Clinical trial NCT03118570
Conditions: Osteogenesis Imperfecta, Type I Osteogenesis Imperfecta Type III Osteogenesis Imperfecta Type IV
Keywords: Osteogenesis Imperfecta Brittle Bone Disease
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2017-09-11; Completion date: 2020-11-12
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to select a suitable dose of BPS804 by measuring the strength/quality of bone using a special type of CT scanner. Participants will be treated for 12 months and followed up for a further 12 months.

Detailed description:
This study was previously posted by Mereo Biopharma and was transferred to Ultragenyx in February 2021.

Arms: arm 1: Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. arm 2: Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. arm 3: Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. arm 4: Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. arm 5: Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
Interventions: intervention 1: setrusumab intervention 2: Calcium intervention 3: Vitamin D intervention 4: zoledronic acid (optional)
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: tablets intervention 3: capsules intervention 4: Following completion of the study treatment (Month 12) participants can receive an optional single dose of zoledronic acid. Participants can receive an optional further dose of zoledronic acid at Month 18 at the discretion of their treating physician.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol MBPS205 
Mereo Biopharma 3 Ltd. 
1 
Protocol 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). 
Protocol Number: MBPS205 Amendment 6 
Compound Number: BPS804 
Sponsor Name and Legal Registered Address: Mereo BioPharma 3 Ltd. 1 Cavendish Place, 
London, W1G 0QF 
Regulatory Agency Identifying Number(s): 
EuDRACT Number: 2016-005096-27  
IND Number: 113385 
Approval Date: 19 July 2019 
Version: 7  Date: 19 Jul 2019
Please see appendix 9 for summaries of amendment changes


CONFIDENTIAL 
Protocol MBPS205 
 
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Table of Contents 
 
1. 
Synopsis............................................................................................................................5 
2. 
Schedule of Activities (SoA) Treatment Period .........................................................14 
3. 
Schedule of Activities (SoA) Follow-Up Period ..........................................................18 
4. 
Introduction ...................................................................................................................20 
4.1. 
Background .....................................................................................................................20 
4.2. 
Study Rationale ...............................................................................................................21 
4.3. 
Benefit/Risk Assessment ................................................................................................22 
5. 
Objectives and Endpoints ............................................................................................23 
6. 
Study Design ..................................................................................................................27 
6.1. 
Overall Design ................................................................................................................27 
6.2. 
Number of Participants ...................................................................................................27 
6.3. 
End of Study Definition ..................................................................................................27 
6.4. 
Scientific Rationale for Study Design ............................................................................27 
6.5. 
Justification for Dose Selection ......................................................................................29 
7. 
Study Population ...........................................................................................................29 
7.1. 
Inclusion Criteria ............................................................................................................29 
7.2. 
Exclusion Criteria ...........................................................................................................30 
7.3. 
Lifestyle Restrictions ......................................................................................................31 
7.3.1. 
Meals and Dietary Restrictions .......................................................................................31 
7.4. 
Screen Failures ................................................................................................................31 
8. 
Treatments .....................................................................................................................32 
8.1. 
Treatments Administered ................................................................................................33 
8.1.1. 
Zoledronic acid therapy ..................................................................................................33 
8.2. 
Method of Treatment Assignment ..................................................................................34 
8.3. 
Blinding ..........................................................................................................................34 
8.4. 
Preparation/Handling/Storage/Accountability ................................................................34 
8.5. 
Treatment Compliance ....................................................................................................35 
8.6. 
Concomitant Therapy .....................................................................................................35 
8.7. 
Treatment After the End of the Study .............................................................................36 
9. 
Discontinuation Criteria...............................................................................................37 
9.1. 
Discontinuation of Study Treatment ...............................................................................37 
9.1.1. 
Temporary Discontinuation ............................................................................................38 
9.1.2. 
Rechallenge .....................................................................................................................38 
9.2. 
Discontinuation from the Study ......................................................................................38 
9.3. 
Lost to Follow-Up ...........................................................................................................39 
10. 
Study Assessments and Procedures.............................................................................39 
10.1. 
Efficacy Assessments .....................................................................................................39 
10.1.1. Radiology ........................................................................................................................39 
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10.1.2. Bone Biopsy ....................................................................................................................41 
10.1.3. Audiometry .....................................................................................................................41 
10.1.4. Patient-Reported Quality of Life ....................................................................................41 
10.2. 
Adverse Events ...............................................................................................................42 
10.2.1. Time Period and Frequency for Collecting AE and SAE/AESI 
Information .....................................................................................................................42 
10.2.2. Method of Detecting AE and SAE/AESI ........................................................................42 
10.2.3. Follow-up of AE and SAE/AESI ....................................................................................42 
10.2.4. Regulatory Reporting Requirements for SAE ................................................................43 
10.2.5. Pregnancy ........................................................................................................................43 
10.3. 
Treatment of Overdose ...................................................................................................43 
10.4. 
Safety ..............................................................................................................................44 
10.4.1. Physical Examinations ....................................................................................................44 
10.4.2. Vital Signs .......................................................................................................................44 
10.4.3. Electrocardiograms .........................................................................................................44 
10.4.4. Clinical Safety Laboratory Assessments ........................................................................44 
10.5. 
Pharmacokinetics ............................................................................................................45 
10.6. 
Pre-Screening Genetics ...................................................................................................45 
10.7. 
Biomarkers ......................................................................................................................46 
10.8. 
Immunogenicity Assessments.........................................................................................46 
10.9. 
Medical Resource Utilisation and Health Economics ....................................................47 
11. 
Statistical Considerations .............................................................................................47 
11.1. 
Sample Size Determination ............................................................................................47 
11.2. 
Populations for Analyses ................................................................................................48 
11.3. 
Statistical Analyses .........................................................................................................49 
11.3.1. Efficacy Analyses ...........................................................................................................50 
11.3.2. Safety Analyses ...............................................................................................................53 
11.3.3. Other Analyses ................................................................................................................54 
11.3.4. Follow-Up Period Analyses ............................................................................................54 
11.3.5. Interim Analyses .............................................................................................................54 
12. 
References ......................................................................................................................55 
13. 
Appendices .....................................................................................................................57 
Appendix 1: Abbreviations and Trademarks .................................................................................58 
Appendix 2: Clinical Laboratory Tests ..........................................................................................61 
Appendix 3: Study Governance Considerations ............................................................................63 
Regulatory and Ethical Considerations .................................................................................63 
Financial Disclosure ..............................................................................................................63 
Informed Consent Process ....................................................................................................63 
Data Protection ......................................................................................................................64 
Committees Structure ............................................................................................................64 
Publication Policy .................................................................................................................64 
Dissemination of Clinical Study Data ...................................................................................65 
Data Quality Assurance ........................................................................................................65 
Source Documents ................................................................................................................66 
Study and Site Closure ..........................................................................................................66 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................67
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information .....................................................................................................................73
Definitions .............................................................................................................................73
Contraception Guidance ........................................................................................................73
Pregnancy Testing .................................................................................................................74
Collection of Pregnancy Information ....................................................................................75
Appendix 6: Radiation Exposure ...................................................................................................76
Appendix 7: Audiometry Scale ......................................................................................................77
Appendix 8: MBPS205 Study Oversight .......................................................................................78
Appendix 9: Summary of Versions and Changes ..........................................................................79
Appendix 10: Sponsor Electronic Signature ..................................................................................91
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1. 
Synopsis 
Protocol 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) 
Rationale: 
There is limited clinical experience with setrusumab (BPS804) in the Osteogenesis Imperfecta 
(OI) patient population. MBPS205 will be the first study to investigate dose-response to 
setrusumab in a large cohort of Type I, III and IV OI patients.  
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 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 
 Tr. vBMD (radius) on HRpQCT and bone 
strength on FEA at 12 months. 
 
Secondary 
 To 
determine 
the 
dose-response 
relationship 
of 
Tr. 
vBMD 
to 
setrusumab 
after 
12 
months 
of 
treatment 
 Tr. vBMD (radius) on HRpQCT at          
12 months. 
 To evaluate the onset of treatment 
effect 
 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. 
 
 To evaluate the effect of setrusumab on 
fracture 
rate 
(peripheral, 
major 
[long-bone], and vertebral fractures)  
 
 Total fracture rate at 12 months 
 Peripheral fracture rate at 12 months 
 Vertebral fracture rate at 12 months 
 Long-bone fracture rate at 12 months 
 
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Objectives 
Endpoints 
 To evaluate the effect of setrusumab on 
vertebral fractures and vertebral height 
 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 
 To evaluate the effect of setrusumab on 
bone mineral density (BMD) 
 Changes in lumbar, whole body, and 
proximal femur dual-energy x-ray 
absorptiometry (DXA) BMD (absolute 
and T-score) from baseline at Month 6 and 
Month 12. 
 To evaluate the effect of setrusumab on 
bone quality 
 Changes in bone histomorphometry 
 
 To 
evaluate 
changes 
in 
radial 
Tr. vBMD on HRpQCT and bone 
strength FEA during the 12 months 
post-setrusumab treatment period 
 Tr. vBMD (tibia & radius) on HRpQCT 
and bone strength on FEA at 18 and 24 
months 
 To evaluate the effect of setrusumab on 
HRpQCT parameters 
 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 porosity on 
HRpQCT and bone strength on FEA at 3 
months in the open-label treatment arm. 
 To evaluate the effect of setrusumab on 
body composition 
 Changes in body height, weight and body 
mass index from baseline at 6 and 12 
months 
 Changes in lean and fat body mass from 
whole body DXA  
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Objectives 
Endpoints 
 To evaluate the effect of setrusumab on 
markers of bone composition 
 Changes in bone turnover markers and 
metabolic biomarkers associated with 
bone (parathyroid hormone [PTH], 
amino-terminal propeptide of type 1 
procollagen [P1NP], carboxy-terminal 
propeptide of type 1 procollagen [P1CP], 
osteocalcin [OC], bone-specific alkaline 
phosphatase [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-], 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 
 To evaluate the effect of setrusumab on 
Patient-Reported Outcomes (PROs) 
and Quality of Life (QoL) 
 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 
 To evaluate the pharmacokinetics (PK) 
of setrusumab 
 Serum concentrations of setrusumab 
 To evaluate potential induction of anti-
drug antibodies (ADAs) by setrusumab 
and their effect on safety and PK 
 Serum concentrations of anti-setrusumab 
antibodies 
 Serum 
concentrations 
of 
setrusumab 
neutralising antibodies 
 To evaluate safety and tolerability of 
setrusumab 
 Treatment-emergent adverse events 
(TEAEs), treatment-emergent serious 
adverse events (TESAEs) 
 Infusion site reactions 
 Vital signs 
 Physical examinations 
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Objectives 
Endpoints 
Electrocardiogram
Clinical laboratory tests
Tertiary/Exploratory 

To evaluate the effect of setrusumab on
bone quality

Changes in Trabecular Bone Score from
baseline at 6 and 12 months

To evaluate the effect of setrusumab on
changes in use of physical aids

Changes in usage or need for physical aids
from baseline at 12 months

To evaluate the effect of setrusumab on
hearing

Change in auditory function from baseline
at 12 months in a subset of patients

To evaluate the effect of setrusumab on
bone 
formation 
and 
resorption
parameters measured by HRpQCT

Change in bone formation from baseline
at 6 and 12 months

Normalised newly mineralised bone
volume (MV/BV)

Normalised newly mineralised
surface area (MS/BS)

Mineralised thickness (MTh)

Normalised formation patch number
density (N.F. Patch/BV)

Formation patch volume
(F.PatchVol.)

3D bone formation rate (3D
BFR/BS)

3D mineral apposition rate (3D
MAR)

Change in bone resorption from baseline
at 6 and 12 months

Normalised newly eroded bone
volume (EV/BV)

Normalised newly eroded surface
area (ES/BS)

Erosion depth (ED)

Normalised resorption cavity
number density (N.R.Cav./BV)

Resorption cavity volume
(R.Cav.Vol.)

3D bone resorption rate (3D
BRR/BS)
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Objectives 
Endpoints 

3D mineral resorption rates (3D
MRR)
Overall Design: 

MBPS205 is a phase 2b, multicentre, multinational, double-blind, dose-finding study
with 3 blinded doses of setrusumab (20 mg/kg, 8 mg/kg and 2 mg/kg) and an open-label
treatment arm (20 mg/kg) in patients diagnosed with Type I, III or IV OI.

Participants will be adults clinically diagnosed with either Type I, III or IV OI and a
confirmed COL1A1/COL1A2 mutation who have fractured in the previous 5 years.

Participants will be excluded if they are over 75 years old, have a history of certain
cardiac events, have confounding skeletal or other medical conditions and/or have been
treated with bisphosphonates in the previous 3 months or other anabolic or anti-
reabsorptive medications in the previous 6 months.

Participants will have HRpQCT scans of their non-dominant distal radius at baseline,
3-month (for open-label participants only), 6-month and 12-month time points to
determine the effect of treatment on Tr. vBMD with the primary analysis and dose
determination being made after all enrolled patients have completed their 12-month
HRpQCT scan.

Other investigations include study of sparse PK, monitoring for safety and tolerability
including immunogenicity, and measurement of the effect of treatment on bone quality,
fractures, QoL and utilisation of resources e.g. physical aids and hospitalisation.

Following completion of the study treatment participants will enter 12 months follow-up
and will have visits at Months 14, 18 and 24. Participants will also receive follow-up
telephone calls at Months 16 and 21.

During the follow-up period all participants will have the option to receive zoledronic
acid at Month 12 and Month 18 at the discretion of their treating physician.

During the follow-up period participants will have HRpQCT scans of their non-dominant
distal radius and tibia at Month 18 and Month 24.

For the purposes of the study protocol 1 month is defined as 28 days.

An Independent Data Monitoring Committee will monitor safety throughout the study
and make recommendations on the selected dose.
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MBPS205 Study Schematic 
Number of Participants: 
The number of participants is based on power considerations for the trabecular vBMD (radius) 
derived from HRpQCT at Month 12. The primary analysis method for this endpoint will be on 
the change from baseline within each treatment group, so the primary hypothesis to be tested is 
H0: µT ≤ 0 vs. H1: µT > 0 
where µT denotes the change from baseline for each dose of Setrusumab. Under the assumptions 
of a maximum change from baseline of 
, a standard deviation at both timepoints 
of 
 and a correlation between both measurements of 
, a sample size of 
25 patients per group yields approximately 80% power for a one-sided test with significance 
level 0.025, if the data are analysed on the log scale using a t-test. 
For a change from baseline of 
, with standard deviation as above the one-sided 
test would have a probability of 80% to yield a p-value below 5%, being considered indicative of 
a trend. 
Following a review of the trabecular vBMD (radius) derived from HRpQCT at Month 6 of those 
subjects within the 20 mg/kg Setrusumab open label treatment group, a change from baseline 
standard deviation of 
³ was observed. This yields to a correlation between 
baseline and Month 6 visits of 
 (much higher than the 
 that was originally assumed). If 
such a correlation is observed at Month 12, given 25 subjects per arm, the one-sided test would 
have a probability of 80% to yield a p-value below 5% for a change in baseline of 
 
.   
As a secondary analysis, the MCPMod approach will be applied to the data in order to assess a 
non-flat dose-response curve and to obtain information about the underlying dose-response 
curve. Due to the missing placebo group, the power of this approach depends heavily on the 
underlying dose-response curve.  
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The following candidate models will be used: 

EMax (ED50 of 1.5 mg)

Exponential (δ = 2)
Under the assumptions of each of the two candidate models being the true dose-response curve, 
and in addition an Sigmoid EMax model with parameters ED50 = 10 mg and h = 2.4, a contrast 
test at a one-sided significance level of 2.5% has the following power for each of the three 
models: 
Model EMax 
Exponential Sigmoid EMax 
Power 13.7% 73.2% 
60.7% 
The total sample size required is therefore determined as 100: 

25 participants on open-label setrusumab (20 mg/kg)

25 participants on each of the active arms (2 mg/kg, 8 mg/kg, 20 mg/kg)
Approximately 100 participants will be randomised. 
Treatment Groups and Duration: 

Participants will be qualified during a 28-day screening period, followed by 12 months of
study treatment. At the end of treatment in MBPS205, participants will continue into the
follow-up period for 12 months. Participants discontinuing setrusumab treatment prior to
the end of the treatment phase for any reason will complete the end of treatment visit and
the 60-day follow-up visit.

After screening, participants will be randomised to 1:1:1:1 to blinded 20 mg/kg, 8 mg/kg
and 2 mg/kg setrusumab or to open label 20 mg/kg setrusumab.

Any participants assigned to placebo according to the previous MBPS205 protocol design
will be transferred to open-label 20 mg/kg treatment for 12 months.

Allocation of treatment will be via Interactive Web Response System (IWRS), which will
also calculate total doses of setrusumab based on participant body weight and track vials
allocation to patients.

Investigators and participants will be blinded to the blinded active arms study treatment
allocation throughout the study; pharmacists will be unblinded to study allocation to
allow for dispensing and reconstitution. The sponsor will be initially blinded but become
unblinded after the primary analysis at which time all the participants will have been
enrolled.

