A study to test product setrusumab in subjects with brittle bone syndrome.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ultragenyx Pharmaceutical Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

8 May 2023 → ongoing

Decision date (initial)

2024-05-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ultragenyx Pharmaceutical Inc.

External identifiers

EU CT number

2024-510919-29-00

EudraCT number

2021-006597-23

ClinicalTrials.gov

NCT05125809

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety, Dose response, Therapy, Pharmacodynamic, Pharmacokinetic, Efficacy

Phase II: Identify a setrusumab dosing strategy in subjects with OI
Phase III: Evaluate the effect of setrusumab vs placebo on reduction in fracture rate, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull

Secondary objectives 11

1. Phase II - Evaluate the pharmacokinetics (PK) of setrusumab doses in subjects with OI
2. Phase II - Determine the pharmacodynamic (PD) effects of setrusumab on bone formation and turnover markers
3. Phase II - Evaluate the effect of setrusumab on lumbar spine bone mineral density (BMD)
4. Phase II - Evaluate the safety profile of setrusumab for the treatment of subjects with OI
5. Phase II - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI
6. Key Secondary Objective: Phase III - Evaluate the effect of setrusumab vs placebo on reduction in fracture rate
7. Key Secondary Objective: Phase III -Evaluate the effect of setrusumab vs placebo on lumbar spine BMD
8. Phase III - Evaluate the effect of setrusumab vs placebo on clinical outcome assessments including subject-/caregiver-reported assessments of physical function, pain, and health-related quality of life
9. Phase III - Assess the safety profile of setrusumab
10. Phase III - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI
11. Key Secondary Objective: Phase III - Evaluate the effect of setrusumab vs placebo on specific fracture rate reduction

Conditions and MedDRA coding

Osteogenesis imperfecta (OI)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002169-PIP01-17

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Males and females 5 to < 26 years of age at time of informed consent
2. 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.
3. ≥ 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
4. 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 be repeated after a minimum of 14 days of vitamin D supplementation as directed by the treating physician
5. Willing to not receive bisphosphonate therapy during the study
6. From the period following informed consent to 60 days after the last dose of 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
7. Willing and able to provide informed consent for subjects ≥ 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
8. Willing to provide access to medical records for the collection of radiographic data, fracture data, growth data, and disease history
9. 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 17

1. For Phase 2 subjects only, a history of major bone surgery within the previous 6 months prior to Screening or planned major bone surgery for the first 3 months of the study
2. History of skeletal malignancies or bone metastases at any time
3. History of neural foraminal stenosis (except if due to scoliosis)
4. Clinically unstable manifestations of Chiari malformation or basilar invagination within the past 2 years. Presence of any other neurologic disease that has been clinically unstable within the past 2 years requires review by the Medical Monitor.
5. 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
6. Rickets or any skeletal condition (other than OI) leading to bone deformities and/or increased risk of fractures
7. History of stroke, myocardial infarction, TIA, or angina. Investigators should consider whether the potential benefits of treatment outweigh the potential risks in patients with other cardiovascular risk factors such as hypertension, hyperlipidemia, familial hyperlipidemia, family history of premature ischemic cardiovascular disease, smoking, diabetes mellitus, and metabolic syndrome.
8. Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limits after a ≥ 4 hour fast
9. Estimated glomerular filtration rate ≤ 29 mL/min/1.73 m2
10. Prior treatment with the following: a. Teriparatide, growth hormone, bone anabolic, or anti-resorptive medications (other than bisphosphonates) within 6 months of the first dose with study drug (Month 0) b. Denosumab within 24 months of the first dose with study drug (Month 0) c. Romosozumab at any time
11. Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence of such abuse, as determined by the Investigator
12. 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
13. Known hypersensitivity to setrusumab or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects
14. History of external radiation therapy
15. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time during the study
16. 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)
17. Concurrent participation in another clinical study without prior approval from the Investigator in consultation with the Medical Monitor

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase II: Percent change in serum P1NP from Baseline at Month 1
2. Phase III: Annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull, at the primary analysis

Secondary endpoints 14

1. Phase II: Serum setrusumab concentration at scheduled time points
2. Phase II - Baseline-corrected AUEC for serum P1NP over a 1- and 2-month timeframe
3. Phase II - Percent change from Baseline in bone turnover markers (P1NP and OCN) over time
4. Phase II - Change from Baseline in DXA lumbar spine BMD z-scores over time
5. Phase II - Percent change from Baseline in DXA lumbar spine BMD over time
6. Phase II - Frequency, severity, and relationship to treatment of TEAEs, SAEs, AESIs
7. Phase II - Incidence of anti-setrusumab binding and neutralizing antibodies at scheduled time points
8. Key Secondary Endpoints: Phase III - 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
9. Key Secondary Endpoints: Phase III - Annualized rate of all radiographically-confirmed fractures at the primary analysis
10. Key Secondary Endpoints: Phase III - Change from Baseline in DXA lumbar spine BMD z-score at the primary analysis
11. Phase III - Change from Baseline at the primary analysis for: • POSNA-PODCI Sports/Physical Functioning and Pain/comfort subscale scores for subjects < 18 years of age at screening • SF-36 PF and BP Domain Scales for subjects ≥ 18 years of age at screening
12. Phase III - Frequency, severity, and relationship to treatment of TEAEs, SAEs, and AESIs
13. Phase III - Incidence of binding and neutralizing anti-setrusumab antibodies at scheduled time points
14. Key Secondary Endpoints: Phase III - Proportion of subjects experiencing new radiographically confirmed fractures, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull at the primary analysis

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ultragenyx Pharmaceutical Inc.

Sponsor organisation

Ultragenyx Pharmaceutical Inc.

Address

60 Leveroni Court Suite 200

City

Novato

Postcode

94949-5746

Country

United States

Scientific contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Functional contact point: Medical Information

Public contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Functional contact point: Ultragenyx trial information group

Third parties 10

Locations

6 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 79 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications