E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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 |
To demonstrate that setrusumab increases radial trabecular volumetric bone mineral density (Tr. vBMD) on high resolution peripheral quantitative computed tomography (HRpQCT) and bone strength on finite element analysis (FEA) in patients with OI Type I, III or IV
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E.2.2 | Secondary objectives of the trial |
- To determine the dose-response relationship of Tr.vBMD to setrusumab after 12 months of treatment - To evaluate the onset of treatment effect - To evaluate the effect of setrusumab on fracture rate - To evaluate the effect of setrusumab on vertebral fractures and vertebral height - To evaluate the effect of setrusumab on Bone Mineral Density and bone quality - To evaluate changes in radial Tr.vBMD on HRpQCT and bone strength FEA during the 12 post-setrusumab treatment period - To evaluate the effect of setrusumab on HRpQCT parameters - To evaluate the effect of setrusumab on body composition - To evaluate the effect of setrusumab on markers of bone composition - To evaluate the effect of setrusumab on Patient-Reported Outcomes and Quality of Life - To evaluate the pharmacokinetics (PK) of setrusumab - To evaluate potential induction of anti-drug antibodies by setrusumab and their effect on safety and PK - To evaluate safety and tolerability of setrusumab |
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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 |
Optional bone biopsy sub-study (included in main study protocol, Section 10.1.2).
Bone biopsies will be performed at Month 6 and 12 in a sub-set of participants. Informed consent will be obtained using a specific bone biopsy consent form.
Double labelling of bone, according to the procedure detailed in the MBPS205 Bone Biopsy Manual, will be carried out before the bone biopsy procedure to allow determination of the level of bone turnover, and bone formation and mineralisation rates.
All biopsies will be analysed at a central laboratory as per the MBPS205 Bone Biopsy Manual.
The study will include an open-label substudy in which subjects will receive setrusumab (20 mg/kg). Participants assigned to placebo according to the previous MBPS205 protocol design will be transferred to this open-label treatment group for 12 months. |
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E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply: Type of Participant and Disease Characteristics 1. Patients with a clinical diagnosis of OI Type I, III, or IV with a defect in COL1A1/COL1A2, as confirmed by genetic testing 2. Age ≥ 18 years 3. One or more non-traumatic long-bone, rib, hand/feet and/or vertebral fracture(s) in the past 5 years Sex 4. Male and female NOTE: The reliability of sexual abstinence for female enrolment eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Male participants: 5. There are no contraception requirements for male participants with female partners who are woman of childbearing potential (WOCBP). Female participants: 6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a WOCBP OR b. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 70 days after the last dose of setrusumab treatment. Informed Consent 7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply: 1. Age > 75 years 2. History of skeletal malignancies or bone metastases at any time 3. History of neural foraminal stenosis (except if due to scoliosis) 4. History of myocardial infarction, angina pectoris, ischaemic stroke or transient ischaemic attack 5. History of or concomitant uncontrolled diseases such as hypo-/hyperparathyroidism, hypo-/hyperthyroidism, Paget’s disease, abnormal thyroid function or thyroid disease or other endocrine disorders or conditions that could affect bone metabolism e.g. Stage IV/V renal disease 6. A history of rickets or osteomalacia or any skeletal condition (other than OI) leading to long-bone deformities and/or increased risk of fractures 7. 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/baseline assessments 8. Documented history of significant psychiatric or medical disorder that would prevent the participant complying with the requirements of the protocol or would make it unsafe for the participant to participate in the study as judged by the investigator 9. Current/previously reported allergy to the study drug or any of its excipients or the class of drug under investigation Prior/Concomitant Therapy 10. History of external radiation 11. Treatment with any bisphosphonates 3 months prior to baseline and teriparatide, denosumab or other anabolic and anti-reabsorptive medications within 6 months prior to baseline. Note: treatment with zoledronic acid during the follow-up period is explicitly allowed at Months 12 and 18 only at the discretion of the treating physician. Prior/Concurrent Clinical Study Experience 12. Participation in any clinical investigation within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initial dosing (or longer if required by local regulations) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Tr. vBMD (radius) on HRpQCT and bone strength on FEA at 12 months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, 6 month and 12 month visits. HRpQCT scans will also be conducted at month 3 for participants receiving open-label treatment |
