A study of test product setrusumab in adults with brittle bone syndrome.

• Register: EUCTR
• Last refreshed on: 5 April 2021
• Main ID: EUCTR2016-005096-27-DK
• Date of registration: 24/03/2017
• Prospective Registration: Yes
• Primary sponsor: Mereo BioPharma 3 Ltd.
• Public title: A study of test product setrusumab in adults with brittle bone syndrome.
• Scientific title: A Phase 2b, Multicentre, Multinational, Double-blind, Dose-finding Study, incorporating an open label substudy, in Adult Patients with Type I, III or IV Osteogenesis Imperfecta Treated with setrusumab (BPS804).
• Date of first enrolment: 23/06/2017
• Target sample size: 100
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-005096-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Subjects will be randomised to 3 double-blinded doses of setrusumab and an open-label treatment arm; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Denmark, France, United Kingdom, United States

Contacts

• Name: Clinical Operations Department
• Affiliation: Mereo Biopharma 3 Ltd.

• Name: Clinical Operations Department
• Affiliation: Mereo Biopharma 3 Ltd.

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 68
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 32

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)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Osteogenesis imperfecta
MedDRA version: 20.0 Level: PT Classification code 10031243 Term: Osteogenesis imperfecta System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: setrusumab
Product Code: BPS804
Pharmaceutical Form: Lyophilisate for solution for infusion
INN or Proposed INN: setrusumab
Other descriptive name: ANTI-SCLEROSTIN MONOCLONAL ANTIBODY
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Trade Name: Zoledronic Acid Kern Pharma 4 mg/100 mL solution for infusion,generic medicinal product
Product Name: Zoledronic Acid Kern Pharma 4 mg/100 mL solution for infusion, generic medicinal product.
Pharmaceutical Form: Solvent for solution for infusion
INN or Proposed INN: ZOLEDRONIC ACID
CAS Number: 118072-93-8
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Primary Outcome(s)

Main Objective: 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

Primary end point(s): Tr. vBMD (radius) on HRpQCT and bone strength on FEA at 12 months.

Secondary Objective: - 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 (PROs) and Quality of Life (QoL)
- To evaluate the pharmacokinetics (PK) of setrusumab
- To evaluate potential induction of anti-drug antibodies (ADAs) by setrusumab and their effect on safety and PK
- To evaluate safety and tolerability of setrusumab

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

Secondary Outcome(s)

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 and 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
- 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 and 12 months
- Changes in Tr. vBMD (tibia) from baseline at 12 months
- 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-ß], 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

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

Secondary ID(s)

MBPS205

113385

Source(s) of Monetary Support

Mereo BioPharma Group Limited

Ethics review

Status: Approved
Approval date: 01/06/2017
Contact: