E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Osteogenesis imperfecta (OI) |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031243 |
E.1.2 | Term | Osteogenesis imperfecta |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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
|
|
E.2.2 | Secondary objectives of the trial |
Phase II: - Evaluate the pharmacokinetics (PK) of setrusumab doses in subjects with OI - Determine the pharmacodynamic (PD) effects of setrusumab on bone formation and turnover markers - Evaluate the effect of setrusumab on lumbar spine bone mineral density (BMD) - Evaluate the safety profile of setrusumab for the treatment of subjects with OI - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI
Phase III: - Evaluate the effect of setrusumab vs placebo on reduction in fracture rate -Evaluate the effect of setrusumab vs placebo on lumbar spine BMD - 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 - Assess the safety profile of setrusumab - Evaluate the immunogenicity of setrusumab for the treatment of subjects with OI |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
UX143-CL301 BONE BIOPSY SUBSTUDY The primary objective of the UX143-CL301 bone biopsy safety substudy is to obtain additional data to rule out any significant adverse effects of setrusumab on bone quality, including impairment of normal bone mineralization. This will be accomplished by qualitative histological analysis of undecalcified sections of transiliac bone biopsies, followed by histomorphometric analysis of standardized static and dynamic parameters. These analyses will provide insight into the effects of setrusumab on bone mineralization and formation at the tissue level, and is required to characterize the safety of setrusumab in this population. |
|
E.3 | Principal inclusion criteria |
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 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 25hydroxyvitamin 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
|
|
E.4 | Principal exclusion criteria |
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. Clinical 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, or other bone anabolic or antiresorptive medications 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 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Phase II: Percent change in serum P1NP from Baseline at Month 1 Phase III: Annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull, during the Double Blind (DB) Treatment Period |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase II: Screening and one month Phase III: The timing of the primary analysis will be determined using a routine blinded information-based assessment approach. Double Blind Treatment Period duration for any single subject will not exceed 24 months. |
|
E.5.2 | Secondary end point(s) |
Phase II: 1) Serum setrusumab concentration at scheduled time points 2) • Baseline-corrected AUEC for serum P1NP over a 1- and 2-month timeframe • Percent change from Baseline in bone turnover markers (P1NP and OCN) over time 3) • Change from Baseline in DXA lumbar spine BMD z-scores over time • Percent change from Baseline in DXA lumbar spine BMD over time 4) Frequency, severity, and relationship to treatment of TEAEs, SAEs, and AESIs 5) Incidence of anti-setrusumab binding and neutralizing antibodies at scheduled time points
Phase III: 1) • Annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures, but including fractures of the fingers, toes, face and skull, during the DB Treatment Period • Annualized rate of all radiographically-confirmed fractures during the DB Treatment Period 2) Change from Baseline in DXA lumbar spine BMD z-score at 12 months 3) Change from Baseline at 12 months 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 4) Frequency, severity, and relationship to treatment of TEAEs, SAEs, and AESIs 5) Incidence of binding and neutralizing anti-setrusumab antibodies at scheduled time points |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase II: setrusumab concentration is measured at baseline, wk 2,3,4, month 1, day 45, month 2, 3, 6, 12, 18 and 24.
Phase III: setrusumab concentration is measured at baseline, week 3, months 1, 2, 3, 6, 12, 18 and 24 - Serum P1NP, CTX, BSAP, OCN at baseline, week 3 and months 1, 2, 3, 6, 12, 18, 24. - Anti-setrusumab binding and neutralizing antibodies at screening, week 3 and months 1, 2, 3, 6, 12, 18, 24. - DXA at 0, 3,6,12, 18 months and 24 months (final visit). - POSNA-PODCI Sports/Physical Functioning measured at 0, 6, 12,18 and 24 months/final visit - SF-36 PF and BP Domain Scales at 0, 6, 12, 18, 24 months /final visit - TEAEs, SAEs, and AESIs - all study visits |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Canada |
United Kingdom |
United States |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Portugal |
Türkiye |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |