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

Osteogenesis Imperfecta Clinical Trial

— Orbit  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05125809
• Other study ID #: UX143-CL301
• Secondary ID: 2021-006597-23
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 21, 2022
• Est. completion date: March 2026

Study information

• Verified date: April 2024
• Source: Ultragenyx Pharmaceutical Inc
• Contact: Patient Contact: Trial Recruitment
• Phone: 1-888-756-8657
• Email: trialrecruitment[@]ultragenyx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 219
• Est. completion date: March 2026
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 25 Years

Eligibility

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

Related Conditions & MeSH terms

• Osteogenesis Imperfecta

Intervention

Biological:
• Setrusumab
A fully human sclerostin neutralizing monoclonal antibody (mAb) administered once a month (QM) via intravenous (IV) infusion

Other:
• Placebo
A 5% dextrose/glucose solution administered QM via IV infusion

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Ultragenyx Pharmaceutical Inc	Mereo BioPharma

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  France,  Germany,  Italy,  Netherlands,  Poland,  Portugal,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 2: Percent Change in Serum Amino-terminal Propeptide of Type 1 Procollagen (P1NP) from Baseline at Month 1		Baseline, Month 1
Primary	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	Phase 2: Serum Setrusumab Concentration		From Predose up to Month 24
Secondary	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
Secondary	Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: P1NP		Baseline, Up to Month 24
Secondary	Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: Osteocalcin (OCN)		Baseline, Up to Month 24
Secondary	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
Secondary	Phase 2: Percent Change from Baseline in DXA Lumbar Spine BMD Over Time		Baseline, Up to Month 24
Secondary	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
Secondary	Phase 2: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies		Up to Month 24
Secondary	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
Secondary	Phase 3: Annualized Rate of All Radiographically-Confirmed Fractures During the Double-Blind Treatment Period		Up to Month 24
Secondary	Phase 3: Change from Baseline in DXA Lumbar Spine BMD Z-score at 12 Months		Baseline, Month 12
Secondary	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
Secondary	Phase 3: Change from Baseline in POSNA-PODCI Pain/Comfort Subscale Score for Pediatric Participants at 12 Months		Baseline, Month 12
Secondary	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
Secondary	Phase 3: Change from Baseline in SF-36 Bodily Pain (BP) Domain Scale for Adult Participants at 12 Months		Baseline, Month 12
Secondary	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
Secondary	Phase 3: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies		Up to Month 24

External Links

•   Ultragenyx Osteogenesis Imperfecta (OI) Research Study Opportunity