All participants will receive monthly 60-minute infusions of 250 mL 5% dextrose with
setrusumab.
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Statistical Methods: 
General Statistical Methods 
The evaluation of the primary efficacy endpoint will be performed on the full analysis set (FAS, 
intention to treat analysis). Results for the per-protocol analysis set will be considered 
supportive. Safety endpoints will be analysed on the safety analysis set. The primary analysis 
will be performed after all patients have completed their initial 12-month study period or have 
withdrawn prior to completion. Analyses for the follow-up period will be carried out separately 
to the primary analysis once all patients have completed the 12 months follow-up period, or have 
withdrawn from it. 
Generally, data will be tabulated by treatment group. Both descriptive and inferential statistics 
will be presented as appropriate. Categorical data will be described using absolute and relative 
frequencies; for continuous variables, the following descriptive summary statistics will be 
presented: number of observations, arithmetic mean, standard deviation, minimum, lower 
quartile, median, upper quartile, maximum. Continuous variables will be log transformed where 
appropriate. Time to event variables (e.g., time to first fracture) will be analysed using 
Kaplan-Meier methods, and quartiles for the median time to event will be presented together 
with their 95% confidence intervals. 
Data for placebo participants and open-label BPS804 20 mg/kg participants will be reported 
separately from the comparison between the randomized, blinded treatment groups. In particular 
for the primary analysis, the open-label BPS804 20 mg/kg participants’ data will not be pooled 
with the blinded BPS804 20 mg/kg participants’ data. 
Efficacy Analysis 
The HRpQCT results will be log transformed and an ANCOVA model will be used to calculate 
Least Square Means (LSMeans) for the change from baseline, using baseline values as a 
covariate and treatment group and stratum as a factor. LSMeans for each treatment group will be 
calculated and tested against the null hypothesis of 0 in an a priori hierarchical approach, starting 
with the highest dose. Differences between LSMeans will also be displayed but will be analysed 
in an exploratory fashion only. The type I error rate will be 5% two-sided. P-values above 5% 
but below 10% (two-sided) will be considered as indicative for a trend. 
The LSMeans will further be analysed using the MCPMod methodology, using the following 
candidate models: 
 EMax (ED50 of 1.5 mg) 
 Exponential (δ = 2) 
 Sigmoid EMax model with parameters ED50 = 10 mg and h = 2.4 
Parameter estimates and predicted values for each dose will be calculated for all models. These 
analyses will be done primarily on the trabecular vBMD (radius). It will be repeated for the bone 
strength on FEA for supportive evidence. 
LSMeans and LSMean differences between treatment groups will be back-transformed to their 
original scale for descriptive purposes. After substracting the geometric mean of the log baseline 
values, the back-transformed LSMeans will correspond to the percentage change from baseline, 
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while the back-transformed LSMeans differences will correspond to the ratio of percentage 
changes from baseline. 
The remaining efficacy variables will be analysed according to their scale using general methods 
as described above. 
Exploratory Analyses 
Exploratory endpoint variables will be analysed according to their scale using general methods 
as described above. 
Safety Analyses 
Variables will be analysed according to their scale using general methods as described above, 
and results will be presented overall and by treatment group. 
Follow-Up Period Analyses 
Variables will be analysed according to their scale using general methods as described above. 
Results will be presented overall and by initial treatment assignment. In addition, subgroup 
analyses will be performed for HRpQCT, DXA, vertebral radiograph, CTX-1 and P1NP based 
on the administration of zoledronic acid during the follow-up phase (none; at Month 12; at 
Month 18). Also, the frequency of administration of zoledronic acid during the follow-up phase 
will be related both to the site and to the 12 months outcome for both primary efficacy endpoints. 
HRpQCT Validation Analysis 
Validation analyses to the HRpQCT measurements will be described in a separate analysis plan. 
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2. 
Schedule of Activities (SoA) Treatment Period  
Procedure 
Screening  
(up to 28 
days 
before Day 
1) 
Months  
Notes 
All visits ± 4 
days. 
Base-
line 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
EOT/ 
12 
 
COL1A1/COL1
A2 Mutation 
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
If not available, 
consent can be 
obtained and test 
conducted prior to 
main study 
screening 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main study 
consent and bone 
biopsy  
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re-confirm at 
Baseline 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination 
including height 
and weight 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Brief physical 
examination 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Past and current 
medical 
conditions   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the last 
2 years 
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Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Months 
Notes 
All visits ± 4 
days. 
Base-
line 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
EOT/ 
12 
Serum pregnancy 
test (WOCBP 
only) 
X 
Urine pregnancy 
tests (WOCBP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
To be collected 
pre-dose 
25-OH-Vitamin
D
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
X 
Study treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight will be 
measured to 
calculate dose 
HRpQCT 
X 
X 
X 
X 
M6 and M12 
scans be 
conducted ±7days 
of visit 
M3 for open-label 
participants only 
DXA 
X 
X 
X 
Calcium tablets 
should not be 
taken 2 hours 
prior to DXA 
lumbar scan 
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Procedure 
Screening  
(up to 28 
days 
before Day 
1) 
Months  
Notes 
All visits ± 4 
days. 
Base-
line 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
EOT/ 
12 
 
Vertebral 
Radiograph 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Fracture 
Assessment & 
Radiograph 
 
=========================================================== 
Radiographs will 
be taken in the 
event of a 
symptomatic 
fracture 
Bone Biomarkers 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Fasting pre-dose 
blood draw, Sub-
set of patients will 
have additional 
blood draws at 8 d 
post- baseline 
(+4 days) and 
14 d post-M9 
visit. 
Bone Biopsy 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Sub-set of 
participants. 
Completed once 
either at M6 or 
M12 
Audiometry 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
This procedure 
can be omitted if 
the investigative 
site does not have 
the capability to 
complete the 
audiometry 
assessment 
Patient-Reported 
Outcomes 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
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Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Months 
Notes 
All visits ± 4 
days. 
Base-
line 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
EOT/ 
12 
Setrusumab PK 
X 
X 
X 
X 
X 
X 
Sub-set of patients 
will have 
additional blood 
draws at 8 d post-
baseline. Samples 
taken pre-dose 
and 10 mins post-
dose at treatment 
visits. One sample 
taken at non-
treatment visits 
Anti-setrusumab 
Antibodies 
X 
X 
X 
X 
X 
X 
Sub-set of patients 
will have 
additional blood 
draws at 8 d post 
baseline. 
Taken pre-dose 
for treatment 
visits 
Zoledronic acid 
treatment 
X 
Optional. Can be 
administered up to 
2 months 
following the visit 
AE/SAE/AESI 
review 
==========================================================
Concomitant 
medication & 
physical 
aid/treatment 
review 
==========================================================
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3. 
Schedule of Activities (SoA) Follow-Up Period 
Procedure 
Months  
Notes 
All visits ± 4 days. 
14 
(Follow-up 
visit +60 
days) 
16 
 
18 
21 
24 
 
Follow-up call 
 
X 
 
X 
 
 
Brief physical 
examination 
X 
 
X 
 
X 
 
Urine pregnancy tests 
(WOCBP) 
X 
 
 
 
 
 
Safety Laboratory 
assessments  
X 
 
X 
 
X 
 
25-OH-Vitamin D 
X 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
Vital signs 
X 
 
X 
 
X 
 
HRpQCT 
 
 
X 
 
X 
Scans be conducted ±7 days 
of visit 
DXA 
 
 
X 
 
X 
Calcium tablets should not 
be taken 2 hours prior to 
DXA lumbar scan 
Vertebral Radiograph 
 
 
X 
 
X 
 
Fracture Assessment 
& Radiograph 
========================================= 
Radiographs will be taken 
in the event of a 
symptomatic fracture 
Patient-Reported 
Outcomes 
 
 
X 
 
X 
 
Setrusumab PK 
X 
 
 
 
 
One sample taken at 
non-treatment visits 
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Procedure 
Months  
Notes 
All visits ± 4 days. 
14 
(Follow-up 
visit +60 
days) 
16 
 
18 
21 
24 
 
Anti-setrusumab 
Antibodies 
X 
 
 
 
 
 
CTX-1 & P1NP 
X 
 
X 
 
 
Tested locally. 
± 2 months of visit 
Zoledronic acid 
treatment 
 
 
X 
 
 
Optional. Can be 
administered ± 1 month 
from visit 
AE/SAE/AESI 
review 
============================================ 
Reporting only SAEs only 
after Month 14 
Concomitant 
medication & 
physical 
aid/treatment review 
============================================ 
 
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4. 
Introduction 
4.1. 
Background 
Osteogenesis imperfecta (OI) is a serious and debilitating genetic disorder that is characterised 
by fragile bones that break easily, often with little or no physical trauma. Patients may suffer 
from recurrent fractures, bone deformity, bone pain, muscle weakness, hearing loss, fatigue, joint 
laxity, curved bones, scoliosis and short stature. In the most severe cases, OI can be 
life-threatening. It has been shown that patients with OI have a higher mortality rate, at all ages, 
with an increased risk of death from respiratory diseases, gastrointestinal diseases and trauma. 
Basilar invagination may lead to neurological consequences. Diagnosis of OI is based on the 
clinical features of the disease but may be confirmed by collagen or DNA testing. OI comprises 
of a group of disorders which primarily arise from mutation in the genes encoding Type I 
collagen. In about 85% of cases, autosomal dominant OI is caused by mutations in COL1A1 and 
COL1A2 genes (17q21.33 and 7q21.3) which encode the alpha 1and 2 chains of Type 1 
collagen. Autosomal recessive forms of OI are also observed and are caused by mutations in the 
LEPRE1, CRTAP, and PPIB genes (1p34.1, 3p22 and 15q21-q22). Autosomal recessive forms 
are in most cases severe or even lethal (Willaert et al, 2009; Ward et al, 2002; 
Lindahl et al, 2014; Valadares et al, 2014).  
Setrusumab is a fully human anti-sclerostin neutralising monoclonal antibody. Sclerostin, 
encoded for by the SOST gene, is an osteocyte-secreted glycoprotein and is functionally a 
negative regulator of bone formation. Lack of sclerostin in humans (sclerosteosis) (Online 
Mendelian Interitance in Man [OMIM] entry #269500) and van Buchem disease (OMIM entry 
#239100) results in life-long increased bone formation in the entire skeleton leading to increased 
bone mineral mass, density and strength (Balemans et al 2001; Brunkow et al 2001; 
Balemans et al 2002; Staehling-Hampton et al 2002). 
Setrusumab has an affinity of 21 pM for human sclerostin and reverses the human 
sclerostin-mediated inhibition of canonical Wnt signalling and in vitro bone mineralisation, a 
surrogate assay for bone formation, with EC50 values of 13 nM and 150 nM, respectively. 
Based on significantly increased bone remodeling (turnover) in untreated OI patients 
(Rauch et al 2000), it is hypothesised that OI patients who receive setrusumab will experience an 
increase in bone mineral density (BMD) via induction of osteoblast differentiation (a pathway 
that is blocked by sclerostin) (Winkler et al 2005), an improvement in bone structure and 
strength, and hence a reduction of fracture incidence. While setrusumab could increase matrix 
and collagen production, it should be noted that a change by setrusumab in the defective collagen 
structure is not expected. 
Setrusumab has been studied in 4 clinical trials involving 106 participants, 83 of whom received 
setrusumab. Study CBPS804A2201 was a randomised, open-label intra-patient dose escalation 
study (5, 10, and 20 mg/kg) with an untreated reference group to evaluate safety and tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of multiple infusions of setrusumab in 
14 adults (male and female participants between 18 and 75 years of age) with moderate OI. After 
administration of setrusumab, median amino-terminal propeptide of type 1 procollagen (P1NP), 
carboxy-terminal propeptide of type 1 procollagen (P1CP), bone-specific alkaline phosphatase 
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(BSAP) activity and osteocalcin (OC) levels were increased at Day 43 by 84%, 53%, 59% and 
44%, respectively, while corresponding biomarkers remained unchanged or declined moderately 
in the untreated reference group. The most commonly reported adverse events (AEs) were 
headache, influenza, arthralgia and fatigue. None were considered related to the study drug and 
gave no indication of target organ toxicity. There were no clinically significant abnormalities of 
haematological, clinical chemistry, urinalysis, electrocardiogram (ECG) or vital sign data. 
Bioanalytical results showed that setrusumab had a very similar PK profile in adult participants 
with moderate OI when compared with other populations studied previously. Serum sclerostin 
levels increased following each dose of 5, 10 and 20 mg/kg with an insignificant increase 
between the 10 and 20 mg/kg doses and a peak time lag behind the PK profile. This is consistent 
with observations from studies in healthy postmenopausal women (CBPS804A2101) and 
participants with hypophosphatasia (CBPS804A2202). Thus, adult participants with moderate OI 
given escalating doses of setrusumab demonstrated significant increases in bone formation 
biomarkers and lumbar spine BMD indicating enhanced skeletal remodeling and bone formation. 
This was the first clinical evidence that an anti-sclerostin antibody can significantly improve 
bone metabolism in adult participants with moderate OI. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of setrusumab is 
provided in the Investigator’s Brochure (IB). 
4.2. 
Study Rationale 
Current management of OI is directed towards preventing or controlling symptoms, maximising 
independent mobility and improving bone mass and muscle strength. Current interventions 
include exercise and physical therapy, rehabilitation, and pain management. Surgery may prove 
necessary for individuals with severe malformations or basilar impression. Rodding, a procedure 
in which metal rods are surgically placed in the long bones of patients with OI to prevent 
fractures, is often used to treat individuals with OI. However, none of these treatments affect the 
underlying bone pathology. 
There are no FDA or EMA approved pharmacological therapies for the treatment of OI. 
Bisphosphonates are widely used in the treatment of OI patients, despite a lack of solid evidence 
that they are beneficial. Studies have shown increased BMD, but there is no strong evidence in 
adults that they improve clinical features of OI, especially fracture rate or other features such as 
deformities, pain, or mobility. Parathyroid hormone (PTH) and analogues have also been studied 
for the treatment of OI, but they do not seem to improve the clinical course of OI and their safety 
profile is a concern. 
Therefore, there is a high unmet need for a safe and effective pharmacological treatment for OI. 
setrusumab has demonstrated an increase in bone formation markers, a decrease in bone 
resorption markers and an increase in BMD in non-clinical and early clinical studies. It is 
therefore considered a good candidate for further development in the treatment of OI. 
The current study aims to determine whether treatment with setrusumab in participants with OI is 
able to improve parameters reflecting bone structure, as measured with high resolution peripheral 
quantitative computed tomography (HRpQCT), towards those of normal (unaffected) 
individuals. As described in Section 6.4, HRpQCT is able to measure not only total volumetric 
BMD (vBMD) but also to discriminate between the cortex and trabecular vBMD (Tr. vBMD), 
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which may be more reflective of the underlying pathology than the standard measure of areal 
BMD as measured by dual-energy x-ray absorptiometry (DXA). This method also provides a 
means by which bone strength can be calculated, using finite element analysis (FEA). Although 
these parameters are not of direct clinical relevance to patients’ clinical wellbeing, they are 
considered to be appropriate at this stage of development because (a) they are objective 
measures, (b) they can be assessed within a reasonable timeframe and (c) they are likely to be 
predictive of clinical benefit. 
In order to determine the most appropriate dose of setrusumab required to achieve these changes, 
3 doses will be studied over a 10-fold dose range. At each dose level, a comparison will be made 
between post-treatment and baseline values. In order to determine the time-course of the effect, a 
substudy will be performed in which one quarter of the patients have additional scans at 
3 months. Since an additional scan cannot be blinded, this part of the study will be open-label.   
4.3. 
Benefit/Risk Assessment 
Since there are no approved pharmacological therapies for OI, patients participating in this study 
have the possibility to receive a potentially beneficial treatment, at a potentially therapeutic dose 
for a period of time considered long enough to achieve a benefit. It is expected that at least one 
of the doses of setrusumab will be sub-therapeutic; therefore patients randomised to this dose are 
not expected to receive any therapeutic benefit from participation. However, no proven therapy 
will be withheld during the study until the final analysis is performed when all subjects in the 
blinded treatment arms have completed 12 months of treatment with setrusumab. Data from this 
study will provide confirmation about whether setrusumab is efficacious for the treatment in 
adult osteogenesis imperfecta. 
The procedures being undertaken in the study are not expected to present any risk to participants. 
Radiation doses are kept to a minimum; HRpQCT uses a relatively low dose of radiation which 
is confined to the periphery and avoids exposure of radiologically sensitive organs. Bone biopsy 
may be unpleasant for participants, but this will not be mandatory and will be done as an optional 
sub-study. 
In non-clinical and early clinical studies with setrusumab, no safety concerns have been 
identified and the maximum dose proposed for the current study is well below the NOAEL from 
non-clinical studies. Further information can be found in the IB. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of setrusumab may be found in the IB and Participant Information Leaflet. 
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5. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 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 
 Tr. vBMD (radius) on HRpQCT and bone 
strength on FEA at 12 months. 
 
Secondary 
 To determine the dose-response 
relationship of Tr. vBMD to setrusumab 
after 12 months of treatment 
 Tr. vBMD (radius) on HRpQCT at 
12 months. 
 To evaluate the onset of treatment effect   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. 
 To evaluate the effect of setrusumab on 
fracture rate (peripheral, major 
[long-bone], and vertebral fractures) 
 
 Total fracture rate at 12 months 
 Peripheral fracture rate at 12 months 
 Vertebral fracture rate at 12 months 
 Long-bone fracture rate at 12 months 
 
 To evaluate the effect of setrusumab on 
vertebral fractures and vertebral height 
 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 
 To evaluate the effect of setrusumab on 
BMD 
 Changes in lumbar, whole body, and 
proximal femur DXA BMD (absolute and 
T-score) from baseline at Month 6 and 
Month 12. 
 To evaluate the effect of setrusumab on 
bone quality 
 Changes in bone histomorphometry 
 
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Objectives 
Endpoints 
 To 
evaluate 
changes 
in 
radial 
Tr.vBMD on HRpQCT and bone 
strength FEA during the 12 months 
post-setrusumab treatment period 
 Tr.vBMD (tibia & radius) on HRpQCT 
and bone strength on FEA at 18 and 
24 months 
 To evaluate the effect of setrusumab on 
HRpQCT parameters 
 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 porosity on 
HRpQCT and bone strength on FEA at 
3 months in the open-label treatment arm. 
 To evaluate the effect of setrusumab on 
body composition 
 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  
 To evaluate the effect of setrusumab on 
markers of bone composition 
 Changes in bone turnover markers and 
metabolic biomarkers associated with 
bone (PTH, P1NP, P1CP, 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-], sclerostin, released 
C-terminal pro-peptide of Type V 
collagen [Pro-C5], neo-epitope of 
MMP-2,9 mediated degradation of Type 
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Objectives 
Endpoints 
V collagen [C5M]) from baseline and 
each visit. 
 To evaluate the effect of setrusumab on 
Patient-Reported Outcomes (PROs) 
and Quality of Life (QoL) 
 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. 
 To evaluate the PK of setrusumab 
 Serum concentrations of setrusumab 
 To evaluate potential induction of anti-
drug antibodies (ADAs) by setrusumab 
and their effect on safety and PK 
 Serum concentrations of anti-setrusumab 
antibodies 
 Serum 
concentrations 
of 
setrusumab 
neutralising antibodies 
 To evaluate safety and tolerability of 
setrusumab 
 Treatment-emergent adverse events 
(TEAEs), treatment-emergent serious 
adverse events (TESAEs) 
 Infusion site reactions 
 Vital signs 
 Physical examinations 
 ECG 
 Clinical laboratory tests 
Tertiary/Exploratory 
 To evaluate the effect of setrusumab on 
bone quality 
 Changes in Trabecular Bone Score (TBS) 
from baseline at 6 and 12 months 
 To evaluate the effect of setrusumab on 
changes in use of physical aids 
 Changes in usage or need for physical aids 
from baseline at 12 months 
 To evaluate the effect of setrusumab on 
hearing 
 Change in auditory function from 
baseline at 12 months in a sub-set of 
patients 
 To evaluate the effect of setrusumab on 
bone 
formation 
and 
resorption 
parameters measured by HRpQCT 
 Change in bone formation from baseline 
at 6 and 12 months 
 
Normalised newly mineralised bone 
volume (MV/BV) 
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Objectives 
Endpoints 
 
Normalised newly mineralised 
surface area (MS/BS) 
 
Mineralised thickness (MTh) 
 
Normalised formation patch number 
density (N.F. Patch/BV) 
 
Formation patch volume 
(F.PatchVol.) 
 
3D bone formation rate (3D 
BFR/BS) 
 
3D mineral apposition rate (3D 
MAR) 
 Change in bone resorption from baseline 
at 6 and 12 months 
 
Normalised newly eroded bone 
volume (EV/BV) 
 
Normalised newly eroded surface 
area (ES/BS) 
 
Erosion depth (ED) 
 
Normalised resorption cavity 
number density (N.R.Cav./BV) 
 
Resorption cavity volume 
(R.Cav.Vol.) 
 
