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    Summary
    EudraCT Number:2016-005096-27
    Sponsor's Protocol Code Number:MBPS205
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2016-005096-27
    A.3Full title of the trial
    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).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of test product setrusumab in adults with brittle bone syndrome.
    A.4.1Sponsor's protocol code numberMBPS205
    A.5.4Other Identifiers
    Name:IND NumberNumber:113385
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMereo BioPharma 3 Ltd.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMereo BioPharma Group Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMereo Biopharma 3 Ltd.
    B.5.2Functional name of contact pointClinical Operations Department
    B.5.3 Address:
    B.5.3.1Street Address1 Cavendish Place
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1G 0QF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number03330237300
    B.5.5Fax number03330237301
    B.5.6E-mailenquiries@mereobiopharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1686
    D.3 Description of the IMP
    D.3.1Product namesetrusumab
    D.3.2Product code BPS804
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsetrusumab
    D.3.9.3Other descriptive nameANTI-SCLEROSTIN MONOCLONAL ANTIBODY
    D.3.9.4EV Substance CodeSUB32049
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Zoledronic Acid Kern Pharma 4 mg/100 mL solution for infusion,generic medicinal product
    D.2.1.1.2Name of the Marketing Authorisation holderKern Pharma, S.L
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZoledronic Acid Kern Pharma 4 mg/100 mL solution for infusion, generic medicinal product.
    D.3.4Pharmaceutical form Solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZOLEDRONIC ACID
    D.3.9.1CAS number 118072-93-8
    D.3.9.4EV Substance CodeSUB00176MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteogenesis imperfecta
    E.1.1.1Medical condition in easily understood language
    Brittle bone syndrome
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10031243
    E.1.2Term Osteogenesis imperfecta
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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 (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
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.
    E.3Principal 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.
    E.4Principal 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)
    E.5 End points
    E.5.1Primary end point(s)
    Tr. vBMD (radius) on HRpQCT and bone strength on FEA at 12 months.
    E.5.1.1Timepoint(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
    E.5.2Secondary 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-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
    E.5.2.1Timepoint(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

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Subjects will be randomised to 3 double-blinded doses of setrusumab and an open-label treatment arm
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 68
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Participants completing the MBPS205 study will be to able discuss other potential treatments for their osteogenesis imperfecta with their investigators when they complete the 12-month follow up period at the end of MBPS205.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-11-12
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