| 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
| |
| 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, including morphometric vertebral fractures
-Evaluate the effect of setrusumab vs placebo on lumbar spine BMD
- Evaluate the effect of setrusumab vs placebo on functional assessments and patient-/caregiver-reported health-related quality of life, including pain
- 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 | No |
| E.3 | Principal inclusion criteria | 1. Males and females 5 to < 26 years of age at time of informed consent
2. Confirmed diagnosis of OI Types I, III, or IV as confirmed by identification of genetic mutation in COL1A1 or COL1A2
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, the subject may be rescreened after a minimum of 14 days of vitamin D supplementation as directed by their 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 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.
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 such as Stage IV/V renal disease
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. Bisphosphonate use prior to Screening that is a minimum of 3 months or the length of the dosing interval (eg, ≥ 4 months off bisphosphonates if dosing is every 4 months) up to 6 months, even if the dosing interval exceeds 6 months.
b. Teriparatide, growth hormone, or other bone anabolic or anti-resorptive medications within 6 months of Screening
c. Denosumab within 24 months of Screening
11. 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
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
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 during the double-blind Treatment Period | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Phase II: Screening and one month
Phase III: Annually 12 and 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, CTX, BSAP, 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, including morphometric vertebral fractures, during the double-blind Treatment Period
2) Change from Baseline in DXA lumbar spine BMD z-score at 18 months (or at 12 months if primary analysis occurs before all subjects have completed 18 months of treatment)
3) Change from Baseline at 18 months (or at 12 months if primary analysis occurs before all subjects have completed 18 months of treatment) in:
• 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 | No |
| E.8.1.3 | Single blind | No |
| 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 | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 States | | Turkey | | Denmark | | France | | Germany | | Italy | | Netherlands | | Poland | | Portugal | | United Kingdom | |
| 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 |