3D bone resorption rate (3D 
BRR/BS) 
 
3D mineral resorption rates (3D 
MRR) 
 
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6. 
Study Design  
6.1. 
Overall Design  
MBPS205 is a phase 2, multicentre, multinational, double-blind, dose range-finding study 
comparing 3 blinded doses of setrusumab (20 mg/kg, 8 mg/kg and 2 mg/kg) and an open-label 
treatment arm (20 mg/kg). Participants will be randomised 1:1:1:1 into the 4 treatment arms and 
will receive study treatment (setrusumab) for 12 months. Participants will have HRpQCT scans 
of their non-dominant distal radius at baseline, 3-month (for open-label participants only), 
6-month and 12-month time points to determine the effect of treatment on Tr. vBMD. Following 
completion of the study treatment participants can receive an optional single dose of zoledronic 
acid and will enter 12 months follow-up period and will have visits at Months 14, 18 and 24 to 
establish the rate of offset of treatment effect. Participants will also receive follow-up telephone 
calls at Months 16 and 21. Participants can receive an optional further dose of zoledronic acid at 
Month 18 at the discretion of their treating physician. During the follow-up period participants 
will have HRpQCT scans of their non-dominant distal radius and tibia at Month 18 and 
Month 24. For the purposes of the study protocol 1 month is defined as 28 days.  
Figure 1: MBPS205 Study Schematic 
 
 
6.2. 
Number of Participants 
Approximately 100 participants will be randomised to complete the study. It is anticipated that 
the study will be conducted in approximately 28 centres in 5 countries. 
6.3. 
End of Study Definition 
The end of the study is defined as the date of the last study visit of the last participant in the 
study. 
6.4. 
Scientific Rationale for Study Design  
The study has been designed as a traditional parallel group dose-finding study, with 3 doses of 
setrusumab over a 10-fold dose range and an open-label arm. The setrusumab doses are predicted 
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to achieve approximately 50, 80 and 90% of maximal sclerostin inhibition and thereby provide 
sufficient information to allow a dose to be selected. At each dose level, a comparison will be 
made between post-treatment and baseline values. In order to determine the time-course of the 
effect, a substudy will be performed in which one quarter of the patients have additional scans at 
3 months. Since an additional scan cannot be blinded, this part of the study will be open-label.  
Fractures in adults with OI are likely to result from a combination of alterations in bone matrix 
quality, bone mass, bone microstructure and bone geometry. A variety of methodologies may be 
used to assess these bone parameters before and after treatment, thereby providing evidence of 
reduced fracture risk. The methodologies include measurement of soluble bone turnover 
biomarkers in the circulation, DXA, high resolution computed tomography, HRpQCT, bone 
biopsy, high resolution magnetic resonance imaging as well as microindentation and 
nanoindentation (OsteoProbe). However, HRpQCT appears to be the best option to measure 
treatment effects in this clinical study for the following reasons. 
HRpQCT is a non-invasive technique that provides high resolution images of the bone that are 
directly amenable to quantification. By focussing on the extremities, HRpQCT not only reduces 
the radiation dose (compared to lumbar quantitative computed tomography (QCT)), but enhances 
patient comfort and compliance. 
HRpQCT is able to measure not only total vBMD but also to discriminate between the cortex 
and trabecular vBMD. In addition, the microstructure of bone can be assessed (trabecular bone 
volume, number of trabeculae per millimetre, inhomogeneity of the network, trabecular 
thickness, cortical thickness and cortical porosity). 
HRpQCT has been used in participants with OI and compared to healthy participants in 2 
independent studies (Kocijan et al., 2015, Folkestad et al., 2012). The data were largely 
consistent between the studies and provide information on HRpQCT endpoints as follows: 
• 
The relevant endpoints and their quantification in OI patients 
• 
The expected variability of the endpoints 
• 
The observed differences between OI and healthy bone provide an indication of potential 
clinically meaningful effect sizes 
• 
The bone lesion in adults with OI resides largely in the trabecular region with the cortical 
region being similar to healthy participants 
• 
Tr. vBMD is the parameter that most effectively differentiates bone density between OI 
and healthy bone 
• 
BV/TV is the parameter that most effectively differentiates bone microstructure between 
OI and healthy bone 
FEA is a well-established modelling technique that moves beyond measures of bone density and 
microstructure and provides a predictive measure of the whole bone strength 
(Engelke et al., 2013). HRpQCT provides images of sufficient resolution to allow effective FEA. 
FEA has been used in OI to determine bone strength as well as response to treatment with 
teriparatide (Orwoll et al., 2014). Accordingly, FEA can provide additional valuable information 
that is relevant for the determination of fracture risk in OI. 
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In addition to HRpQCT, the other methodologies for examining the likely impact of setrusumab 
on bone quality will be investigated. BMD measured by DXA, vertebral radiographs, bone 
turnover markers and qualitative examination of bone biopsies will also be studied in order to 
further characterise the effects of setrusumab and help to confirm the activity of the selected 
dose. 
6.5. 
Justification for Dose Selection 
Setrusumab doses targeting the EC50 (1.5 to 2 mg/kg monthly), EC75-80 (6 to 8 mg/kg monthly) 
and EC90 (15 to 20 mg/kg) for sclerostin inhibition were identified through modelling and 
simulation using the available data from clinical studies with setrusumab. Adult participants with 
moderate OI given escalating doses of setrusumab demonstrated significant increases in bone 
formation biomarkers and lumbar spine BMD indicating enhanced skeletal remodeling and bone 
formation.  
Therefore, study participants will receive either 2, 8 or 20 mg/kg setrusumab IV, administered 
monthly for 12 months. Since 90% of maximal sclerostin inhibition is expected to occur with the 
highest dose (20 mg/kg) this dose will be used for the open label group, which is designed to 
determine the rate of onset of effect with more frequent scans. 
The dose with the most positive benefit/risk profile based on HRpQCT analysis and safety after 
12 months of treatment will be selected for further study. Participants will continue on their 
allocated dose until 12 months to evaluate whether treatment effect is maintained at 12 months.  
7. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.1. 
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. 
 
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Male participants: 
5. There are no contraception requirements for male participants with female partners 
who are woman of childbearing potential (WOCBP) (See Appendix 5). 
Female participants:  
6. A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies: 
a. Not a WOCBP as defined in Appendix 5 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 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 as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
7.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
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 
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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) 
7.3. 
Lifestyle Restrictions 
7.3.1. 
Meals and Dietary Restrictions 
Refrain from consumption of food or drinks (except water) for 8 hours prior to visits that require 
blood draws for bone biomarkers.  
7.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomised. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse events (SAE) and adverse events of special interest (AESI). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  
However, the screening period may be extended beyond 28 days in the following circumstances 
with the discussion and with the approval of the medical monitor: 
 All screening inclusion/exclusion criteria are met but the participant’s schedule, including 
genetic testing or HRpQCT scan, prevented them from being randomised within the 
screening period.  
Additionally, individual lab parameters or screening test may be repeated if the result is 
considered aberrant or not clinically consistent with the patient’s health status. Decisions to 
re-test should be made in conjunction with the study medical monitor.  
Participants who have individual laboratory parameters re-tested should have the results entered 
in the electronic case report form (eCRF). 
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8. 
Treatments  
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
 
 
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8.1. 
Treatments Administered 
 
Study Treatment 
Name: 
 
Setrusumab 
Concomitant Vitamin 
D and Calcium 
Therapy 
Zoledronic Acid 
Dosage Formulation: 
 
Lyophilised 
powder for 
solution 
Calcium tablets and 
Vitamin D capsules 
Solution for infusion 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
150 mg 
500mg Calcium and 
800 IU Vitamin D 
4 mg single dose 
Route of 
Administration: 
IV 
Oral 
IV 
Dosing Instructions: 
 
60-minute 
infusion 
Oral with water 
15-minute infusion 
Packaging and 
Labelling: 
 
Study Treatment 
will be provided 
in labelled vials 
packed into in 
cartons 
containing 20 
vials. Each vial 
and carton will 
be labelled as 
required per 
country 
requirement  
Not applicable 
Stocks will be labelled 
with study information 
and standard 
packaging.  
Responsible 
Manufacturer: 
Mereo 
Biopharma 3 
Ltd, 1 Cavendish 
Place, London, 
W1G 0QF 
Provided by 
Investigational sites 
Provided by Mereo 
Biopharma 3 Ltd, 
1 Cavendish Place, 
London, W1G 0QF 
8.1.1. 
Zoledronic acid therapy 
Following the end of setrusumab therapy all participants will have the option to receive a dose of 
zoledronic acid at 12 and 18 months. This will be prescribed at the discretion of the treating 
physician and in line with local guidelines. 
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8.2. 
Method of Treatment Assignment  
All participants will be centrally randomised using an Interactive Web Response System (IWRS) 
in a 1:1:1:1 ratio to receive either 20 mg/kg, 8 mg/kg, 2 mg/kg or open-label 20 mg/kg. Subject 
to informed consent being given by the participant, all participants assigned to placebo prior to 
protocol amendment 4.0 will be reassigned to begin 12 months of open-label 20 mg/kg 
setrusumab treatment. ICON Biostatistics will produce a randomisation list that links participant 
numbers to randomisation numbers. These randomisation numbers will be linked to different 
treatment regimens and the randomisation scheme will be stratified according to the Sillence 
Clinical Classification of OI type into 2 groups (Type I or III/IV). 
Following confirmation from the investigator, the pharmacist will contact the IWRS and be 
issued with a treatment regimen. Should the participant be allocated to a setrusumab regimen, 
then the pharmacist will input the patient’s weight into the IWRS and receive a calculated dose 
per participant.  
Before the study is initiated, the web address for the IWRS and the log in information & 
directions will be provided to each site. 
Study treatment will be dispensed and dosed at the study visits summarised in the Schedule of 
Activities. 
8.3. 
Blinding  
With the exception of the open-label treatment arm, investigators and participants will remain 
blinded to each participant’s assigned study treatment throughout the course of the study. In 
order to maintain this blind, an otherwise uninvolved 3rd party (pharmacist) will be responsible 
for the reconstitution and dispensation of all study treatment. A separate unblinded Clinical 
Research Associate (CRA) will monitor the pharmacy. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study treatment records at the site(s) to verify that randomisation/dispensing has been performed 
accurately. 
The IWRS will be programmed with blind-breaking instructions. The study blind may be broken 
if, in the opinion of the investigator, it is in the participant’s best interest to know the study 
treatment assignment. Mereo must be notified before the blind is broken unless identification of 
the study treatment is required for a medical emergency in which the knowledge of the specific 
blinded study treatment will affect the immediate management of the participant’s condition (eg, 
antidote is available). In this case, Mereo must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in the source 
documentation and eCRF, as applicable. 
8.4. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment 
On written confirmation by the investigators, the pharmacist will contact the IWRS, enter the 
participant number and weight. The IWRS will inform the pharmacist of the treatment allocation 
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and dose required for the participant, based on their weight. The IWRS will provide the number 
of vials required to reconstitute and mix the appropriate dose for the participant. The pharmacist 
will select and record the vials used to reconstitute and mix the dose in the IWRS.  
Further details of the preparation and administration of the study treatment, please refer to the 
Study Treatment Administration Guide and the MBPS205 Pharmacy Manual. 
Only participants enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the handling, disposition and accountability of study 
treatment are provided in the MBPS205 Pharmacy Manual. 
8.5. 
Treatment Compliance   
The per protocol dosage, timing and mode of administration of study medication may not be 
changed. Any departures from the intended regimen must be recorded in the eCRF and notified 
to the sponsor. 
8.6. 
Concomitant Therapy 
Concomitant Vitamin D and Calcium Therapy 
Vitamin D levels should be 50 nmol/L or higher during the study. If less than 50 nmol/L at 
screening the participant should be treated as per the local guidelines and retested during the 
study to maintain vitamin D levels above 50 nmol/L. Calcium levels should be in the normal 
range for study entry. For the duration of the study participants can, if required, receive a daily 
dose of 500 mg calcium and/or 800 I.U. vitamin D as background treatment, but if the participant 
already receives a higher dose, they can stay on the dose they receive. Calcium tablets should not 
be taken 2 hours prior to DXA lumbar scan. 
The following classes of medication listed below are not permitted to be taken during the 
conduct of the study starting from screening (for details of screening criteria concerning 
medications, see Section 7.2): 
1. Bisphosphonates (oral and injectable) 
2. RANKL antibodies (Denosumab) 
3. PTH and analogues 
4. All other monoclonal antibodies 
5. Medications known to affect bone physiology (e.g. aromatase inhibitors) 
6. Systemic corticosteroid drugs 
Physical aids and physiotherapy are explicitly allowed. 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.  
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrolment or receives 
during the study must be recorded along with: 
 reason for use 
 dates of administration including start and end dates 
 dosage information including dose and frequency 
All other concomitant medications are allowed, unless they are explicitly not allowed or are 
known to affect bone or bone metabolism.  
The ICON Medical Monitor can be contacted if there are any questions regarding concomitant or 
prior therapy. 
8.7. 
Treatment After the End of the Study  
Participants completing the MBPS205 study will be able to 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.  
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9. 
Discontinuation Criteria 
9.1. 
Discontinuation of Study Treatment  
Participants may voluntarily discontinue investigational treatment for any reason at any time. If 
the participant no longer wants to take part in the study, they will be asked to attend an end of 
treatment visit and 60-day follow-up visit and be discontinued from the study. 
The investigator should discontinue investigational treatment of a given participant if, on 
balance, he/she believes that continuation would be detrimental to the participant’s well-being. 
However, the participant should be followed up to the end of the study and all study procedures 
should be performed per protocol.  
Investigational treatment must be discontinued under the following circumstances and then 
further steps need to be discussed with the medical monitor: 
1. Anaphylactic reaction or other severe systemic reaction to study drug injection 
2. Diagnosis of malignancy during study 
3. Evidence of pregnancy 
4. Absolute corrected QT interval (QTc) corrected using Fridericia’s formula (QTcF) is 
>500 msec and rise from baseline, confirmed by triplicate ECGs, is ≥60 msec (Refer to 
Section 10.4.3) 
5. Any of the following confirmed laboratory abnormalities: 
 Renal function values that require discontinuation: 
o Discontinue investigational treatment for a participant if individual serum 
creatinine increases ≥ 50% compared to baseline (and is considered clinically 
significant), or in the event of treatment-emergent proteinuria (albumin: creatinine 
ratio > 300 mg/g or > 30 mg/mmol; protein: creatinine ratio (PCR) ≥ 500 mg/g or 
> 50 mg/mmol), unless the event is not drug related, or if the risk/benefit 
assessment supports continuing investigational treatment. 
Note: A renal event leading to participant discontinuation should be followed up until 
event resolution (serum creatinine within 10% of baseline, PCR within 50% of baseline), 
stabilises or becomes not clinically significant, or is assessed as being chronic. 
 Liver laboratory values that require discontinuation 
o Confirmed alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 5 times the upper limit of normal (ULN) (for more than 2 weeks) 
o Confirmed ALT or AST > 3 times the ULN and confirmed bilirubin total 
> 2 times ULN (unless elevated bilirubin is related to confirmed Gilbert’s 
syndrome) 
Note: If the laboratory abnormality is considered causally related to study drug, study 
treatment will be permanently discontinued. In cases in which a causal relationship to 
study drug can be reasonably excluded, (ie, an alternative cause is evident), study 
treatment will be discontinued but it may be resumed when the laboratory abnormality is 
sufficiently normalised. A decision to resume study treatment will be made jointly by the 
investigator and medical monitor (medical monitor’s written approval is required). 
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6. Withdrawal of informed consent 
7. Significant non-compliance of the participant with study procedures 
8. Sponsor decision 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTcF after enrolment; the investigator or qualified designee will determine if the participant 
can continue in the study and if any change in participant management is needed. This review of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
Refer to the SoA for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed. 
9.1.1. 
Temporary Discontinuation  
Study drug dosing may be temporarily suspended in the event of: 
1. Clinically important laboratory abnormalities 
2. Other intercurrent illnesses or major surgery 
3. Use of prohibited treatment 
4. Any other protocol deviation that results in a significant risk to the participant’s safety 
5. Sponsor decision 
After a laboratory abnormality leading to a delay of dosing normalises sufficiently, study 
treatment may resume at the discretion of the principal investigator in consultation with the 
medical monitor. Similarly, study treatment may resume after the medication leading to 
suspension of dosing is discontinued. A decision to discontinue study drug and/or to reinstitute 
study treatment should be discussed with the medical monitor. The investigator may suspend 
study treatment at any time, even without consultation with the medical monitor if the urgency of 
the situation requires immediate action and if this is determined to be in the participant’s best 
interest. However, the medical monitor should be contacted as soon as possible in any case of 
study drug discontinuation. 
9.1.2. 
Rechallenge 
Resumption of study treatment after temporary discontinuation should always be discussed with 
the medical monitor. 
9.2. 
Discontinuation from the Study 
 A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, or 
administrative reason. 
 If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
 Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
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9.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 In cases in which the participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
10. 
Study Assessments and Procedures 
Study procedures and their timing are summarised in the SoA.  
 Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
 The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 480 mL over the 
duration of the study. 
 Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
10.1. 
Efficacy Assessments 
10.1.1. 
Radiology 
In order to ensure the consistent assessment of BMD and fractures, site-based radiology staff and 
central readers will be fully trained. Details of each radiological assessment, procedures for 
calibration of equipment to ensure assessment continuity and central reading procedures will be 
provided in the MBPS205 Imaging Charter and Training Manual and made available.  
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10.1.1.1. HRpQCT 
HRpQCT scans, including calibration, should be performed according to MBPS205 Imaging 
Charter and Training Manual on distal non-dominant arms unless the arm has been supported 
with rods or there is significant deformity. In this case, the investigator should document that the 
dominant limb was selected and specify the rationale. If rodding (or other metal implant) is 
present in both distal tibiae, or if severe deformities do not physically allow entry of either lower 
limb into the HRpQCT scanner, please discuss the participant’s involvement in the study with 
the study medical monitor prior to inclusion in the study.  
HRpQCT will be used to measure the primary efficacy endpoint of trabecular volumetric BMD 
of the radius (see SoA). 
In addition, HRpQCT will be used to examine other aspects of the tibial and radial trabecular and 
cortical bone volume and microarchitecture. Morphological analysis will measure or derive bone 
volume, trabecular number, thickness and spacing, cortical volume and thickness, structure 
model index, connectivity density and degree of anisotropy.  
Exploratory end points will be assessed with time-lapse dynamic in vivo morphometry of 
HRpQCT image datasets.  
Morphological analysis procedures are described in detail by (Liu et al 2010) and in the 
MBPS205 Imaging Charter and Manual.  
Refer to Appendix 6 for Radiation Exposure. 
10.1.1.2. Dual-Energy X-ray Absorptiometry 
Bone mineral density will also be evaluated using DXA. T-Score will be calculated based on 
actual measured bone density value. Change in TBS from baseline will be assessed from DXA 
images using TBS (iNsight software). Lean and fat body mass will be evaluated using whole 
body DXA. Calcium tablets should not be taken 2 hours prior to DXA lumbar scan. 
Refer to Appendix 6 for Radiation Exposure and the MBPS205 Imaging Charter and Imaging 
Training Manual for further details of the DXA including patient positioning. 
10.1.1.3. Radiography 
Vertebral radiographs will be used to assess the number of historic vertebral fractures, the 
percentage change in numbers of vertebral fractures from baseline at 6 and 12 months and the 
percentage change in vertebral height from baseline.  
Genant’s semi-quantitative method and 6-point quantitative morphometry will be used to 
evaluate vertebral fractures and vertebral height, as detailed in the Imaging Charter. 
Fracture assessment, confirmed by central radiographic reading, will be carried out separately for 
peripheral including all major long bones, minor bone (digits, ribs) and vertebral fractures. 
Fractures without clinical symptoms, detected only by means of radiographic investigations will 
not be included in the analysis. 
Date of diagnosis (defined as first occurrence of symptoms of fracture) will be adopted for all 
time to event analyses.  
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Refer to Appendix 6 for Radiation Exposure and the MBPS205 Imaging Charter and Manual for 
further details. 
10.1.2. 
Bone Biopsy 
Bone biopsies will be performed once at either Month 6 or Month 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.  
10.1.3. 
Audiometry 
This procedure can be omitted if the investigative site does not have the capability to complete 
the audiometry assessment. Participants will be asked to remove anything which might affect the 
test results such as spectacles, earrings and hearing aids. The ear will be examined with an 
otoscope to assess the requirement for wax removal and to determine whether the eardrum has 
suffered any damage which may reduce the ability of sound to be transported to the cochlea. The 
audiometric test will be carried out using standard or automatic audiometers. The participant will 
be asked to indicate whether they can just hear or cannot hear a certain sound; the sound level 
may be increased from a very low level or reduced from a high level. Headphones will be fitted 
to the participant and the test performed on each ear. A threshold test will be performed first in 
which each ear will be subjected to sound at a frequency of 1 kHz at varying levels of intensity 
ranging from low to high and high to low. This will be repeated several times in order to derive 
an average threshold for the test. Following this pre-check, both of the participant’s ears will be 
tested through a range of frequencies (0.5, 1, 2, 3, 4, 6 and 8 kHz) and hearing loss recorded for 
each frequency via a series of sound exposures. The decibel hearing loss will be recorded using 
the grading scores in Appendix 7. 
10.1.4. 
Patient-Reported Quality of Life 
The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, 
role limitations due to physical health, bodily pain, general health perceptions, vitality, social 
functioning, role limitations due to emotional problems, and mental health. It yields scale scores 
for each of these 8 domains and 2 summary measures of physical and mental health: The 
Physical Component Summary and the Mental Component Summary. 
The EQ-5D-5L is a standardised measure of health status comprised of a descriptive system of 
5 health-related quality of life states (i.e., mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression) and a Visual Analogue Scale (VAS) of overall health. Each dimension is 
rated on a 5-point response scale indicating severity of problems, where 1 is “no problems” and 5 
is “extreme problems”. The 5 questions are scored and together contribute to the EQ-5D index 
(utility) score between 0 and 1 (1 being perfect health), which will be calculated using the 
developers’ algorithm based on country-specific reference score sets. The EQ-5D VAS is a 
measure of overall self-rated health status, used and analysed separately from the index score. 
The VAS ranges from 0 to 100, with higher scores indicative of better overall health. 
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The OIQoL-A is a PRO instrument for use in adults with OI Type I, III, or IV. The OIQoL-A 
currently measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, 
taking care/Concerns, Social and Family Life and Activities); data collected from the phase 2b 
trial will be used to validate the instrument prior to its use within the phase 3 study. 
10.2. 
Adverse Events 
The definitions of an AE or SAE/AESI can be found in Appendix 4. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE/AESI and remain responsible for following up 
AE that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue the study treatment (see Section 8.7).  
10.2.1. 
Time Period and Frequency for Collecting AE and 
SAE/AESI Information 
All AE and SAE/AESI will be collected from the signing of the ICF until the follow-up visit at 
the time points specified in the SoA (Section 2). 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF. 
All SAEs/AESIs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix 4. The investigator will submit any updated SAE/AESI data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE/AESI in former study participants. 
However, if the investigator learns of any SAE/AESI, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE/AESI and the 
procedures for completing and transmitting SAE/AESI reports are provided in Appendix 4. 
10.2.2. 
Method of Detecting AE and SAE/AESI 
Care will be taken not to introduce bias when detecting AE and/or SAE/AESI. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
10.2.3. 
Follow-up of AE and SAE/AESI 
After the initial AE/SAE/AESI report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs/AESIs, will be followed until resolution, 
stabilisation, until the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 9.3). Further information on follow-up procedures is given in Appendix 4. 
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10.2.4. 
Regulatory Reporting Requirements for SAE 
 Prompt notification by the investigator to the sponsor of SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met.  
 The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
 An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
10.2.5. 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study treatment and until 70 days after the last dose. 
If a pregnancy is reported, the investigator should inform the Safety Clinical Research 
Organisation (CRO) within 24 hours of learning of the pregnancy and should follow the 
procedures outlined in Appendix 5. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE. 
10.3. 
Treatment of Overdose 
For this study, any dose of setrusumab greater than 120% of the calculated dosage will be 
considered an overdose. 
Mereo does not recommend specific treatment for an overdose.  
In the event of an overdose, the pharmacist / unblinded CRA should: 
1. Contact the ICON Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE/AESI and laboratory abnormalities until 
setrusumab can no longer be detected systemically (at least 60 days). 
3. Obtain a plasma sample for PK analysis within 14 days from the date of the last dose 
of study treatment if requested by the medical monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF and source documents. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
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10.4. 
Safety  
Planned time points for all safety assessments are provided in the SoA. 
10.4.1. 
Physical Examinations 
 A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, Musculoskeletal and Neurological systems. 
Height and weight will also be measured and recorded. 
 A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
10.4.2. 
Vital Signs 
 Tympanic or oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed. 
 Blood pressure and pulse measurements will be assessed in the semi-Fowler’s position with a 
manual device, unless a manual device is not available.  
 Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (eg, television, cell phones). 
 Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (after the participant has been sitting for 5 minutes, 
3 consecutive blood pressure readings will be recorded at intervals of at least 1 minute). The 
average of the 3 blood pressure readings will be recorded on the eCRF. 
 For the first 2 administrations of study drug per patient, oral or tympanic temperature, blood 
pressure and pulse will be monitored at the beginning of the infusion at 5, 15 and 30 minutes 
after the start of infusion, and at 60 minutes after the end of the infusion. For the remaining 
infusions, vital signs will be monitored during the infusion. 
10.4.3. 
Electrocardiograms 
 Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Refer 
to Section 9.1 for QTc withdrawal criteria and additional QTc readings that may be 
necessary. 
 If triplicate ECGs are required (Refer to Section 9.1), 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set 
of triplicates should be completed in less than 4 minutes. 
10.4.4. 
Clinical Safety Laboratory Assessments 
 Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.  
 The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
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laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 60 days after the last dose of study treatment should be 
repeated until the values return to normal or baseline. If such values do not return to 
normal/baseline within a period of time judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.  
 If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the 
results must be recorded in the eCRF.  
10.5. 
Pharmacokinetics 
 Approximately 3 mL of whole blood to provide serum samples of approximately 1.5 mL will 
be collected for measurement of serum concentrations of setrusumab as specified in the SoA.  
 A maximum of 2 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. Instructions for the 
collection and handling of biological samples will be provided by the sponsor in MBPS205 
Laboratory Manual. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
 Samples will be used to evaluate the PK of setrusumab. Each serum sample will be divided 
into 2 aliquots (1 each for setrusumab PK, and a back-up]). Samples collected for analyses of 
setrusumab serum concentration may also be used to evaluate safety or efficacy aspects that 
address concerns arising during or after the study. 
 Genetic analyses will not be performed on these serum samples. Participant confidentiality 
will be maintained. At visits during which samples for the determination of serum 
concentration of setrusumab will be taken, 1 blood draw of sufficient volume can be used. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.  
Further details of sampling and processing requirements for the PK samples can be found in the 
MBPS205 Laboratory Manual. 
10.6. 
Pre-Screening Genetics 
A documented historical confirmed mutation in the COL1A1/COL1A2 genes can be used to 
satisfy the entry criteria. However, if the COL1A1/COL1A2 mutation is not confirmed, 
investigators will be able to pre-screen participants using a local facility for analysis or 
alternatively, one of the facilities listed in the MBPS205 Laboratory Manual.  
In the event of a test being required, participants can be consented using the separate genotyping 
consent. Approximately 10 mL of blood will be required for DNA isolation. Details on processes 
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for collection and shipment of these samples may be found by contacting local laboratories or 
can be found in the MBPS205 Laboratory Manual. 
In the event of DNA extraction failure, a replacement screening genetics blood sample may be 
requested from the participant.  
The final disposition of samples will be conducted per local regulations. 
10.7. 
Biomarkers 
Collection of samples for bone biomarker research is also part of this study. 10 mL fasting blood 
samples will be collected from all participants in this study as specified in the SoA. 
Additional, optional 10 mL blood samples for biomarker research should be collected from 
participants in the study at 8 days post-baseline and 14 days post-Month 9 Visit. 
In the treatment period samples will be tested for PTH, P1NP, P1CP, OC, BSAP, CTX-1, 
NTX-1, RANKL, osteoprotegerin, TGF-, sclerostin, Pro-C5, and C5M to evaluate their 
association with the observed clinical responses in bone turnover to setrusumab. In the follow-up 
period samples can be tested for CTX-1 and P1NP. 
All samples will be processed within 3 months of the end of study. 
Further details of sampling and processing requirements for the bone biomarker blood samples 
can be found in the Study MBPS205 Laboratory Manual. 
10.8. 
Immunogenicity Assessments 
Antibodies to setrusumab will be evaluated in serum samples collected from all participants 
according to the SoA. Additionally, serum samples should also be collected at the final visit from 
participants who discontinued study treatment or were withdrawn from the study. These samples 
will be tested by the sponsor or sponsor's designee. 
Serum samples will be screened for antibodies binding to setrusumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to BPS804 and/or to further characterise the immunogenicity of setrusumab. 
The detection and characterisation of antibodies to setrusumab will be performed using a 
validated assay method by or under the supervision of the sponsor. All samples collected for 
detection of antibodies to study treatment will also be evaluated for setrusumab serum 
concentration to enable interpretation of the antibody data. Antibodies may be further 
characterised and/or evaluated for their ability to neutralise the activity of the study 
treatment(s). Samples may be stored for a maximum of 1 year following the last participant’s last 
visit for the study at a facility selected by the sponsor to enable further analysis of immune 
responses to setrusumab.  
Further details of sampling and processing requirements for the Immunogenicity blood samples 
can be found in the MBPS205 Laboratory Manual. 
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10.9. 
Medical Resource Utilisation and Health Economics  
Medical resource utilisation and health economics data, associated with medical encounters, will 
be collected in the eCRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and medical encounters are excluded.  
The data collected may be used to conduct exploratory economic analyses and will include: 
 Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient). 
 Duration of hospitalisation (total days or length of stay, including duration by wards 
[eg, intensive care unit]). 
 Number and type of diagnostic and therapeutic tests and procedures. 
 Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications). 
 Use and change of use of physical aids. 
11. 
Statistical Considerations 
11.1. 
Sample Size Determination  
The number of participants is based on power considerations for the trabecular vBMD derived 
from HRpQCT at Month 12. The primary analysis method for this endpoint will be on the 
change from baseline within each treatment group, so the primary hypothesis to be tested is 
H0: µT ≤ 0 vs. H1: µT > 0 
where µT denotes the change from baseline for each dose of Setrusumab. Under the assumptions 
of a maximum change from baseline of
, a standard deviation at both timepoints 
of 
 and a correlation between both measurements of 
, a sample size of 
25 patients per group yields approximately 80% power for a one-sided test with significance 
level 0.025, if the data are analysed on the log scale using a t-test. 
For a change from baseline of 
, with standard deviation as above the one-sided 
test would have a probability of 80% to yield a p-value below 5%, being considered indicative of 
a trend. 
Following a review of the trabecular vBMD (radius) derived from HRpQCT at Month 6 of those 
subjects within the 20 mg/kg Setrusumab open label treatment group, a change from baseline 
standard deviation of 
 was observed. This yields to a correlation between 
baseline and Month 6 visits of 
 (much higher than the 
 that was originally assumed). If 
such a correlation is observed at Month 12, given 25 subjects per arm, the one-sided test would 
have a probability of 80% to yield a p-value below 5% for a change in baseline of 
 
.   
As a secondary analysis, the MCPMod approach will be applied to the data in order to assess a 
non-flat dose-response curve and to obtain information about the underlying dose-response 
curve. Due to the missing placebo group, the power of this approach depends heavily on the 
underlying dose-response curve.  
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The following candidate models will be used: 
 EMax (ED50 of 1.5 mg) 
 Exponential (δ = 2) 
Under the assumptions of each of the two candidate models being the true dose-response curve, 
and in addition an Sigmoid EMax model with parameters ED50 = 10 mg and h = 2.4, a contrast 
test at a one-sided significance level of 2.5% has the following power for each of the three 
models: 
Model EMax 
Exponential Sigmoid EMax 
Power 13.7% 73.2% 
60.7% 
The total sample size required is therefore determined as 100: 
 25 participants on open-label setrusumab (20 mg/kg) 
 25 participants on each of the active arms (2 mg/kg, 8 mg/kg, 20 mg/kg) 
 Approximately 100 participants will be randomised. 
11.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled  
All participants who sign the ICF. 
Full Analysis Set (FAS) 
All participants who are randomised to one of the blinded 
treatment arms and take at least 1 dose of study treatment. 
Participants will be analysed according to the randomised 
treatment. 
Modified Full Analysis Set 
(mFAS) 
All participants from the FAS who have sufficient cross-sectional 
overlap across HRpQCT scans (details to be further described in 
the Statistical Analysis Plan). Participants will be analysed 
according to the randomised treatment. 
Per-protocol 
All participants from the mFAS who have been treated according 
to the protocol and fulfill the following criteria (to be further 
described in the Statistical Analysis Plan [SAP]): 
1. All inclusion/exclusion criteria satisfied 
2. Absence of relevant protocol violations with respect to 
factors likely to affect the efficacy of treatment where the 
nature of protocol violation will be defined before breaking 
the blind 
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3. Adequate study medication compliance which will be 
determined before breaking the blind. 
Non-restricted FAS 
All participants who are randomised and take at least 1 dose of 
study treatment. Participants will be analysed according to the 
randomised treatment. Analyses using the Non-restricted FAS 
will comprise of such where the two 20 mg/kg dose group are 
pooled (for the follow-up analysis), and those where they are not. 
Safety 
All participants who are administered at least 1 dose of study 
treatment. Participants will be analysed according to the 
treatment they actually received. Analyses using the Safety 
population will comprise of such where the two 20 mg/kg dose 
group are pooled (for the follow-up analysis), and those where 
they are not. 
PK 
All participants in the Safety Population who have at least 1 
quantifiable setrusumab serum concentration. 
11.3. 
Statistical Analyses 
The statistical evaluation will be performed by ICON using SAS®, Version 9.3 or later and 
ADDPLAN DF 4.0 or later.  
The main population for efficacy analysis will be the FAS. Results for the mFAS, per-protocol 
(PP) population and the Non-restricted FAS will be considered supportive. 
Data for placebo participants and open-label BPS804 20 mg/kg subjects will be reported 
separately from the comparison between the randomized, blinded treatment groups. In particular 
for the primary analysis, the open-label BPS804 20 mg/kg participants’ data will not be pooled 
with the blinded BPS804 20 mg/kg participants’ data. 
The primary analysis will be performed after all participant have completed their initial 
12-month study period or have withdrawn prior to completion. Analyses for the follow-up period 
will be carried out separately from the primary analysis when all participants have completed the 
12 months follow-up period, or have withdrawn from it. 
Data will be analysed by either enumeration of participants displaying distinctive characteristics 
within each treatment regimen or by descriptive statistical summaries such as means, standard 
deviations (SD), minimum, lower quartile, median, upper quartile and maximum for continuous 
measures. Continuous measures will be log transformed where appropriate. Categorical variables 
will be presented by the number of observations and absolute and relative (%) frequency. Time 
to event variables will be analysed using Kaplan-Meier methods, and quartiles for the median 
time to event will be presented together with their 95% confidence intervals (CIs). 
For efficacy data summary statistics (N, mean, SD, median, minimum and maximum for 
continuous data, and N [%] for categorical data) will be presented at each visit. 
Similarly, changes from baseline (or percentage change from baseline if appropriate) will be 
summarised in a similar manner. 
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ANCOVA dealing with nested observations within a patient (e.g., vertebral assessments) will 
consider this relationship in the modelling. Patient will be modelled as a random factor. 
Unless stated otherwise the baseline value for a variable will be the latest value taken prior to 
first dose of study medication. 
Data in summary tables will generally be presented on an Observed Cases basis. 
Unless stated otherwise, all statistical tests will be 2-sided and conducted at the 5% level, and all 
quoted CIs will be 2-sided 95% CIs. 
Analysis of the technical performance of the HRpQCT endpoints will be conducted to 
demonstrate reliability in accordance with standard metrological standards. Details of the 
analysis and methods are provided in a separate statistical validation analysis plan. 
A primary efficacy analysis and unblinding will be performed when all data up to and including 
Month 12 has been collected in the blinded treatment arms. A Clinical Study Report (CSR) will 
be prepared based upon the results of this analysis. The data collected during the 12-month 
follow-up period will be analysed separately and published in the CSR addendum. 
The SAP will be developed and finalised before database lock and will describe the selection of 
participants to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints. 
11.3.1. 
Efficacy Analyses 
Analyses for the primary efficacy endpoints and selected secondary endpoints will be analysed 
on the FAS, mFAS, the Non-restricted FAS and the PP samples, while analyses for the 
remaining secondary efficacy endpoints will be analysed on the FAS sample only. The mFAS 
will be used for analysis of HRpQCT endpoints only. General methods as described above will 
be applied to the efficacy endpoints; specific analyses are described below. 
Endpoint 
Statistical Analysis Methods 
Primary 
The HRpQCT results for the Trabecular vBMD (radius) will be log 
transformed and an ANCOVA model will be used to calculate Least 
Square Means (LSMeans) for the change from baseline, using 
baseline values as a covariate and treatment group and stratum as a 
factor. LSMeans for each treatment group will be calculated and 
tested against the null hypothesis of 0 in an a priori hierarchical 
approach, starting with the highest dose. Differences between 
LSMeans will also be displayed but will be analysed in an 
exploratory fashion only. The type I error rate will be 5% two-sided. 
P-values above 5% but below 10% (two-sided) will be considered as 
indicative for a trend. 
For supportive evidence, this analysis will be repeated on the mFAS, 
Non-restricted FAS in both versions and the PP population. Further, 
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Endpoint 
Statistical Analysis Methods 
the following analyses will be performed, again on the FAS, mFAS, 
the Non-restricted FAS in both versions and the PP population: 
The LSMeans will further be analysed using the MCPMod 
methodology, using the following candidate models: 
 EMax (ED50 of 1.5 mg) 
 Exponential (δ = 2) 
 Sigmoid EMax model with parameters ED50 = 10 mg and 
h = 2.4 
Parameter estimates and predicted values for each dose will be 
calculated for all models. 
These analyses will be done primarily on the trabecular vBMD 
(radius). It will be repeated for the bone strength on FEA for 
supportive evidence. 
LSMeans and LSMean differences between treatment groups will be 
back-transformed to their original scale for descriptive purposes. After 
substracting the geometric mean of the log baseline values, the 
back-transformed LSMeans will correspond to the percentage change 
from baseline, while the back-transformed LSMeans differences will 
correspond to the ratio of percentage changes from baseline. 
 
Secondary 
 Tr. vBMD (tibia): An ANCOVA will be calculated on log 
transformed data as described above on the FAS, mFAS, the 
PP population, the FAS and the Non-Restricted FAS in both 
versions 
 DXA BMD: Changes will be compared treatment groups using 
an ANCOVA as described above on the percent change from 
baseline and on the T-scores for the following variables on 
the FAS, the PP population, the FAS and the Non-Restricted 
FAS in both versions: 
o Lumbar BMD 
o Whole body BMD 
o Proximal femur BMD 
 Vertebral assessments: 
o Vertebral fractures assessed by Genant’s 
semi-quantitative method: 
 2x2 table analysis for occurrence of new and 
new or worsening fractures (yes/no)  
 Poisson regression for number of new and new 
or worsening fractures, if appropriate 
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Endpoint 
Statistical Analysis Methods 
 Shift tables to investigate the change in grade 
for existing fractures 
 An ANCOVA with baseline value as covariate 
and treatment group and stratum as factors to 
investigate the percent change from baseline in 
numbers of vertebral fractures 
 An ANCOVA with baseline value as covariate 
and treatment group and stratum as factors to 
investigate the total sum of vertebral gradings 
o Vertebral height derived from 6-point quantitative 
morphometry: The maximum change from baseline in 
the HA/HP and the HM/HP ratio for fractured vertebrae 
will be analysed using ANCOVA  
 Change in bone histomorphometry 
 HRpQCT parameters: 
o Total vBMD 
o Cortical vBMD 
o BV/TV 
o Met/Inn 
o TbTh 
o TbN 
o Inhomogeneity 
o Cortical thickness 
o Cortical porosity (tibia and radius) 
 Body composition: Comparisons between treatment groups will 
be performed using an ANCOVA as described above 
o Body height 
o Body weight 
o BMI 
o Lean body mass 
o Fat body mass 
 Change from baseline to each visit for bone turnover markers 
and metabolic biomarkers 
 Fracture rate: Chi square tests will be calculated to assess 
differences across treatment groups on the following on the 
FAS, the PP population, the FAS and the Non-Restricted FAS 
in both versions: 
o Total fracture rate 
o Peripheral fracture rate 
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Endpoint 
Statistical Analysis Methods 
o Vertebral fracture rate 
o Long-bone fracture rate 
 The time to first fracture will also be analysed for each fracture 
category for the FAS, the PP population, the FAS and the 
Non-Restricted FAS in both versions 
 PROs and QoL (FAS and Non-restricted FAS in both versions): 
o SF-12 
o EQ-5D-5L 
o OIQoL-A 
Exploratory 
Will include change in TBS, and will be described in the SAP 
finalised before database lock 
  
11.3.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Endpoint 
Statistical Analysis Methods 
Primary 
Adverse Events 
AEs will be coded using the most recent version available of the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries will be by system 
organ class and preferred term. TEAEs are defined as any AE occurring or 
worsening on or after the first dose of study medication. If a participant 
experiences the same preferred term multiple times then the event will be 
counted only once and by the greatest severity. 
The frequency and incidence of TEAEs will be presented by system organ class 
and preferred term for each treatment regimen (number and percentage of 
participants experiencing at least 1 AE per preferred term as well as the number 
of observed events per preferred term). These tables will be presented on both 
the pooled and the non-pooled version of the Safety population. 
Remaining safety tables will be on the pooled version of the Safety population 
only. 
Separate tables will be presented by severity and by relationship. All AEs will 
be presented in full in a comprehensive listing including participant number, 
treatment regimen, severity, seriousness, action taken, outcome, relationship to 
treatment, onset/stop and duration. Details of SAEs/AESIs and AEs leading to 
withdrawal will be listed separately. 
Secondary 
All secondary safety analyses will be on the pooled version of the Safety 
population only. 
Infusion Site reactions 
Infusion site reactions will be tabulated and summarised by treatment regimen. 
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Endpoint 
Statistical Analysis Methods 
Vital Signs 
Vital signs will be summarised as actual values and change from baseline by 
treatment regimen and visit. 
Physical Examination 
Physical examination results will be listed by participant and body system. 
ECG 
The overall ECG interpretation will be summarised by presenting the number 
and percentage of participants with “Normal” “Abnormal, not clinically 
significant” and “Abnormal, clinically significant”. 
ECG parameter values (e.g., QTcF) will be summarised as actual values and 
change from baseline by treatment regimen and visit. 
Clinical Laboratory 
Descriptive statistics will be presented for quantitative laboratory parameters 
for each treatment regimen and time point. Similarly, changes from baseline 
will be summarised. 
Values outside the normal range will be categorised as H (above the normal 
range) or L (below the normal range) based on the laboratory’s reference range 
and these will be flagged in the listings of individual participant data.  
Tertiary / 
Exploratory 
Will be described in the SAP finalised before database lock 
 
11.3.3. 
Other Analyses  
Exploratory endpoint variables will be analysed according to their scale using general methods 
as described above. 
PK, PD, and biomarker exploratory analyses will be described in the SAP finalised before 
database lock. The population PK analysis and PD analyses will be presented separately from the 
main CSR.  
11.3.4. 
Follow-Up Period Analyses 
Variables will be analysed according to their scale using general methods as described above. 
Results will be presented overall and by initial treatment assignment. In addition, subgroup 
analyses will be performed for HRpQCT, DXA, vertebral radiograph, CTX-1, and P1NP based 
on the administration of zoledronic acid during the follow-up period (none; at Month 12; at 
Month 18). Also, the frequency of administration of zoledronic acid during the follow-up period 
will be related both to the site and to the 12 months outcome for both primary efficacy endpoints.  
11.3.5. 
Interim Analyses  
There is no formal interim analysis planned.  
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12. 
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Study CBPS804A2101 A first in human, randomised, double-blind, placebo-controlled study to 
evaluate safety and tolerability, PK, and PD of escalating single iv doses of BPS804 in healthy 
postmenopausal women. 
Study CBPS804A2201 a randomised, open-label intra-patient dose escalation study with an 
untreated reference group to evaluate safety and tolerability, PK, and PD of multiple infusions of 
BPS804 in adults with moderate osteogenesis imperfecta. 
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Study CBPS804A2202 An open-label, intra-patient dose-escalation study to evaluate the safety 
and tolerability, PK, PD and preliminary efficacy of multiple infusions of BPS804 in adults with 
hypophosphatasia. 
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type VII: and autosomal recessive form of brittle bone disease. Bone 2002;31(1):12-18. 
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osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification 
of the splice form responsible for prolyl 3-hydroxylation. J Med Genet. 2009;46(4):233-241. 
Winkler DG, Sutherland MS, Ojala E, et al. Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 
cell differentiation is indirect and mediated by bone morphogenetic proteins. J Biol Chem. 
2005;280(4):2498-502. 
 
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13. 
Appendices 
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Appendix 1: Abbreviations and Trademarks 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BSAP 
Bone-Specific Alkaline Phosphatase 
BV/TV 
Bone Volume Fraction 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CONSORT Consolidated Standards of Reporting Trials 
CRA 
Clinical Research Assistant 
CRO 
Clinical Research Organisation 
C5M 
Neo-Epitope of MMP-2,9 mediated degradation of Type V Collagen 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTX-1 
Carboxy-terminal Telo-peptide 
DMC 
Data Monitoring Committee 
DXA 
Dual-energy X-ray Absorptiometry 
EC50 
Half Maximal Efficacy Concentration 
ED50 
Median Effective Dose 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQol 5-dimension 5-level descriptive system 
EUDRACT European Union Drug Regulatory Agency Clinical Trial 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEA 
Finite Element Analysis 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
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HRpQCT 
High Resolution Peripheral Quantitative Computed Tomography 
HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
LSMeans 
Least Square Means 
mAb 
Mono-clonal Antibody 
MCP-Mod 
Multiple Comparison Procedure Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
Met/Inn 
Peripheral to Medullary Trabecular Bone Density Ratio 
mFAS 
Modified Full Analysis Set 
MMP 
Matrix Metalloproteinase 
NOAEL 
No Observed Adverse Effect Level 
NTX-1 
Amino-terminal Telo-peptide 
OC 
Osteocalcin 
OI 
Osteogenesis Imperfecta 
OIQoL-A     Osteogenesis Imperfecta specific Quality of Life Questionnaire for Adults 
P1CP 
Carboxy-terminal Propeptide of Type 1 Procollagen 
P1NP 
Amino-terminal Propeptide of Type 1 Procollagen 
PCR 
Protein: Creatinine Ratio 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PRO 
Patient-Reported Outcome 
Pro-C5 
C-terminal Pro-Peptide of Type V collagen 
PTH 
Parathyroid Hormone 
QCT 
Quantitative Computed Tomography 
QoL 
Quality of Life 
QTC 
Corrected QT Interval 
QTCF 
QTC by Fridericia’s correction Formula 
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RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-12 
Short Form 12 Health Survey 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SOST 
Gene Coding for Sclerostin 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TbN 
Trabecular Number 
TbTh 
Trabecular Thickness 
TBS 
Trabecular Bone Score 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TGF- 
Transforming Growth Factor Beta 
Tr. vBMD 
Trabecular Volumetric Bone Mineral Density 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
vBMD 
Volumetric Bone Mineral Density 
WOCBP 
Women of Childbearing Potential 
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Appendix 2: Clinical Laboratory Tests  
 The tests detailed in the table below will be performed by a central laboratory unless 
otherwise stated.  
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 7 of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
White Blood Cell count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red Blood Cell Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
Blood Urea 
Nitrogen 
Potassium 
Chloride, 
Bicarbonate/Carbon 
dioxide 
 
AST  
ALT  
Alkaline 
phosphatase 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Thyroid 
stimulating 
hormone 
Total Protein 
 
Glucose (non-
fasting) 
Calcium 
Vitamin D 
Lipase 
Prothrombin 
Time/ 
international 
normalised ratio 
Routine 
Urinalysis 
 Specific gravity 
 pH, glucose, protein, blood, ketones by dipstick 
 Microscopic examination (if blood or protein is abnormal) 
 Albumin creatinine ratio and protein creatinine ratio to be tested at site (if 
albumin or protein is abnormal) 
Other 
screening 
Tests 
 Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only) 
  Serum or urine human chorionic gonadotropin pregnancy test (as needed 
for women of childbearing potential)2 
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 The estimated glomerular filtration rate (eGFR) will be calculated based 
on Cockcroft-Gault formula: 
eGFR = ((140 - Age) / (SerumCreat)) * (Weight/72) 
 All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of COL1A1/COL1A2 genotyping. The 
results of each test must be entered into the eCRF. 
NOTES: 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments 
after liver stopping or monitoring event are given in Section 9.1. All events of ALT 3 × ULN 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international 
normalised ratio (INR) >1.5, if INR measured which may indicate severe liver injury (possible 
Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
 
2 Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
 
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Appendix 3: Study Governance Considerations 
Regulatory and Ethical Considerations 
 This study will be conducted by Mereo and ICON in accordance with the protocol and 
with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences International Ethical Guidelines 
o Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
 The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
 In case of substantial amendment approval from the Competent Authority (or relevant 
regulatory agencies) will be sought by Mereo prior to implementation.  
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
o Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.  
 Participants must be informed that their participation is voluntary. Participants or their 
legally authorised representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
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Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study centre.  
 The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.  
Data Protection 
 Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
 The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  
 The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
Committees Structure 
A Data Monitoring Committee (DMC) will be established to review the efficacy and safety 
results. The DMC will have access to unblinded data. Based on the data the DMC will submit its 
recommendations in written form to the sponsor who is responsible for responding to the 
recommendations of the DMC and to take appropriate action. The investigators will only be 
informed by the sponsor in case of stopping the trial. The DMC may choose to request additional 
evaluations at any time if they feel this is warranted from the standpoint of safety. 
The DMC will act according to its own written standard operating procedure (SOP) described in 
a charter and will prepare written minutes of its meetings.  
 
Publication Policy 
The sponsor shall retain the ownership of all data. When the study is complete the sponsor shall 
arrange the analysis and tabulation of data. A CSR shall then be prepared, which may be used for 
publication, presentation at scientific meetings or submission to regulatory authorities. All 
proposed publications based on this study must be participant to the sponsor's approval 
requirements. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
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multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
Dissemination of Clinical Study Data 
At the end of the study, investigators will be informed of the outcome of the study including the 
treatment allocation as soon as the results are available and can be reported. These may be shared 
with participants in the study.  
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and finalisation 
of the study report, the results of this trial will be submitted for publication and/or posted in a 
publicly accessible database of clinical trial results. 
 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.  
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
 Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 2 years after the last approval of a marketing 
application in an ICH region unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period without 
the written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
 
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Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
 Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 Definition of what constitutes source data can be found in the Study Manual and 
Monitoring Plan. 
 
Study and Site Closure 
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.  
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (e.g. an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) whether or 
not considered related to the medicinal product. 
 
Events Meeting the AE Definition  
 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE.  
 
 
 
 
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Events NOT Meeting the AE Definition  
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalisation for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
In general, hospitalisation signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalisation are AE. If a complication prolongs hospitalisation or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred 
or was necessary, the AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
 
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d. 
Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalisation, or development of drug dependency or drug abuse. 
Definition of AESI 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterise and understand it. Depending on the nature 
of the event, rapid communication by the trial sponsor to other parties (e.g. regulators) might also 
be warranted (CIOMS VI and ICH E2F) 
AESIs for setrusumab  
Some AEs, despite their severity or outcome, will be expedited due to the relevance for participant 
safety or study treatment safety profile. These events should be reported to the Sponsor/designee 
within 24 hours. This is to enable follow-up to be performed on all these reported adverse events 
that have not been reported as serious adverse events (SAEs). The AESIs for setrusumab are: 
 
Fractures 
 
Cardiovascular events 
Cardiovascular events that are considered to be clinically significant by the PI and/ or medical 
team will also be submitted to the independent DMC for CV adjudication. 
Recording AE and SAE/AESI 
AE and SAE/AESI Recording 
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 
When an AE/SAE/AESI occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event. 
 
The investigator will then record all relevant AE/SAE/AESI information in the SAE/AESI 
report form and the eCRF. 
 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Safety CRO in lieu of completion of the SAE/AESI report form. 
 
There may be instances when copies of medical records for certain cases are requested by 
the Safety CRO. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the Safety 
CRO. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE/AESI. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE/AESI reported during 
the study and assign it to one of the following categories:  
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
 
Moderate: An event that causes sufficiently discomfort and interferes with normal everyday 
activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilised for rating the intensity of 
an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE/AESI. 
 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
 
The investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
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 
For each AE/SAE/AESI, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE/AESI and has provided an assessment of causality. 
 
There may be situations in which an SAE/AESI has occurred and the investigator has 
minimal information to include in the initial report to the Safety CRO. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE/AESI data to the Safety CRO. 
 
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE/AESI follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AE and SAE/AESI 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Safety CRO 
to elucidate the nature and/or causality of the AE or SAE/AESI as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 
If a participant dies during participation in the study or during a recognised follow-up period, 
the investigator will provide the Safety CRO with a copy of any post-mortem findings 
including histopathology. 
 
New or updated information will be recorded in the SAE/AESI report form and completed 
eCRF. 
 
The investigator will submit any updated SAE/AESI data to the sponsor within 24 hours of 
receipt of the information. 
 
SAE Reporting to the Safety CRO via SAE/AESI Report Form 
 
The primary mechanism for reporting SAE/AESI to the Safety CRO will be the SAE/AESI 
report form. 
 
The site will submit the SAE/AESI data on the SAE/AESI report form as soon as it becomes 
available. 
 
Facsimile transmission of the SAE/AESI report form is the preferred method to transmit this 
information to the Safety CRO Drug Safety team. The following contacts may be used: 
Fax Number: 001-877-464-7787 
 
In case of issues with fax, Email: safetyreporting@syneoshealth.com 
 
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 
Contacts for SAE/AESI reporting can be found in above or in the MBPS205 Investigator 
Site File. 
 
 
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Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
 
Women in the Following Categories Are not Considered WOCBP 
1. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
2. Premenarchal  
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
 Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
 
Contraception Guidance 
Males Participants 
 Male participants with female partners of childbearing potential do not need to use 
contraception during the treatment period. Setrusumab is non-genotoxic and, 
teratogenicity or feto-toxicity is not expected at sub-therapeutic levels*. In that situation 
no male contraception is required with WOCBP (Clinical Trial Facilitation Group 
Guidelines) 
*The female exposure from vaginal transference of a monoclonal antibody (mAb) is from a male 
partner is very limited. Semen levels are 1-2% of plasma and that vaginal absorption is assumed 
maximum 10% (in cyno its only 1%). Therefore the systemic levels in a female partner after a 
single 6 mL semen exposure are 250,000 -500,000 x less than the levels in the male 
 
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Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationb  
 
oral  
 
intravaginal  
 
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
 
oral  
 
injectable  
Highly Effective Methods That Are User Independent  
 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
Vasectomised partner  
(A vasectomised partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.)  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.  
Female Participants 
Female participants of reproductive potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
above.  
Pregnancy Testing  
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
Additional pregnancy testing should be performed at regular intervals as per SoA during the 
treatment period and at 60 days after the last dose of study treatment. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected.  
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Pregnancy testing, with a sensitivity of 5 mIU/mL will be performed and assayed in the central 
laboratory. 
Collection of Pregnancy Information  
Male Participants With Partners of Reproductive Potential Who Become Pregnant  
Investigator will attempt to collect pregnancy information on any female partner of a male study 
participant who becomes pregnant while participating in this study. This applies only to 
participants who receive study treatment. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
Safety CRO within 24 hours of learning of the partner’s pregnancy. 
Partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Safety CRO. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. 
 
Female Participants Who Become Pregnant  
Investigator will collect pregnancy information on any female participant, who becomes 
pregnant while participating in this study. 
Information will be recorded on the appropriate form and submitted to the Safety CRO within 
24 hours of learning of a participant's pregnancy.  
Participant will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on participant and neonate, which will be forwarded to the Safety 
CRO. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.   
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  
A spontaneous abortion is always considered to be an SAE and will be reported as such.   
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the investigator, will be reported to the Safety CRO as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating will be withdrawn from the 
study. 
 
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Appendix 6: Radiation Exposure 
 
Assessment 
Radiation dose per visit 
(mSv) 
Visits at which 
performed 
Total radiation dose 
(mSv) 
DXA scan, lumbar, whole 
body, proximal femur 
0.004-0.0081 
Baseline, Month 6, 
12/EOT, M18 & M24 
0.020-0.0405 
HRpQCT 
0.006 
Baseline, (Month 3 for 
open-label arm), Month 
6, Month 12/EOT, M18 
& M24 
0.030-0.036 
Lateral vertebral radiograph 
0.6 
Baseline, Month 6, 
Month 12/EOT, M18 & 
M24 
3.0 
 
Total 
3.035-3.0585 
Abbreviations: 
DXA = Dual-energy x-ray absorptiometry; HRpQCT = high resolution peripheral quantitative 
computed tomography, EOT = End of Treatment 
 
Typical Effective and Organ Doses for Various Diagnostic X-ray Examinations 
Examination 
Effective dose (mSv) 
Organ dose (mGy) 
Relevant organs 
Dental radiography (intraoral) 
0.005 
0.005 
Brain 
Chest radiography (posterior-anterior) 
0.02 
0.01 
Lung 
X-ray mammography 
0.4 
3 
Breast 
Adult abdominal CT 
8 
10 
Stomach 
Source: Damilakis, J., Adams, J. E., Guglielmi, G., & Link, T. M. (2010). Radiation exposure in X-ray-based 
imaging techniques used in osteoporosis. European radiology, 20(11), 2707-2714. 
Abbreviations: CT = Computed Tomography 
 
 
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Appendix 7: Audiometry Scale 
 
Grade on audiometry (db loss) 
Score 
<21 
undetectable hearing loss 
21-35 
mild 
36-60 
moderate 
>60 
severe 
 
 
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Appendix 8: MBPS205 Study Oversight 
 
Function 
Name 
Contact Details 
Sponsor Signatory 
 
Mereo BioPharma 3 Ltd. 
1 Cavendish Place London W1G 0QF 
United Kingdom (UK) 
Sponsor Clinical 
Operations Oversight 
 
 
 
 
Clinical Research 
Organisation 
ICON Clinical Research 
Ltd. 
South County Business Park, 
Leopardstown, Dublin 18, Ireland 
Safety Clinical 
Research Organisation 
Syneos Health 
3201 Beechleaf Court, Suite 600, 
Raleigh, NC 27604-1547 
Biostatistician 
 
3rd Floor, Marlow International, 
Marlow, Buckinghamshire, SL7 1YL, 
UK 
Tel No.: 
 
 
 
 
Chief Coordinating 
Investigator 
 
6410 Rockledge Drive, Suite 403, 
Bethesda, MD 20817, United States of 
America 
Coordinating 
Investigator for 
Americas 
 
Shriner’s Hospital for Children, 
1003 Decarie Blvd, Montreal, 
H4A 0A9, Quebec, Canada 
Coordinating 
Investigator for Europe 
 
Oxford University of Hospitals Trust, 
Nuffield Orthopaedic Centre, 
Windmill Road, Oxford, OX3 7HE 
UK 
 
 
 
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Appendix 9: Summary of Versions and Changes 
 
Summary of Versions 
 
Protocol  
Version 
Date 
Summary of Change 
Original 
Version 1.0 
10 Jan 2017 
Not applicable 
Amendment 1 
Version 2.0 
27 Jan 2017 
Change to OI-PRO-A End-points, minor 
administrative changes 
Amendment 2 
Version 3.0 
2 May 2017 
UK Regulatory Agency request for 60-day 
follow-up period, clarification of schedule of 
activities and administrative changes 
Amendment 3 
Version 4.0 
18 Jan 2018 
Adjust primary analysis to 12 months and 
remove DXA vertebral fracture assessment 
as study endpoint. 
Amendment 4 
Version 5.0 
18 May 
2018 
Placebo arm replaced by open-label 
treatment arm and addition of 12-month 
follow-up period following treatment end. 
Amendment 5 
Version 6.0 
12 Dec 
2018 
Addition of optional zoledronic acid therapy 
during follow up period. 
 