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E.5.2 | Secondary end point(s) |
- Tr. vBMD (radius) on HRpQCT at 12 months - Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA at 6 months - Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA at 3, 6 & 12 months in the open-label treatment arm - Total fracture rate, peripheral fracture rate, vertebral fracture rate, long-bone fracture rate from baseline at 12 months - Changes in vertebral fractures and vertebral height with Genant’s semi-quantitative method and 6-point quantitative morphometry from baseline at 6 and 12 months - Changes in lumbar, whole body, and proximal femur dual-energy x-ray absorptiometry bone mineral density (DXA BMD) (absolute and T-score) from baseline at Month 6 and Month 12. - Changes in bone histomorphometry - Tr.vBMD on HRpQCT and bone strength on FEA at 18 and 24 months - Changes (tibial and radial) in Total vBMD, cortical vBMD, bone volume fraction (BV/TV), peripheral to medullary trabecular bone density ratio (Met/Inn), trabecular thickness (TbTh), trabecular number (TbN), Inhomogeneity, cortical thickness, and cortical porosity from baseline at 6, 12, 18 and 24 months - Changes in Tr. vBMD (tibia) from baseline at 12, 18 and 24 months - Changes (tibial and radial) in Total vBMD, cortical vBMD, bone volume fraction (BV/TV), peripheral to medullary trabecular bone density ratio (Met/Inn), trabecular thickness (TbTh), trabecular number (TbN), Inhomogeneity, cortical thickness, and cortical porosityon HRpQCT and bone strength on FEA at 3 months in the open-label treatment arm. - Changes in body height, weight and body mass index (BMI) from baseline at 6 and 12 months - Changes in lean and fat body mass from whole body DXA - Changes in bone turnover markers and metabolic biomarkers associated with bone (parathyroid hormone [PTH], P1NP, P1CP, osteocalcin [OC], BSAP, carboxy-terminal telo-peptide [CTX-1], amino-terminal telo-peptide [NTX-1], receptor activator of nuclear factor kappa-B ligand [RANKL], osteoprotegerin, transforming growth factor beta [TGF-β], sclerostin, released C terminal pro-peptide of Type V collagen [Pro-C5], neo-epitope of MMP-2,9 mediated degradation of Type V collagen [C5M]) from baseline and each visit. - Change in total scores from baseline to Month 6 and 12 on Short Form 12 Health Survey (SF-12, ), EuroQol 5-dimension 5-level descriptive system (EQ- 5D- 5L) and Osteogenesis Imperfecta specific Quality of Life Questionnaire for Adults (OIQoL-A.) - Change in OIQoL-A pain and activity sub-scale scores from baseline to Month 6 and 12. - Serum concentrations of setrusumab - Serum concentrations of anti-setrusumab antibodies - Serum concentrations of setrusumab neutralising antibodies - Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs) - Infusion site reactions - Vital signs - Physical examinations - ECG - Clinical laboratory tests |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, 6 and 12 month visits, except: - Tr. vBMD (tibia & radius) and bone strength; changes in Tr. vBMD (tibia): screening and 6 month visit - Changes in bone turnover markers and metabolic biomarkers associated with bone: baseline, 1, 3, 6, 9 and 12 month visits - TEAEs, TESAEs vital signs: all study visits - Serum concentrations of setrusumab, anti-setrusumab antibodies and setrusumab neutralising antibodies - baseline, Day 8 post-baseline (optional), 1, 2, 3, 6, 12 and 14 month visits - Infusion site reactions: baseline, 1-11 month visits - ECG: screening, 6, 12, 14 month visits - Clinical laboratory tests: screening, baseline, 1, 2, 3, 6, 9, 12, 14, 18 and 24 month visits
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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 | No |
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 | Yes |
E.6.13 | Others | No |
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) | No |
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 | Yes |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Subjects will be randomised to 3 double-blinded doses of setrusumab and an open-label treatment arm |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Canada |
Denmark |
France |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |