AUEC) for Serum P1NP Over a 1 and 2-Month Period |  | Baseline, Up to Month 2 | 
| Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: P1NP |  | Baseline, Up to Month 24 | 
| Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: Cross-linked C-telopeptide of Type I Collagen (CTx) |  | Baseline, Up to Month 24 | 
| Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: Bone-specific Alkaline Phosphatase (BSAP) |  | Baseline, Up to Month 24 | 
| Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: Osteocalcin (OCN) |  | Baseline, Up to Month 24 | 
| Phase 2: Change from Baseline in Dual Energy X-ray (DXA) Lumbar Spine Bone Mineral Density (BMD) Z-score Over Time |  | Baseline, Up to Month 24 | 
| Phase 2: Percent Change from Baseline in DXA Lumbar Spine BMD Over Time |  | Baseline, Up to Month 24 | 
| Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) |  | Up to Month 24 | 
| Phase 2: Number of Participants With Anti-setrusumab Binding and Neutralizing Antibodies at scheduled Timepoints |  | Up to Month 24 | 
| Phase 3: Annualized Rate of all Radiographically-confirmed Fractures, Including Morphometric Vertebral Fractures, During the Double-blind Treatment Period |  | Up to Month 24 | 
| Phase 3: Change from Baseline in DXA Lumbar Spine BMD Z-score at 18 Months |  | Baseline, Month 18 | 
| Phase 3: Change from Baseline in Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI) Sports/Physical Functioning Subscale Score for Pediatric Participants at 18 Months |  | Baseline, Month 18 | 
| Phase 3: Change from Baseline in POSNA-PODCI Pain/Comfort Subscale Score for Pediatric Participants at 18 Months |  | Baseline, Month 18 | 
| Phase 3: Change from Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain Scale for Adult Participants at 18 Months |  | Baseline, Month 18 | 
| Phase 3: Change from Baseline in SF-36 Bodily Pain Domain Scale for Adult Participants at 18 Months |  | Baseline, Month 18 | 
| Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) |  | Up to Month 24 | 
| Phase 3: Number of Participants With Anti-setrusumab Binding and Neutralizing Antibodies at Scheduled Timepoints |  | Up to Month 24 |