Protocol Amendment 6 Summary of Changes 
Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Tr. vBMD (tibia & radius) on 
HRpQCT and bone strength on 
FEA at 3 & 6 months in the 
open-label treatment arm. 
Tr. vBMD (tibia & radius) on 
HRpQCT and bone strength on 
FEA at 3, 6 & 12 months in the 
open-label treatment arm. 
Synopsis: 
Objectives 
& Endpoints 
Clarification that 
open-label data 
will be assessed 
up to Month 12 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
MBPS205 Study Schematic: 
Post Study options:  
All consenting patients transfer 
to the MBPS206 Study. 
MBPS205 Study Schematic 
Removed.  
Synopsis: 
MBPS205 
Study 
Schematic  
Removal of 
reference to 
MBPS206 study in 
study schematic.  
For a change from baseline of 
 which can be 
considered to be a clinically 
relevant change, with standard 
deviation as above the one-sided 
test would have a probability of 
80% to yield a p-value below 
5%, being considered indicative 
of a trend. 
For a change from baseline of 
, with standard 
deviation as above the 
one-sided test would have a 
probability of 80% to yield a 
p-value below 5%, being 
considered indicative of a trend. 
Synopsis: 
Number of 
Participants  
Removal of 
reference to 
clinically 
significant change 
related to initial 
sample size 
calculation.   
Not applicable 
Following a review of the 
trabecular vBMD (radius) 
derived from HRpQCT at 
Month 6 of those subjects 
within the 20 mg/kg 
Setrusumab open label 
treatment group, a change from 
baseline standard deviation of 
 was 
observed. This yields to a 
correlation between baseline 
and Month 6 visits of
 
(much higher than the
 that 
was originally assumed). If such 
a correlation is observed at 
Month 12, given 25 subjects per 
arm, the one-sided test would 
have a probability of 80% to 
yield a p-value below 5% for a 
change in baseline of 
 
Synopsis: 
Number of 
participants 
Addition of further 
details of 
statistical 
calculations for 
study based on the 
initial results from 
the open-label 
treatment arm 
results at 6 months 
of treatment.   
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Participants will be qualified 
during a 28-day screening period, 
followed by 12 months of study 
treatment. At the end of 
treatment in MBPS205, 
participants will continue into the 
follow-up period for 12 months 
after which participants will be 
offered the option to continue 
into the MBPS206 Study, in 
which treatment with setrusumab 
will be offered at the dose 
selected in MBPS205. 
Participants will be qualified 
during a 28-day screening 
period, followed by 12 months 
of study treatment. At the end of 
treatment in MBPS205, 
participants will continue into 
the follow-up period for 
12 months. 
Protocol 
Synopsis: 
Treatment 
Groups and 
Duration 
Removal of 
reference to 
participants being 
offered the option 
to continue into 
the MBPS206 
study.  
Data for placebo participants and 
open-label BPS804 20 mg/kg 
participants will be reported 
separately from the comparison 
between the randomized, blinded 
treatment groups. In particular 
the open-label BPS804 20 mg/kg 
participants’ data will not be 
pooled with the blinded BPS804 
20 mg/kg participants’ data. 
Data for placebo participants 
and open-label BPS804 20 
mg/kg participants will be 
reported separately from the 
comparison between the 
randomized, blinded treatment 
groups. In particular for the 
primary analysis, the open-label 
BPS804 20 mg/kg participants’ 
data will not be pooled with the 
blinded BPS804 20 mg/kg 
participants’ data. 
Protocol 
Synopsis: 
General 
Statistical 
Methods 
Additional 
clarification for 
the primary 
analysis the 
BPS804 
open-label 20 
mg/kg data will 
not be pooled with 
the blinded 
BPS804 20 mg/kg 
data.  
The LSMeans will further be 
analysed using the MCPMod 
methodology, using the 
following candidate models: 
 EMax (ED50 of 1.5 mg) 
 Exponential (δ = 2) 
The LSMeans will further be 
analysed using the MCPMod 
methodology, using the 
following candidate models: 
 EMax (ED50 of 1.5 mg) 
 Exponential (δ = 2) 
 Sigmoid EMax model 
with parameters 
ED50 = 10 mg and 
h = 2.4 
Protocol 
Synopsis: 
Efficacy 
Analysis 
Correction to 
include reference 
in efficacy section 
as well as the 
patient population 
section.   
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Bone Biopsy: 
Month 6 
Sub-set of participants.  
Bone Biopsy: 
Month 6 
Month 12 
Sub-set of participants. 
Completed once either at M6 or 
M12.  
Schedule of 
Activities 
Addition of option 
to have bone 
biopsy at M12 
visit.  
Month 24 
(Can also be MBPS206 baseline 
visit) 
Month 24 
Schedule of 
Activities 
Removal of 
reference to the 
MBPS206 study in 
schedule of 
activities.  
MBPS205 Study Schematic: 
Post Study options:  
All consenting patients transfer 
to the MBPS206 Study. 
MBPS205 Study Schematic 
Removed.  
Protocol 
Figure 1: 
MBPS205 
Study 
Schematic 
Removal of 
reference to 
MBPS206 study in 
study schematic.  
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Since there are no approved 
pharmacological therapies for OI, 
patients participating in this 
study have the possibility to 
receive a potentially beneficial 
treatment, at a potentially 
therapeutic dose for a period of 
time considered long enough to 
achieve a benefit. It is expected 
that at least one of the doses of 
setrusumab will be 
sub-therapeutic; therefore 
patients randomised to this dose 
are not expected to receive any 
therapeutic benefit from 
participation. However, no 
proven therapy will be withheld 
during the study and all patients 
will have the possibility to 
continue on to study MBPS206, 
in which all participants will 
receive active drug. Therefore, 
all participants in this study will 
ultimately have the opportunity 
to benefit from treatment, either 
during the study itself or in the 
follow on studies. 
Since there are no approved 
pharmacological therapies for 
OI, patients participating in this 
study have the possibility to 
receive a potentially beneficial 
treatment, at a potentially 
therapeutic dose for a period of 
time considered long enough to 
achieve a benefit. It is expected 
that at least one of the doses of 
setrusumab will be 
sub-therapeutic; therefore 
patients randomised to this dose 
are not expected to receive any 
therapeutic benefit from 
participation. However, no 
proven therapy will be withheld 
during the study until the final 
analysis is performed when all 
subjects in the blinded treatment 
arms have completed 12 months 
of treatment with setrusumab. 
Data from this study will 
provide confirmation about 
whether setrusumab is 
efficacious for the treatment in 
adult osteogenesis imperfecta. 
Section 4.3: 
Benefit/Risk 
Assessment 
Adjustment to 
benefit risk 
assessment section 
to remove 
reference to the 
possibility of 
treatment in 
MBPS206 study.  
Tr. vBMD (tibia & radius) on 
HRpQCT and bone strength on 
FEA at 3 & 6 months in the 
open-label treatment arm. 
Tr. vBMD (tibia & radius) on 
HRpQCT and bone strength on 
FEA at 3, 6 & 12 months in the 
open-label treatment arm. 
Section 5: 
Objectives 
& Endpoints 
Clarification that 
open-label data 
will be assessed 
up to Month 12 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Participants completing the 
MBPS205 study will be able to 
discuss other potential treatments 
with their investigators or be 
offered the option to continue 
into the MBPS206 Study, in 
which treatment with setrusumab 
will be offered. Participation in 
MBPS206 will be subject to 
meeting any inclusion/exclusion 
criteria and restrictions on 
concomitant medication for this 
study. 
All Participants will be offered 
participation in MBPS206 at the 
end of MBPS205. In the event 
that a participant does not wish to 
participate in MBPS206, they 
will be able to discuss alternative 
treatment options or approaches 
with their investigator. 
Participants completing the 
MBPS205 study will be able to 
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. 
Section 8.7: 
Treatment 
After the 
End of the 
Study.  
Section updated to 
remove reference 
to the option to 
join the MBPS206 
study. 
Bone biopsies will be performed 
at Month 6 in a sub-set of 
participants. Informed consent 
will be obtained using a specific 
bone biopsy consent form. 
Bone biopsies will be 
performed once at either Month 
6 or Month 12 in a sub-set of 
participants. Informed consent 
will be obtained using a specific 
bone biopsy consent form. 
Section 
10.1.2: Bone 
Biopsy 
Adjustment to 
bone biopsy 
timing to allow 
collection at 
Month 12 visit as 
well as Month 6 
visit.  
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
In the treatment period samples 
will be tested for PTH, P1NP, 
P1CP, OC, BSAP, CTX-1, NTX-
1, RANKL, osteoprotegerin, 
TGF-, sclerostin, Pro-C5, and 
C5M to evaluate their association 
with the observed clinical 
responses in bone turnover to 
setrusumab. In the follow-up 
period samples will be tested for 
CTX-1 and P1NP. 
In the treatment period samples 
will be tested for PTH, P1NP, 
P1CP, OC, BSAP, CTX-1, 
NTX-1, RANKL, 
osteoprotegerin, TGF-, 
sclerostin, Pro-C5, and C5M to 
evaluate their association with 
the observed clinical responses 
in bone turnover to setrusumab. 
In the follow-up period samples 
can be tested for CTX-1 and 
P1NP. 
Section 
10.7: 
Biomarkers 
Adjustment to 
bone biomarkers 
collected in follow 
up period should 
be completed if 
possible.   
For a change from baseline of 
, which can be 
considered to be a clinically 
relevant change, with standard 
deviation as above the one-sided 
test would have a probability of 
80% to yield a p-value below 
5%, being considered indicative 
of a trend. 
For a change from baseline of 
, with standard 
deviation as above the 
one-sided test would have a 
probability of 80% to yield a 
p-value below 5%, being 
considered indicative of a trend. 
Section 11.1 
Sample Size 
Determinati
on 
Removal of 
reference to 
participants being 
offered the option 
to continue into 
the MBPS206 
study. 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Not applicable 
Following a review of the 
trabecular vBMD (radius) 
derived from HRpQCT at 
Month 6 of those subjects 
within the 20 mg/kg 
Setrusumab open label 
treatment group, a change from 
baseline standard deviation of 
 was 
observed. This yields to a 
correlation between baseline 
and Month 6 visits of 
 
(much higher than the 
 that 
was originally assumed). If such 
a correlation is observed at 
Month 12, given 25 subjects per 
arm, the one-sided test would 
have a probability of 80% to 
yield a p-value below 5% for a 
change in baseline of 
 
.   
Section 
11.1: 
Sample Size 
Determinati
on 
Additional 
clarification for 
the primary 
analysis the 
BPS804 open-
label 20 mg/kg 
data will not be 
pooled with the 
blinded BPS804 
20 mg/kg data. 
Not applicable 
Modified Full Analysis Set 
(mFAS) 
All participants from the FAS 
who have sufficient cross-
sectional overlap across 
HRpQCT scans (details to be 
further described in the 
Statistical Analysis Plan). 
Participants will be analysed 
according to the randomised 
treatment. 
Section 
11.2: 
Population 
for Analyses 
Inclusion of 
modified full 
analysis set 
(mFAS) to ensure 
sufficient cross-
sectional overlap 
in HRpQCT scans. 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
All participants from the FAS 
who have been treated according 
to the protocol and fulfill the 
following criteria (to be further 
described in the Statistical 
Analysis Plan [SAP]): 
1. All inclusion/exclusion
criteria satisfied
2. Absence of relevant
protocol violations with
respect to factors likely to 
affect the efficacy of
treatment where the
nature of protocol
violation will be defined
before breaking the blind
3. Adequate study
medication compliance
which will be determined
before breaking the blind.
All participants from the mFAS 
who have been treated 
according to the protocol and 
fulfill the following criteria (to 
be further described in the 
Statistical Analysis Plan 
[SAP]): 
1. All inclusion/exclusion
criteria satisfied
2. Absence of relevant
protocol violations with
respect to factors likely
to affect the efficacy of
treatment where the
nature of protocol
violation will be defined
before breaking the
blind
3. Adequate study
medication compliance
which will be
determined before
breaking the blind.
Section 
11.2: 
Population 
for Analyses 
Inclusion of 
mFAS definition 
within per-
protocol analysis 
population.  
Non-restricted FAS: 
All participants who are 
randomised and take at least 1 
dose of study treatment. 
Participants will be analysed 
according to the randomised 
treatment. Analyses using the 
Non-restricted FAS will 
comprise of such where the two 
20 mg/kg dose group are pooled, 
and those where they are not. 
Non-restricted FAS: 
All participants who are 
randomised and take at least 1 
dose of study treatment. 
Participants will be analysed 
according to the randomised 
treatment. Analyses using the 
Non-restricted FAS will 
comprise of such where the two 
20 mg/kg dose group are pooled 
(for the follow-up analysis), and 
those where they are not. 
Section 
11.2: 
Population 
for Analyses 
Additional 
clarification the 
pooled analysis 
will take place as 
part of the follow-
up analysis. 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Safety: 
All participants who are 
administered at least 1 dose of 
study treatment. Participants will 
be analysed according to the 
treatment they actually received. 
Analyses using the Safety 
population will comprise of such 
where the two 20 mg/kg dose 
group are pooled, and those 
where they are not. 
Safety: 
All participants who are 
administered at least 1 dose of 
study treatment. Participants 
will be analysed according to 
the treatment they actually 
received. Analyses using the 
Safety population will comprise 
of such where the two 20 mg/kg 
dose group are pooled (for the 
follow-up analysis), and those 
where they are not. 
Section 
11.2: 
Population 
for Analyses 
Additional 
clarification the 
pooled analysis 
will take place as 
part of the follow-
up analysis. 
The main population for efficacy 
analysis will be the FAS. Results 
for the per-protocol (PP) 
population and the Non-restricted 
FAS will be considered 
supportive. 
The main population for 
efficacy analysis will be the 
FAS. Results for the mFAS, 
per-protocol (PP) population 
and the Non-restricted FAS will 
be considered supportive. 
Section 
11.3: 
Statistical 
Analyses 
Inclusion of 
mFAS analysis 
population.  
Data for placebo participants and 
open-label BPS804 20 mg/kg 
subjects will be reported 
separately from the comparison 
between the randomized, blinded 
treatment groups. In particular, 
the open-label BPS804 20 mg/kg 
participants’ data will not be 
pooled with the blinded BPS804 
20 mg/kg participants’ data. 
Data for placebo participants 
and open-label BPS804 20 
mg/kg subjects will be reported 
separately from the comparison 
between the randomized, 
blinded treatment groups. In 
particular for the primary 
analysis, the open-label BPS804 
20 mg/kg participants’ data will 
not be pooled with the blinded 
BPS804 20 mg/kg participants’ 
data. 
Section 
11.3: 
Statistical 
Analyses 
Additional 
clarification for 
the primary 
analysis the 
BPS804 
open-label 
20 mg/kg data will 
not be pooled with 
the blinded 
BPS804 20 mg/kg 
data. 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Analyses for the primary efficacy 
endpoints and selected secondary 
endpoints will be analysed on the 
FAS, the Non-restricted FAS and 
the PP samples, while analyses 
for the remaining secondary 
efficacy endpoints will be 
analysed on the FAS sample 
only. General methods as 
described above will be applied 
to the efficacy endpoints; specific 
analyses are described below. 
Analyses for the primary 
efficacy endpoints and selected 
secondary endpoints will be 
analysed on the FAS, mFAS, 
the Non-restricted FAS and the 
PP samples, while analyses for 
the remaining secondary 
efficacy endpoints will be 
analysed on the FAS sample 
only. The mFAS will be used 
for analysis of HRpQCT 
endpoints only. General 
methods as described above will 
be applied to the efficacy 
endpoints; specific analyses are 
described below. 
Section 
11.3.1: 
Efficacy 
Analyses 
Inclusion of 
mFAS analysis 
population within 
efficacy analysis 
section.  
The LSMeans will further be 
analysed using the MCPMod 
methodology, using the 
following candidate models: 

EMax (ED50 of 1.5 mg)

Exponential (δ = 2)
The LSMeans will further be 
analysed using the MCPMod 
methodology, using the 
following candidate models: 

EMax (ED50 of 1.5 mg)

Exponential (δ = 2)

Sigmoid EMax model
with parameters
ED50 = 10 mg and
h = 2.4
Section 
11.3.1: 
Efficacy 
Analyses 
Correction to 
include reference 
in efficacy section 
as well as the 
patient population 
section.   
Sponsor Medical Expert & 
Sponsor Signatory: 
 
Removed 
Appendix 8: 
MBPS205 
Study 
Oversight 
Removal of 
 
 
from study 
oversight section. 
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Original 
Protocol Amendment 6 
Change 
Sections 
Applied 
Rationale 
Biostatistician: 
 
3rd Floor, Marlow International, 
Marlow, Buckinghamshire, UK 
Tel No.: 
 
Biostatistician: 
 
3rd Floor, Marlow International, 
Marlow, Buckinghamshire, SL7 
1YL, UK 
Tel No.: 
 
Appendix 8: 
MBPS205 
Study 
Oversight 
Update to Study 
Statistician’s name 
and contact 
details. 
Version: 7  Date: 19 Jul 2019


CONFIDENTIAL 
Protocol MBPS205 
Mereo Biopharma 3 Ltd. 
91 
Appendix 10: Sponsor Electronic Signature 
Version: 7  Date: 19 Jul 2019


Signature Page for MBPS205 - Protocol v7.0
Signature Page for VV-TMF-00266 v7.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 19-Jul-2019 11:58:50 GMT+0000
Reason for signing: Approved
Name: 
Role: R
ad of Clinical Operations
Date of signature: 19-Jul-2019 12:10:29 GMT+0000
Version: 7  Date: 19 Jul 2019
92

SAP_001.pdf: 
 
Statistical Analysis Plan (SAP) 
 
 
 
Statistical Analysis Plan 
Protocol Number: MBPS205 
                       Version: Final 1.0, Date: 22 October 2019
 
                                                                          Page 1 of 50 
 
Protocol 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) 
Protocol Number: 
MBPS205 
Protocol Version, Date 
Version 7, 19 July 2019 
 
ICON ID:  
3082/0003 
Document Version, Date: 
1.0, 22 October 2019 
 
 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
Mereo BioPharma 3 Ltd. 1 Cavendish Place, London, W1G 0QF 
 
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons 
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 


Statistical Analysis Plan (SAP)
Statistical Analysis Plan
Protocol Number: MBPS205
                       Version: Final1.0, Date: 22October 2019
                                                                        Page 2of 
50
Prepared at ICON Clinical Research by: 
 Senior Statistician I
Date 
(DD Mmm YYYY)
Reviewed at ICON Clinical Research by: 
, Senior Programming Manager
Biostatistics and Programming
Date 
(DD Mmm YYYY)
Approvedat Mereo BioPharma 3Ltdby:
Head of Clinical Operations
Mereo BioPharma 3 Ltd
Date 
(DD Mmm YYYY)


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MBPS205  
                   Version: Final 1.0, Date: 22 October 2019 
                                                                    Page 3 of 50 
 
 
 
 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
1.0/ 22OCT2019 
Initial approved 
version 
N/A 
N/A 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: MBPS205  
                       Version: Final 1.0, Date: 22 October 2019 
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SIGNATURE PAGE 
....................................................................................................................... 2 
REVISION HISTORY 
.................................................................................................................... 3 
TABLE OF CONTENTS 
................................................................................................................ 4 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
1 INTRODUCTION 
..................................................................................................................... 7 
2 STUDY OBJECTIVES 
............................................................................................................. 8 
2.2 Secondary objectives 
........................................................................................................ 8 
2.3 Exploratory objectives 
...................................................................................................... 8 
3 STUDY DESIGN 
.................................................................................................................... 10 
3.1 General study design ...................................................................................................... 10 
3.2 Randomisation and blinding 
........................................................................................... 11 
3.3 Study treatments and assessments 
.................................................................................. 12 
4 STUDY ENDPOINTS 
............................................................................................................. 13 
4.1 Primary efficacy endpoint .............................................................................................. 13 
4.2 Secondary endpoints 
....................................................................................................... 13 
4.3 Exploratory endpoints .................................................................................................... 14 
5 SAMPLE SIZE AND POWER 
............................................................................................... 16 
6 ANALYSIS POPULATIONS 
................................................................................................. 18 
6.1 Full Analysis Set (FAS) 
.................................................................................................. 18 
6.2 Modified Full Analysis Set (mFAS) 
............................................................................... 18 
6.3 Non-restricted FAS 
........................................................................................................ 18 
6.4 Per-Protocol population (PP) 
.......................................................................................... 19 
6.5 Safety population (Safety) 
.............................................................................................. 19 
6.6 PK population 
...............................................................
.................................................. 19 
6.7 Other Populations Defined for Tables and Listings 
....................................................... 19 
6.8 Protocol deviations/violations and exclusions from analysis sets 
.................................. 19 
7 Statistical Considerations and analysis 
................................................................................... 20 
7.1 Derived Variables 
...............................................................
............................................ 20 
7.2 Handling of missing data and outliers 
............................................................................ 24 
8 STATISTICAL METHODS.................................................................................................... 26 
8.1 General statistical conventions 
....................................................................................... 26 
8.2 Patient disposition .......................................................................................................... 28 
8.3 Protocol deviations 
...............................................................
.......................................... 28 
8.4 Demographics and baseline characteristics 
.................................................................... 28 
8.5 Efficacy analyses 
............................................................................................................ 30 
8.6 Safety analyses ............................................................................................................... 37  
8.7 Other analysis 
...............................................................
.................................................. 40 
9 CHANGES TO PLANNED ANALYSIS FROM PROTOCOL 
............................................. 41 
10 REFERENCES 
........................................................................................................................ 42 
11 APPENDICES 
......................................................................................................................... 43 
 
 


 
 
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Protocol Number: MBPS205  
                       Version: Final 1.0, Date: 22 October 2019 
                                                                        Page 5 of 50 
 
 
The following abbreviations will be used within this SAP. 
 
