Clinical trial NCT05125809: Setrusumab vs Placebo for Osteogenesis Imperfecta
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Osteogenesis Imperfecta
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
Collaborators: name: Mereo BioPharma
First posted: 2021-11-18
Enrollment: 182
Sex: ALL
Minimum age (years): 5
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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. 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 (≥ 8 years) consisting of a bone biopsy following at least 12 months of setrusumab exposure to investigate the impact of setrusumab on bone histomorphology.

Eligibility criteria: 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, bone anabolic, or anti-resorptive medications (other than bisphosphonates) within 6 months of the first dose with study drug (Month 0)
  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

Primary outcomes:
measure: Phase 2: Percent Change in Serum Amino-terminal Propeptide of Type 1 Procollagen (P1NP) from Baseline at Month 1
timeFrame: Baseline, Month 1
measure: Phase 3: Annualized Rate of All Radiographically-Confirmed Fractures, Excluding Morphometric Vertebral Fractures and Fractures of the Fingers, Toes, Face, and Skull at the Primary Analysis
timeFrame: Up to Month 24
Secondary outcomes:
measure: Phase 2: Serum Setrusumab Concentration
timeFrame: From Predose up to Month 24
measure: Phase 2: Baseline-Corrected Area Under the Effect Curve (AUEC) for Serum P1NP Over a 1 and 2-Month Period
timeFrame: Baseline, Up to Month 2
measure: Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: P1NP
timeFrame: Baseline, Up to Month 24
measure: Phase 2: Percent Change from Baseline Over Time in Bone Turnover Marker: Osteocalcin (OCN)
timeFrame: Baseline, Up to Month 24
measure: Phase 2: Change from Baseline in Dual Energy X-ray (DXA) Lumbar Spine Bone Mineral Density (BMD) Z-score Over Time
timeFrame: Baseline, Up to Month 24
measure: Phase 2: Percent Change from Baseline in DXA Lumbar Spine BMD Over Time
timeFrame: Baseline, Up to Month 24
measure: Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
timeFrame: Up to Month 24
measure: Phase 2: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies
timeFrame: Up to Month 24
measure: Phase 3: Annualized Rate of All Radiographically-Confirmed Fractures, Excluding Morphometric Vertebral Fractures, but Including Fractures of the Fingers, Toes, Face and Skull at the Primary Analysis
timeFrame: Up to Month 24
measure: Phase 3: Annualized Rate of All Radiographically-Confirmed Fractures at the Primary Analysis
timeFrame: Up to Month 24
measure: Phase 3: Change from Baseline in DXA Lumbar Spine BMD Z-score at the Primary Analysis
timeFrame: Baseline, Month 12
measure: 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 the Primary Analysis
timeFrame: Baseline, Month 12
measure: Phase 3: Change from Baseline in POSNA-PODCI Pain/Comfort Subscale Score for Pediatric Participants at the Primary Analysis
timeFrame: Baseline, Month 12
measure: Phase 3: Change from Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain Scale for Adult Participants at the Primary Analysis
timeFrame: Baseline, Month 12
measure: Phase 3: Change from Baseline in SF-36 Bodily Pain (BP) Domain Scale for Adult Participants at the Primary Analysis
timeFrame: Baseline, Month 12
measure: Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
timeFrame: Up to Month 24
measure: Phase 3: Number of Participants With Anti-Setrusumab Binding and Neutralizing Antibodies
timeFrame: Up to Month 24
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Sacramento
country: United States
facility: Shriners Hospital for Children - Northern California
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Wilmington
country: United States
facility: Nemours/ Alfred i. duPoint Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Shriners Hospitals for Children - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Hospital
state: Indiana
city: Baltimore
country: United States
facility: Kennedy Krieger Institute
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center
state: Nebraska
city: Albuquerque
country: United States
facility: New Mexico Clinical Research & Osteoporosis Center, Inc.
state: New Mexico
city: Charlotte
country: United States
facility: Atrium Health Levine Children's Hospital
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital- Ohio State University College of Medicine
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Madison
country: United States
facility: UW Health University Hospital
state: Wisconsin
city: South Brisbane
country: Australia
facility: Queensland Paediatric Endocrinology
state: Queensland
city: Melbourne
country: Australia
facility: Royal Children's Hospital
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Centre
city: Toronto
country: Canada
facility: University of Toronto- The Hospital for Sick Children (SickKids)
city: Paris
country: France
facility: Institut Imagine
city: Cologne
country: Germany
facility: University of Cologne
city: Magdeburg
country: Germany
facility: Otto von Guericke University Magdeburg
city: Würzburg
country: Germany
facility: Musculoskeletal Center Würzburg
city: Bologna
country: Italy
facility: Istituto Ortopedico Rizzoli
city: Rome
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Umberto I
city: Verona
country: Italy
facility: Universita Degli Studi Di Verona
city: Utrecht
country: Netherlands
facility: Wilhelmina Children's Hospital
city: Łódź
country: Poland
facility: Uniwersytet Medyczny w Lodzi - Klinika Endokrynologii i Chorob Metabolicznych
city: Lisbon
country: Portugal
facility: Hospital de Santa Maria
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto
city: Ankara
country: Turkey
facility: Gazi University
city: Istanbul
country: Turkey
facility: Marmara University
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children's NHS Foundation Trust
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Ultragenyx Medical Director
role: STUDY_DIRECTOR
References: