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

Phase 2

Active, not recruiting

• Conditions: Osteogenesis Imperfecta
• Interventions: Biological: Setrusumab; Other: Placebo

• Registration Number: NCT05125809
• Lead Sponsor: Ultragenyx Pharmaceutical Inc

Brief Summary

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

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 Timeline

• Study First Submitted: 2021-11-08
• Study First Submitted QC: 2021-11-08
• Study First Posted: 2021-11-18
• Study Start: 2022-02-21
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-01
• Last Update Posted: 2024-08-02
• Primary Completion: 2025-03
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 182

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Low Dose Setrusumab -> Open-Label (OL) Setrusumab Selected Dose	Setrusumab	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
High Dose Setrusumab -> OL Setrusumab Selected Dose	Setrusumab	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
Setrusumab Selected Dose -> OL Setrusumab Selected Dose	Setrusumab	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
Placebo -> OL Setrusumab Selected Dose	Placebo	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
Placebo -> OL Setrusumab Selected Dose	Setrusumab	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

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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: Osteocalcin (OCN)	Baseline, Up to Month 24
Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: P1NP	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: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies	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 SF-36 Bodily Pain (BP) Domain Scale for Adult Participants at 12 Months	Baseline, Month 12
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: 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: 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	Up to Month 24

Trial Locations

Locations (47)

Nationwide Children's Hospital- Ohio State University College of Medicine; 🇺🇸 Columbus, Ohio, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Nemours/ Alfred i. duPoint Hospital for Children; 🇺🇸 Wilmington, Delaware, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Shriners Hospitals for Children - Chicago; 🇺🇸 Chicago, Illinois, United States

Kennedy Krieger Institute; 🇺🇸 Baltimore, Maryland, United States

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

New Mexico Clinical Research & Osteoporosis Center, Inc.; 🇺🇸 Albuquerque, New Mexico, United States

The Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Queensland Paediatric Endocrinology; 🇦🇺 South Brisbane, Queensland, Australia

UW Health University Hospital; 🇺🇸 Madison, Wisconsin, United States

Royal Children's Hospital; 🇦🇺 Melbourne, Australia

Sydney Children's Hospital; 🇦🇺 Randwick, Australia

University of Toronto- The Hospital for Sick Children (SickKids); 🇨🇦 Toronto, Canada

McGill University Health Centre; 🇨🇦 Montréal, Canada

London Health Sciences Center; 🇨🇦 London, Ontario, Canada

Magic Clinic Ltd; 🇨🇦 Calgary, Canada

University of Cologne; 🇩🇪 Cologne, Germany

Institut Imagine; 🇫🇷 Paris, France

Musculoskeletal Center Würzburg; 🇩🇪 Würzburg, Germany

Otto von Guericke University Magdeburg; 🇩🇪 Magdeburg, Germany

Uniwersytet Medyczny w Lodzi - Klinika Endokrynologii i Chorob Metabolicznych; 🇵🇱 Łódź, Poland

Wilhelmina Children's Hospital; 🇳🇱 Utrecht, Netherlands

Centro Hospitalar do Porto; 🇵🇹 Porto, Portugal

Hospital de Santa Maria; 🇵🇹 Lisbon, Portugal

Gazi University; 🇹🇷 Ankara, Turkey

Marmara University; 🇹🇷 Istanbul, Turkey

Royal Manchester Childrens Hospital; 🇬🇧 Manchester, United Kingdom

Sheffield Children's NHS Foundation Trust; 🇬🇧 Sheffield, United Kingdom

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

Hospital de Ninos; 🇦🇷 Buenos Aires, Argentina

Connecticut Children's Medical Center; 🇺🇸 Hartford, Connecticut, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Istituto Ortopedico Rizzoli; 🇮🇹 Bologna, Italy

Azienda Ospedaliera Universitaria Policlinico Umberto I; 🇮🇹 Rome, Italy

Universita Degli Studi Di Verona; 🇮🇹 Verona, Italy

Indiana University Hospital; 🇺🇸 Indianapolis, Indiana, United States

Atrium Health Levine Children's Hospital; 🇺🇸 Charlotte, North Carolina, United States

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

Shriners Hospital for Children - Northern California; 🇺🇸 Sacramento, California, United States

Yale New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States

Children's Hospital and Medical Center; 🇺🇸 Omaha, Nebraska, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

University of South Florida; 🇺🇸 Tampa, Florida, United States

Children's Mercy Hospital; 🇺🇸 Kansas City, Missouri, United States