Abbreviation or 
special term 
Explanation 
 
 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMD 
Bone mineral density 
BMI 
Body Mass Index 
BV/TV 
Bone volume fraction 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTMS 
Clinical Trial Management System 
DXA 
Dual-energy x-ray absorptiometry 
ED50 
Median Effective Dose 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
Euroqol 5-dimension 5-level descriptive system 
FAS 
Full analysis set 
FEA 
Finite Element Analysis 
HR 
Heart Rate 
HRpQCT 
High Resolution peripheral Quantitative Computed Tomography 
ICH 
International Conference on Harmonisation 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
LSMeans 
Least Square Means 


 
 
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MCP-Mod 
Multiple Comparison Procedure Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
OI 
Osteogenesis Imperfecta 
P1CP 
Carboxy-Terminal Propeptide of type 1 Procollagen 
P1NP 
Procollagen 1 N-terminal propeptide 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
QoL 
Quality of Life 
QTc 
Corrected QT interval of the electrocardiogram 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SF-12 
Short Form 12 Health Survey 
SI 
Standard International 
SOC 
System Organ Class 
TbN 
Trabecular number 
TbTh 
Trabecular thickness 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TFLs 
Tables, Figures and Listings 
Tr. vBMD 
Trabecular volumetric bone mineral density 
VAS 
Visual analogue scale 
WBC 
White Blood Cell 
WHO 
World Health Organisation 


 
 
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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol MBPS205 Amendment 5 
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)
The table of contents and templates for the 
Tables, Figures and Listings (TFLs) will be produced in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Conference on Harmonisation (ICH) 
E91. 
All data analyses and generation of TFLs will be performed using SAS 9.4® or higher. 
Note: This plan does not address the validation analyses to the HRpQCT measurements or the 
pharmacokinetic (PK) analyses. These analyses will be described in a separate analysis plan. 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: MBPS205  
                       Version: Final 1.0, Date: 22 October 2019 
                                                                        Page 8 of 50 
 
2 
STUDY OBJECTIVES 
The study is designed to investigate the dose-response to setrusumab in a large cohort of Type I, III 
and IV OI patients. 
2.1 Primary 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. 
2.2 Secondary objectives 
The secondary objectives are: 
1. To determine the dose-response relationship of Tr. vBMD to setrusumab after 12 
months of treatment 
2. To evaluate the onset of treatment effect 
3. To evaluate the effect of setrusumab on fracture rate (peripheral, major [long-bone], 
and vertebral fractures)  
4. To evaluate the effect of setrusumab on vertebral fractures and vertebral height  
5. To evaluate the effect of setrusumab on bone mineral density (BMD) 
6. To evaluate the effect of setrusumab on bone quality 
7. To evaluate changes in radial Tr. vBMD on HRpQCT and bone strength FEA during 
the 12 months post setrusumab treatment period 
8. To evaluate the effect of setrusumab on HRpQCT parameters 
9. To evaluate the effect of setrusumab on body composition 
10. To evaluate the effect of setrusumab on markers of bone composition 
11. To evaluate the effect of setrusumab on Patient-Reported Outcomes (PROs) and 
Quality of Life (QoL) 
12. To evaluate the pharmacokinetics (PK) of setrusumab 
13. To evaluate potential induction of antidrug antibodies (ADAs) by setrusumab and their 
effect on safety and PK 
14. To evaluate safety and tolerability of setrusumab 
2.3 Exploratory objectives 
The exploratory objectives are: 
1. To evaluate the effect of setrusumab on bone quality 
2. To evaluate the effect of setrusumab on changes in use of physical aids 
3. To evaluate the effect of setrusumab on hearing 


 
 
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4. To evaluate the effect of setrusumab on bone formation and resorption parameters 
measured by HRpQCT 
 


 
 
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                       Version: Final 1.0, Date: 22 October 2019 
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3 
STUDY DESIGN 
3.1 General study design 
MBPS205 is a phase 2, multicentre, multinational, double-blind, dose range-finding study 
comparing 3 blinded doses of setrusumab (20 mg/kg, 8 mg/kg and 2 mg/kg) and an open-label 
treatment arm (20 mg/kg).  
Following a screening period lasting up to 28 days, eligible participants will be randomised 1:1:1:1 
into the 4 treatment arms stratified by OI type (Type I or III/IV) and will receive study treatment 
(setrusumab) for 12 months. Any participants assigned to placebo according to the previous 
MBPS205 protocol design will be transferred to open-label 20 mg/kg treatment for 12 months. 
Participants will have HRpQCT scans of their non-dominant distal radius at baseline, 3-month (for 
open-label participants only), 6-month and 12-month time points to determine the effect of 
treatment on Tr. vBMD. The primary analysis will be conducted once all data up to month 12 has 
been collected for the blinded treatment groups. 
Following completion of the study treatment participants can receive an optional single dose of 
zoledronic acid and will enter 12 months follow-up period and will have visits at Months 14, 18 
and 24 to establish the rate of offset of treatment effect. Participants will also receive follow-up 
telephone calls at Months 16 and 21. Participants can receive an optional further dose of zoledronic 
acid at Month 18 at the discretion of their treating physician. During the follow-up period 
participants will have HRpQCT scans of their non-dominant distal radius and tibia at Month 18 and 
Month 24. 
The Study Flow Chart is presented in Figure 1. 
 
Figure 1: Study Flow Chart 
 
An Independent Data Monitoring Committee will monitor safety throughout the study and make 
recommendations on the selected dose. 


 
 
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Protocol Number: MBPS205  
                       Version: Final 1.0, Date: 22 October 2019 
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3.2 Randomisation and blinding 
3.2.1 Randomisation 
All participants will be centrally randomised using an Interactive Web Response System (IWRS) in 
a 1:1:1:1 ratio to receive either 20mg/kg, 8mg/kg, 2mg/kg or open-label 20 mg/kg stratified by OI 
type (Type I or III/IV). Subject to informed consent being given by the participant, all participants 
assigned to placebo prior to protocol amendment 4.0 will be reassigned to begin 12 months of 
open-label 20 mg/kg setrusumab treatment. ICON Biostatistics will produce a randomisation list 
that links participant numbers to randomisation numbers. These randomisation numbers will be 
linked to different treatment regimens and the randomisation scheme will be stratified according to 
the Sillence Clinical Classification of OI type into 2 groups (Type I or III/IV). 
Following confirmation from the investigator, the pharmacist will contact the IWRS and be issued 
with a treatment regimen. Should the participant be allocated to a setrusumab regimen, then the 
s weight into the IWRS and receive a calculated dose per 
participant.  
3.2.2 Blinding 
Study Blinding is conducted to ensure that treatment assignment is unbiased and concealed from 
patients and investigator staff. With the exception of the open-label treatment arm, investigators 
course of the study. In order to maintain this blind, an otherwise uninvolved 3
rd party (pharmacist) 
will be responsible for the reconstitution and dispensation of all study treatment. A separate 
unblinded Clinical Research Associate (CRA) will monitor the pharmacy.  
3.2.3 Unblinding 
Upon completion of the treatment period (final Month 12 or EOT data collected for the final 
patient) the blind will be broken and the primary efficacy analysis completed. Analyses for the 
follow-up period will be carried out separately to the primary analysis once all patients have 
completed the 12 months follow-up period, or have withdrawn from it. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study 
treatment records at the site(s) to verify that randomisation/dispensing has been performed 
accurately.  
The IWRS will be programmed with blind-breaking instructions. The study blind may be broken if, 
assignment. Mereo must be notified before the blind is broken unless identification of the study 
treatment is required for a medical emergency in which the knowledge of the specific blinded study 
available). In this case, Mereo must be notified within 24 hours after breaking the blind. The date 


 
 
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and reason that the blind was broken must be recorded in the source documentation and electronic 
case report form (eCRF), as applicable. 
3.3 Study treatments and assessments 
During the treatment period study participants will receive 2 mg/kg, 8 mg/kg or 20 mg/kg 
setrusumab IV, administered monthly for 12 months via 60 minute infusions of 250mL 5% 
dextrose with setrusumab. Patients randomised prior to Protocol Amendment 4.0 may have 
received a matching placebo during the treatment period prior to transitioning to open label 20 
mg/kg. 
Dose changes are not permitted during the treatment period. 
The maximum study duration from randomisation to end of the safety follow-up period is 24 
months. 
A detailed description of procedures and assessments to be conducted during this study can be 
found in the protocol. 
 
 


 
 
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Protocol Number: MBPS205  
                       Version: Final 1.0, Date: 22 October 2019 
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4 
STUDY ENDPOINTS 
4.1 Primary efficacy endpoint 
The primary efficacy endpoint of this study is the change from baseline in Tr. vBMD (radius) on 
HRpQCT and change from baseline in bone strength on FEA at 12 months. 
4.2 Secondary endpoints 
The secondary efficacy endpoints of this study are: 
1. Tr. vBMD (radius) on HRpQCT at 12 months. 
2. Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA at 6 months  
3. Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA at 3 & 6 months in the 
open-label treatment arm 
4. Total fracture rate at 12 months 
5. Peripheral fracture rate at 12 months 
6. Vertebral fracture rate at 12 months 
7. Long-bone fracture rate at 12 months 
8. Changes in vertebral fractures and vertebral height with Genants semi-quantitative method 
and 6-point quantitative morphometry from baseline at 6 and 12 months 
9. Changes in lumbar, whole body, and proximal femur DXA BMD (dual-energy x-ray 
absorptiometry bone mineral density) (absolute and T-score) from baseline at Month 6 and 
Month 12 
10. Changes in bone histomorphometry 
11. Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA at 18 and 24 months 
12. 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 
13. Changes in Tr. vBMD (tibia) from baseline at 12, 18, and 24 months 
14. 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 on HRpQCT and bone strength on FEA at 3 months in the open-label treatment 
arm. 
15. Changes in body height, weight and body mass index (BMI) from baseline at 6 and 12 
months 
16. Changes in lean and fat body mass from whole body DXA  


 
 
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17. Changes from baseline at each visit in bone turnover markers and metabolic biomarkers 
associated with bone including:  
 Parathyroid hormone [PTH] 
 Aminoterminal propeptide of type 1 procollagen [P1NP]  
 Carboxy-terminal propeptide of type 1 procollagen [P1CP]  
 Osteocalcin [OC],  
 Bone-specific alkaline phosphatase [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-] 
 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]) 
18. 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 (OIQoLA) 
19. Change in OIQoL-A pain and activity subscale scores from baseline to Month 6 and 12 
20. Serum concentrations of setrusumab 
21. Serum concentrations of anti-setrusumab antibodies 
22. Serum concentrations of setrusumab neutralising antibodies 
23. Safety and Tolerability endpoints including: 
 Treatment-emergent adverse events (TEAEs)/Treatment-emergent serious adverse 
events (TESAEs)  
 Infusion site reactions  
 Vital signs 
 Physical examinations 
 ECG 
 Clinical laboratory tests 
4.3 Exploratory endpoints 
The exploratory endpoints of this study are: 
1. Changes in Trabecular Bone Score (TBS) from baseline at 6 and 12 months 
2. Changes in usage or need for physical aids from baseline at 12 months 
3. Change in auditory function from baseline at 12 months in a subset of patients 
4. Change in bone formation from baseline at 6 and 12 months, including: 


 
 
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 Normalised newly mineralised bone volume (MV/BV) 
 Normalised newly mineralised surface area (MS/BS) 
 Mineralised thickness (MTh) 
 Normalised formation patch number density (N.F. Patch/BV) 
 Formation patch volume (F.PatchVol.) 
 3D bone formation rate (3D BFR/BS) 
 3D mineral apposition rate (3D MAR) 
5. Change in bone resorption from baseline at 6 and 12 months, including: 
  Normalised newly eroded bone volume (EV/BV) 
  Normalised newly eroded surface area (ES/BS) 
  Erosion depth (ED) 
  Normalised resorption cavity number density (N.R.Cav./BV) 
  Resorption cavity volume (R.Cav.Vol.) 
  3D bone resorption rate (3D BRR/BS) 
  3D mineral resorption rates (3D MRR) 
 


 
 
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5 
SAMPLE SIZE AND POWER 
The number of participants is based on power considerations for the trabecular vBMD (radius) 
derived from HRpQCT at Month 12. The primary analysis method for this endpoint will be on the 
change from baseline within each treatment group, so the primary hypothesis to be tested is  
H0: T  0 vs. H1: T > 0 
where µT denotes the change from baseline for each dose of Setrusumab. Under the assumptions of 
a maximum change from baseline of
, a standard deviation at both timepoints of  
 and a correlation between both measurements of
 a sample size of 25 patients per 
group yields approximately 80% power for a one-sided test with significance level 0.025, if the 
data are analysed on the log scale using a t-test. 
For a change from baseline of 
, with standard deviation as above the one-sided test 
would have a probability of 80% to yield a p-value below 5%, being considered indicative of a 
trend. 
Following a review of the trabecular vBMD (radius) derived from HRpQCT at Month 6 of those 
patients within the 20mg/kg Setrusumab open label treatment group, a change from baseline 
standard deviation of
 was observed. This yields to a correlation between 
baseline and month 6 visits of 
 (much higher than the
 that was originally assumed). If 
such a correlation is observed at month 12, given 25 subjcts per arm, the one-sided test would have 
a probability of 80% to yield a p-value below 5% for a change in baseline of 
.   
As a secondary analysis, the MCPMod approach will be applied to the data in order to assess a 
non-flat dose-response curve and to obtain information about the underlying dose-response curve. 
Due to the missing placebo group, the power of this approach depends heavily on the underlying 
dose-response curve.  
The following candidate models will be used: 
 EMax (ED50 of 1.5 mg) 
 
 
Under the assumptions of each of the two candidate models being the true dose-response curve, and 
in addition an Sigmoid EMax model with parameters ED50 = 10 mg and h = 2.4, a contrast test at a 
one-sided significance level of 2.5% has the following power for each of the three models: 
Model EMax Exponential Sigmoid EMax  
Power 13.7% 73.2% 
60.7% 


 
 
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The total sample size required is therefore determined as 100: 
 25 participants on open-label setrusumab (20 mg/kg) 
 25 participants on each of the active arms (2 mg/kg, 8 mg/kg, 20 mg/kg)
Approximately 100 participants will be randomised.  


 
 
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6 
ANALYSIS POPULATIONS 
Analyses for the primary efficacy endpoints and selected secondary endpoints will be analysed on 
the FAS, the Non-restricted FAS and the PP samples, while analyses for the remaining secondary 
efficacy endpoints will be analysed on the FAS sample only. Data collected for patients while 
taking placebo prior to protocol amendment 4.0 will not be included in any efficacy analysis (i.e 
treatment comparisons), however will be included in efficacy descriptive statistic summaries.    
Safety and tolerability endpoints will be analysed using the safety population. Data collected for 
patients while taking placebo prior to protocol amendment 4.0 will be included in all safety 
summaries. 
Pharmacokinetic data will be analysed using the PK population. 
6.1 Full Analysis Set (FAS) 
The Full Analysis set consists of all participants who are randomised to one of the blinded 
treatment arms and take at least 1 dose of study treatment. This does not include patients 
randomised to placebo prior to protocol amendment 4.0.  
Participants will be analysed according to the randomised treatment. 
6.2 Modified Full Analysis Set (mFAS) 
The Modified Full Analysis Set consists of all participants from the FAS who have sufficient cross-
sectional overlap across HRpQCT scans. Subjects must have at least 70% overlap across all 
performed scans (either Radius or Tibia). 
For all analysis utilising the mFAS population only scans with at least 70% overlap will be 
included for each associated location (Radius or Tibia). 
Participants will be analysed according to the randomised treatment. 
6.3 Non-restricted FAS 
The Non-restricted FAS consists of all participants who are randomised and take at least 1 dose of 
study treatment. This includes data for patients taking placebo prior to protocol amendment 4.0 and 
those randomised to open label 20mg/kg. Data from the two 20 mg/kg dose group maybe pooled 
for the follow-up analysis. 
Participants will be analysed according to the randomised treatment.  


 
 
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6.4 Per-Protocol population (PP) 
The Per-protocol population consists of all participants from the FAS who have been treated 
according to the protocol and fulfill the following criteria (to be further described in the 
classification meeting plan): 
1) Specific inclusion/exclusion criteria satisfied 
2) Absence of relevant protocol violations with respect to factors likely to affect the efficacy 
of treatment where the nature of protocol violation will be defined before breaking the 
blind 
3) Adequate study medication compliance which will be determined before breaking the 
blind. 
Participants will be analysed according to the treatment to which they were randomised. 
6.5 Safety population (Safety) 
The Safety Population consists of all participants who are administered at least 1 dose of study 
treatment. This includes data for patients taking placebo prior to protocol amendment 4.0 and those 
randomised to open label 20mg/kg. Data from the two 20 mg/kg dose group maybe pooled for the 
follow-up analysis. 
Participants will be analysed according to the treatment they actually received.  
6.6 PK population 
The PK population consists of all participants in the Safety Population who have at least 1 
quantifiable setrusumab serum concentration. 
Patients will be analysed according to their randomised treatment. 
6.7 Other Populations Defined for Tables and Listings 
For the purposes of tables and listings a further two populations are defined: 
 All enrolled patients (i.e patients who have signed informed consent) 
 Randomised population (all randomised patients). 
6.8 Protocol deviations/violations and exclusions from analysis sets 
All violations and exclusions of subjects from analysis populations will be identified and 
data will be conducted using (but not limited to) the following sources of information: 
 Supportive subject listings, provided by the ICON ahead of the Classification Meeting, 
based on data recorded on the eCRF. 
 Protocol Deviation Logs, retrieved from Clinical Trial Management System (CTMS). 
 


