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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Biological: Setrusumab; Other: Placebo

Detailed Description

Participants in Phase 2 will be randomized 1:1 to receive low dose or high dose setrusumab. Phase 2 participants will continue receiving their assigned dose of setrusumab until all Phase 2 participants have completed the Month 6 study visit. After this point, Phase 2 participants will begin receiving the selected dosing strategy in the Phase 2 open-label Treatment Extension Period. Phase 3 participants will be randomized 2:1 to receive setrusumab or placebo during the double-blind treatment period. Phase 3 participants will transition to the open-label Treatment Extension Period after the end of the double-blind period (when the participant has completed 24 months in the double-blind period or when the Sponsor determines the timing of the primary analysis, 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, and have the option to remain in the open-label treatment period until setrusumab is commercially available in their region. An optional substudy will be conducted in approximately 10 participants (≥ 8years) consisting of a bone biopsy following at least 12 months of setrusumab exposure to investigate the impact of setrusumab on bone histomorphology.

• Study Type: Interventional
• Enrollment (Actual): 182
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • Hospital de Ninos
• Australia
  • Melbourne, Australia
    • Royal Children's Hospital
  • Randwick, Australia
    • Sydney Children's Hospital
  • Queensland
    • South Brisbane, Queensland, Australia, QLD 4101
      • Queensland Paediatric Endocrinology
• Canada
  • Calgary, Canada
    • Magic Clinic Ltd
  • Montréal, Canada, H4A 3J1
    • McGill University Health Centre
  • Toronto, Canada
    • University of Toronto- The Hospital for Sick Children (SickKids)
  • Ontario
    • London, Ontario, Canada
      • London Health Sciences Center
• France
  • Paris, France
    • Institut Imagine
• Germany
  • Cologne, Germany
    • University of Cologne
  • Magdeburg, Germany, 39106
    • Otto von Guericke University Magdeburg
  • Würzburg, Germany, 97074
    • Musculoskeletal Center Würzburg
• Italy
  • Bologna, Italy
    • Istituto Ortopedico Rizzoli
  • Rome, Italy, 00161
    • Azienda Ospedaliera Universitaria Policlinico Umberto I
  • Verona, Italy
    • Universita Degli Studi Di Verona
• Netherlands
  • Utrecht, Netherlands
    • Wilhelmina Children's Hospital
• Poland
  • Łódź, Poland
    • Uniwersytet Medyczny w Lodzi - Klinika Endokrynologii i Chorob Metabolicznych
• Portugal
  • Lisbon, Portugal, 1649-028
    • Hospital de Santa Maria
  • Porto, Portugal, 4099-001
    • Centro Hospitalar do Porto
• Turkey
  • Ankara, Turkey
    • Gazi University
  • Istanbul, Turkey
    • Marmara University
• United Kingdom
  • Manchester, United Kingdom
    • Royal Manchester Childrens Hospital
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's NHS Foundation Trust
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Sacramento, California, United States, 95817
      • Shriners Hospital for Children - Northern California
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours/ Alfred i. duPoint Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • University Of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60707
      • Shriners Hospitals for Children - Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Clinical Research & Osteoporosis Center, Inc.
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Atrium Health Levine Children's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital- Ohio State University College of Medicine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • UW Health University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of OI Type I, III, or IV as confirmed by identification of pathogenic or likely pathogenic genetic variants in COL1A1 or COL1A2. If a variant of uncertain significance is identified, then clinical presence of the expected phenotype can be used to confirm the diagnosis
• ≥ 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 25-hydroxyvitamin D levels are below 20 ng/mL, 25-hydroxyvitamin D testing can repeated after a minimum of 14 days of vitamin D supplementation as directed by the 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:

• 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:

  1. Teriparatide, growth hormone, or other bone anabolic or anti-resorptive medications within 6 months of Screening
  2. Denosumab within 24 months of Screening
  3. Romosozumab at any time
• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose Setrusumab -> Open-Label (OL) Setrusumab Selected Dose; Single-blind setrusumab low dose during phase 2 followed by open-label setrusumab selected dose During treatment and treatment extension periods, participants may receive supplementation with calcium and vitamin D to maintain normal values as directed by the treating physician	Biological: Setrusumab; A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion; Other Names: BPS804; UX143
Experimental: High Dose Setrusumab -> OL Setrusumab Selected Dose; Single-blind setrusumab high dose during phase 2 followed by open-label setrusumab During treatment and treatment extension periods, participants may receive supplementation with calcium and vitamin D to maintain normal values as directed by the treating physician	Biological: Setrusumab; A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion; Other Names: BPS804; UX143
Experimental: Setrusumab Selected Dose -> OL Setrusumab Selected Dose; Double-blind setrusumab selected dose during phase 3 followed by open-label setrusumab During treatment and treatment extension periods, participants may receive supplementation with calcium and vitamin D to maintain normal values as directed by the treating physician	Biological: Setrusumab; A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion; Other Names: BPS804; UX143
Placebo Comparator: Placebo -> OL Setrusumab Selected Dose; Double-blind placebo during phase 3 followed by open-label setrusumab During treatment and treatment extension periods, participants may receive supplementation with calcium and vitamin D to maintain normal values as directed by the treating physician	Biological: Setrusumab; A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion; Other Names: BPS804; UX143; Other: Placebo; A 5% dextrose/glucose solution administered QM via IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 and Fractures of the Fingers, Toes, Face, and Skull During the Double-Blind Treatment Period	Up to Month 24

Secondary Outcome Measures

Outcome Measure	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: 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 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 2: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies	Up to Month 24
Phase 3: Annualized Rate of all Radiographically-confirmed Fractures, Excluding Morphometric Vertebral Fractures, but Including Fractures of the Fingers, Toes, Face and Skull During the Double-Blind Treatment Period	Up to Month 24
Phase 3: Annualized Rate of All Radiographically-Confirmed Fractures During the Double-Blind Treatment Period	Up to Month 24
Phase 3: Change from Baseline in DXA Lumbar Spine BMD Z-score at 12 Months	Baseline, Month 12
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 12 Months	Baseline, Month 12
Phase 3: Change from Baseline in POSNA-PODCI Pain/Comfort Subscale Score for Pediatric Participants at 12 Months	Baseline, Month 12
Phase 3: Change from Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain Scale for Adult Participants at 12 Months	Baseline, Month 12
Phase 3: Change from Baseline in SF-36 Bodily Pain (BP) Domain Scale for Adult Participants at 12 Months	Baseline, Month 12
Phase 3: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies	Up to Month 24

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborators: Mereo BioPharma
• Investigators: Study Director: Ultragenyx Medical Director, Ultragenyx Pharmaceutical Inc

Publications and helpful links

Helpful Links

• Ultragenyx Osteogenesis Imperfecta (OI) Research Study Opportunity

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2022
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: November 8, 2021
• First Submitted That Met QC Criteria: November 8, 2021
• First Posted (Actual): November 18, 2021

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: May 1, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta
• Other Study ID Numbers: UX143-CL301; 2021-006597-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No