 
 
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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 Derived Variables 
7.1.1 General Variables 
Study Day 
The derived study day will be relative to the date of first active (i.e non-placebo) study medication 
(Derived Study Day 1) and calculated as:  
 (assessment date  date of first dose of study medication) + 1, for assessments on or after 
the first dose of study medication 
 (assessment date  date of first dose of study medication), for assessments prior to date of 
first dose of study medication. 
7.1.2 Definitions relative to demographic and other baseline characteristics 
Age 
Age at randomisation will be calculated as:  
Age (years) = (date of randomisation - date of birth + 1) / 365.25 
Weight, Height and BMI 
Weight, recorded in pounds on the eCRF, will be converted in kilograms (1 pound = 0.45359 kg). 
Height, recorded in inches on the eCRF, will be converted in centimetres (1 inch = 2.54 cm) 
(International System of Units). 
Body mass index (BMI) will be calculated in kg/m2 as: weight (kg)/(height (m))
2. 
Temperature 
Temperature, recorded in Fahrenheit degrees on the eCRF, will be converted in Celsius degrees: 
Celsius degrees = (Fahrenheit degrees - 32) x (5/9) 
Time since last Fracture 
Time since last Fracture in months will be calculated as:  
(Date of first dose of study medication  date of last fracture + 1) / 30.4375 


 
 
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7.1.3 Definitions relative to efficacy parameters 
7.1.3.1 HRpQCT Assessments 
HRpQCT scans are overlapped with all previous visit scans within a patient so that a common area 
is assessed across all visit timepoints. As such for all summaries and analyses only the assessments 
derived from the common area will be used. Such assessments can be identified where the 
that has there final scan at month 12, all assessments where analysis timepoint is populated with 
 
7.1.3.2 Vertebral fracture assessments 
The lateral spine radiographs will be assessed for vertebral fractures using the Genant 
Semiquantitative Scoring Method assigning each vertebra a grade between 0 and 3 (SQ score): 
 Grade 0: normal  
 Grade 1: mild fracture 
 Grade 2: moderate fracture 
 Grade 3: severe fracture 
A new vertebral fracture is defined as an SQ score >=1 at a post baseline visit where the baseline 
SQ score = 0 for the associated vertebrae. A subject is defined as having a new fracture at a visit if 
they have at least 1 vertebra with a new fracture. 
A worsening vertebral fracture is defined as an increase in SQ score >=1 from the previous visit 
(where the baseline SQ score >0) for the associated vertebrae. A subject is defined as having a 
worsening fracture at a visit if they have at least 1 vertebra with a worsening fracture. 
The sum of all grades at a visit is defined as sum of all SQ scores across all vertebrae assessed at a 
visit by the Genant Semiquantitative Scoring Method. 
The below vertebral height parameters (for each vertebra) will be derived from the 6-point 
vertebral morphometry assessments: 
 Anterior /Posterior  height ratio (HA/HP) 
 Mid / Posterior  height ratio (HM/HP) 
7.1.3.3 Time to first fracture 
The time to first fracture for each fracture category (Total, Peripheral, Vertebral, Non-vertebral and 
Long-bone)is defined as the time (in days) from the date of first dose of active study medication
until the date of date of diagnosis (defined as first occurrence of symptoms of fracture) of each 
specific fracture type. 


 
 
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Patients who do not have a facture will be censored at the date of completion/discontinuation of the 
treatment period for each category. 
7.1.3.4 Short Form 12 Health Survey (SF-12) 
SF-12  
The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, 
role limitations due to physical health, bodily pain, general health perceptions, vitality, social 
functioning, role limitations due to emotional problems, and mental health. It yields scale scores for 
each of these 8 domains and 2 summary measures of physical and mental health: The Physical 
Component Summary and the Mental Component Summary. Please see Appendix A Error! 
Reference source not found.for detailed scoring of each domain and component scores. 
7.1.3.5 5-level descriptive system (EQ-5D-5L) 
EQ-5D-5L  
The EQ-5D-5L is a standardised measure of health status comprised of a descriptive system of 5 
health-related quality of life states (i.e., mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) and a Visual Analogue Scale (VAS) of overall health.  
Each dimension is rated on a 5-
EQ-5D index (utility) score between 0 and 1 (1 being perfect health), which will be calculated 
-specific reference score sets. Please see 
Appendix B for detailed scoring of the EQ-5D index score. 
The EQ-5D VAS is a measure of overall self-rated health status, used and analysed separately from 
the index score. The VAS ranges from 0 to 100, with higher scores indicative of better overall 
health. 
7.1.3.6 Osteogenesis Imperfecta specific Quality of Life Questionnaire for 
Adults (OIQoL-A) 
OIQoL-A  
The OIQoL-A is a PRO instrument for use in adults with OI Type I, III, or IV. The OIQoL-A 
currently measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, 
taking care/Concerns, Social and Family Life and Activities). For each visit the OIQOL-A total 
score and pain and activity subscale scores will be derived. Please see Appendix C for detailed 
scoring of the total and subscale scores. 


 
 
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7.1.4 Definitions relative to safety parameters 
7.1.4.1 Adverse Event (AE) 
Treatment Emergent Adverse Event (TEAE) 
A Treatment Emergent AE (TEAE) is defined as an AE occurring or worsening on or after the first 
dose of study medication. AEs that occurred for subjects while taking placebo prior to protocol 
amendment 4.0 will not be considered treatment emergent for the active treatment groups. TEAEs 
will also be split between AEs that started during the Patient
on or after the first day of the follow-up period. 
Duration of AEs 
The duration of an AE will be calculated as the resolution date minus the start date plus 1. 
7.1.4.2 Treatment Compliance 
Duration of Exposure 
The duration of Exposure to study medication (number of days) will be defined as: 
(date of last dose of study medication  date of first dose of study medication) + 28 days  
7.1.4.3 Prior, Concomitant and Follow-up Medications/Procedures 
Medications and Procedures will be assigned as being prior to study treatment, concomitant with 
study treatment or taken during the follow-up phase based on the start and stop dates of the 
medication and dosing dates. 
If the medication/procedure stop date is before the date of the first dose of study medication, the 
medication/procedure will be assigned as being prior to study treatment. Otherwise, the 
medication/procedure will be assigned as being concomitant with study treatment unless the start 
date of the medication/procedure is after the date of entry into the follow-up period, when it will 
then be classified as occurring in the follow-up phase.  
Medications/procedures that occurred for patients while taking placebo (prior to protocol 
amendment 4.0) will be considered as being prior to study medication as well as concomitant for 
placebo. 
7.1.4.4 
 
Patient
riteria if their ALT or AST > 3x ULN and 
bilirubin > 2 x ULN at the same visit. 
Further assessment to determine that no other reason can be found to explain the combination of 
increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, 


 
 
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ischemia, pre-existing liver disease, or another drug capable of causing the observed injury will be 
conducted.  
7.1.4.5 Duration of Hospitalisation 
The duration of hospitalization (number of days) will be defined as: 
(date of discharge  date of admission) + 1   
7.2 Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
Unless specified, data in summary tables will be presented using Observed Case (OC) data and 
therefore no missing data will be imputed. 
For data listings, unless specified, all data will be presented as they have been recorded (e.g. 
missing and partial dates will not be replaced). 
7.2.2 Handling of missing or incomplete data 
7.2.2.1 Partial dates of last fracture 
In order to calculate the time since last fracture, the following rules will be applied for partial dates: 
 if the day of the month is missing it is imputed to be the 15
th 
 if both the day and month are missing, they are imputed to be June 30th 
 missing years will be left as missing. 
The above will be flagged and described as a footnote in the appropriate listings. 
7.2.2.2 Missing items within PRO data 
The 
recommendation. Details can be found in Section 7.1.3. 
7.2.2.3 Concomitant medications definitions and handling of missing or 
incomplete dates 
Should the start date for a medication/procedure be missing or incomplete to the extent that it could 
be before or after the time of start of study medication, then it will be assumed that the 
medication/procedure began after the start of study medication (i.e. reported as concomitant 
medication/procedure). Similarly, if it is not clear whether the medication/procedure start date was 
on or before the date of entry into the follow-up period, then it will be assumed the 
medication/procedure began on or before the entry date (i.e. reported as a concomitant 
medication/procedure) (worst case approach). 
For listings of medications, dates will be presented as they have been recorded (missing and partial 
dates will not be replaced). 


 
 
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7.2.2.4 Definition of treatment-emergent AEs and handling of missing or 
incomplete dates 
In the event of an incomplete onset date, the event will be considered to be treatment-emergent 
unless the partial onset date information or complete or partial end date confirms onset or end prior 
to the first dose of study medication date. 
For AEs listings, dates will be presented as they have been recorded (missing and partial dates will 
not be replaced). 


 
 
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8 
STATISTICAL METHODS 
8.1 General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher and ADDPLAN DF 
4.0 or later. 
8.1.1 Populations for analysis 
Demographic and baseline characteristics will be summarised by the Safety population, unless 
otherwise stated. 
Analyses of the primary efficacy endpoint and selected secondary endpoints will be performed on 
the FAS population and also on the mFAS, PP population and Non-restricted FAS as a sensitivity 
analysis. 
The remaining secondary and exploratory efficacy endpoints will be analysed using the FAS and 
Non-restricted FAS only. 
All safety and tolerability variables will be analysed using the Safety population. 
PK data will be analysed using the PK population. 
8.1.2 Treatment groups 
Statistics will be displayed for the following treatment groups: 
 Setrusumab20 mg/Kg  
 Setrusumab8 mg/Kg  
 Setrusumab2 mg/Kg  
 Open Label Setrusumab 20 mg/Kg  
 Pooled Setrusumub 20 mg/Kg (where applicable) 
 Placebo 
 Total: overall (where applicable). 
Pooled Setrusumub 20 mg/Kg may only be used for the follow-up analysis. 
8.1.3 Descriptive statistics 
Continuous variables will be summarised using descriptive statistics including number of non-
missing observations (n), means (Mean), standard deviations (SD), minimum (Min),  median, and 
maximum (Max). One additional decimal point for mean and median and 2 additional decimal 
points for SD will be used.  
For categorical variables, summaries will include the number of non-missing observations (n) or 
the number of patients in the population (N) as applicable, the counts of patients and percentages. 


 
 
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Percentages will be rounded to one decimal place. The number of missing values will be presented 
as a separate category with no percentage, but only if any missing value is recorded in the data for 
that summary. 
Data in summary tables will be presented on an Observed Cases (OC) basis and summary statistics 
will only be presented at each visit for which the parameter is scheduled to be collected. 
8.1.4 Statistical significance 
Unless otherwise stated, all statistical testing will be two-sided and conducted at the significance 
(alpha) level of 0.05. Two-sided 95% confidence intervals (CIs) will be provided when relevant.  
For the primary analysis the LSMeans for each blinded treatment group will be calculated and 
tested against the null hypothesis of 0 in an a priori hierarchical approach, starting with the highest 
dose. 
For secondary and exploratory endpoints treatment groups will be assessed by pairwise 
comparisons for secondary efficacy data, and no adjustment for multiplicity will be made. 
8.1.5 Definition of Baseline 
Unless otherwise stated, Baseline will be the last assessment value before first study dose of study 
medication. For patients that were randomised to placebo prior to protocol amendment 4.0, 
assessments taken while on placebo may be utilized for the baseline derivation of each parameter.  
For HRpQCT scan parameters baseline assessments maybe collected up to 10 days post the first 
dose of study medication.  
Change from Baseline is defined as (value at assessment date  baseline value). 
8.1.6 Visit dates 
For each visit, the date recorded by the Investigator in the eCRF will be considered as the visit date 
in all the algorithms and the listings. 
Outputs will include all data collected from screening through to the end of the follow-up period. 
8.1.7 Data re-allocation 
The following general rules to handle repeated assessments will be considered: 
 12-lead ECG: 
o in case of multiple measurements associated to the same timepoint (e.g. triplicate 
ECGs), the average value will be considered for HR, PR interval, QRS duration, 
QT interval and QTcF interval. 
8.1.8 Data listings 
All the relevant patient data, including those derived and those assessments prior to protocol 


 
 
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amendment 4.0 on the placebo arm, will be presented in individual patient data listings. All listings 
will be sorted by treatment group, investigational site, patient number, date/time and visit. The 
ings will be 
based on all patients randomised. 
Unscheduled visit results will be included in date/time chronological order within patient listings, 
but will not be tabulated. 
8.2 Patient disposition 
All patients who provided informed consent will be included in a summary of patient disposition. 
The number of patients screened, the number of screen failures, the frequency of patients 
randomised (by treatment group and overall), the frequency and percentage of patients in the Safety 
population, in the FAS population, in the mFAS population , in the Non-restricted FAS population, 
in the PP population and in the PK population (by treatment group and overall) will be 
summarised.  
Patient disposition information will be summarised by treatment group and overall. The number of 
patients completing and withdrawing the treatment period and follow-up period will be tabulated in 
the study disposition table which will also include the reasons for treatment discontinuation and 
early withdrawal of the patient as reported on the eCRF.  
Finally, the reasons for screen failure as reported on the eCRF will be tabulated. 
A listing will include the randomisation/kit numbers, randomisation date/time and study disposition 
data (using the enrolled population). 
8.3 Protocol deviations 
The number of patients excluded from FAS, mFAS, Non-restricted FAS, Safety, PP and PK 
populations and reasons for exclusion will be summarised by treatment group and overall.  
All key protocol deviations identified will be summarised by treatment group and overall. 
In addition all protocol deviations will be listed based on data recorded on the eCRF and/or 
protocol deviation Logs (from CTMS). 
8.4 Demographics and baseline characteristics 
No formal comparison between treatment regimens on demographics and baseline characteristics 
will be conducted. 


 
 
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8.4.1 Demographics 
Demographics including age, sex, race, ethnicity, weight, height, BMI and child-bearing potential 
will be listed and summarised using descriptive statistics for continuous variables and tabulated for 
categorical variables. Summary will be produced using the Safety Population. 
8.4.2 Fracture/OI history  
Fracture/ OI history including the number patients experiencing any fracture within the last 2 years 
(5 years from protocol amendment 4.0), time since last fracture (months), description of fracture 
(location), fracture anatomical location, percentage compression (vertebral only), evidence of 
interval healing, fracture history patient reported (Y/N), OI Type and COL1A1/COL1A2 testing 
(Y/N) will be summarised by treatment group and overall using the safety population.  
8.4.3 Medical and Physical Aids History 
A summary of Medical and Physical Aids history will be presented by medical history code, 
system organ class (SOC) and preferred term (PT), by treatment group and overall using Medical 
Dictionary for Regulatory Affairs® (MedDRA) using the Safety population. 
8.4.4 Prior, Concomitant and Follow-up medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. 
Prior, concomitant and follow-up medications will be summarised by Anatomical Therapeutic 
Chemical (ATC) classification level 4 and Preferred Name by treatment group and overall for the 
Safety population. 
8.4.5 Concomitant Procedures/Physical Aids 
All concomitant Procedures and Physical Aids will be coded using the World Health Organization 
(WHO) Drug Dictionary and will be presented by medication class, treatment group and overall.   
8.4.6 Concomitant Therapy 
The number of patients taking Vitamin D and Calcium Therapy during the treatment and follow-up 
periods will be summarised by treatment and overall.  
In addition the number of patients taking Zoledronic Acid Therapy at Month 12, Month 18 and not 
at all during the follow-up period will be summarised by site, treatment and overall.   
8.4.7 Extent of exposure 
8.4.7.1 Treatment duration 
Duration of treatment (in months) will be categorised in intervals (0-1, 1-3, 3-5, 5-7, 7-9, 9-11 >11) 
and summarised descriptively by treatment regimen on the Safety population. 


 
 
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Study drug exposure (in months) will be summarised by treatment group on the Safety population 
using descriptive statistics. 
8.4.7.2 Treatment compliance 
The number of subjects with infusion interruptions and incomplete infusions will be summarised at 
each month and overall.  
8.5 Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary, secondary and 
exploratory efficacy variables. Analyses for the primary efficacy endpoints and selected secondary 
endpoints will be analysed on the FAS, mFAS, the Non-restricted FAS and the per-protocol 
populations, while analyses for the remaining secondary and exploratory efficacy endpoints will be 
analysed on the FAS population only. 
All definitions relative to efficacy and exploratory endpoints are detailed in Section 7.1.3. 
8.5.1 Analysis methods 
For all continuous outcomes, where appropriate, an ANCOVA model analysis will be performed. 
Analyses will include the fixed, categorical effects of treatment and randomisation stratum as well 
as the associated baseline value as a covariate. Significance tests for treatment differences (between 
Setrusumab doses) will be based on least-squares means (LSMeans). 
ANCOVA analyses dealing with nested observations within a patient (e.g., vertebral assessments) 
will consider this relationship in the modelling by specifying patient as a random factor. 
If the input data is log-transformed then LSMeans and LSMean differences between treatment 
groups will be back-transformed to their original scale for descriptive purposes. After substracting 
the geometric mean of the log baseline values, the back-transformed LSMeans will correspond to 
the percentage change from baseline, while the back-transformed LSMeans differences will 
correspond to the ratio of percentage changes from baseline. 
Time to event variables (e.g., time to first fracture) will be analysed using Kaplan-Meier methods, 
and quartiles for the median time to event will be presented together with their 95% confidence 
intervals. 
Count variables (e.g number of new fractures) will be analysed using Poisson regression. Analyses 
will include treatment and randomisation as fixed effects and the logarithm of the duration of 
exposure to study medication will be included as an offset variable in the model. In case over 
dispersion is a concern, the negative-binomial regression model will be applied instead. 
For binary outcomes the proportion of patients with a response will be summarised and compared 
between treatment groups using Chi squared test.  


 
 
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8.5.1.1 Multiplicity 
All treatment groups will be assessed by pairwise comparisons. No adjustment will be made for 
multiple comparisons except for primary analysis. 
8.5.1.2 Treatment by center interaction analysis (multi-center study) 
No analysis will be made to assess the treatment-by-center interaction. 
8.5.2 Analysis of primary efficacy endpoint 
The primary efficacy endpoint for this study is the change in baseline in Tr. vBMD (radius) on 
HRpQCT and change from baseline in bone strength on FEA at 12 months. The primary endpoint 
and dose response analysis for the primary endpoint will be performed on the FAS population and 
repeated on the mFAS, Non-restricted FAS and the PP populations   
8.5.2.1 Primary analysis 
The HRpQCT results for the Trabecular vBMD (radius) will be log transformed and an ANCOVA 
model will be used to calculate the LSMeans for the change from baseline as described in Section 
8.5.1. The change from baseline LSMeans for each treatment group will be tested against the null 
hypothesis of 0 using a t-test, in an a priori hierarchical approach, starting with the highest dose.  
The LSMeans and standard errors will be displayed at each visit aswell as the corresponding P-
value from each t-test.  
Differences between LSMeans, their confidence intervals and P-values will also be displayed but 
will be analysed in an exploratory fashion only. The type I error rate will be 5% two-sided. P-
values above 5% but below 10% (two-sided) will be considered as indicative for a trend. 
LSMeans and LSMean differences between treatment groups will be back-transformed to their 
original scale for descriptive purposes. After subtracting the geometric mean of the log baseline 
values, the back transformed LSMeans will correspond to the percentage change from baseline, 
while the back-transformed LSMeans differences will correspond to the ratio of percentage 
changes from baseline. 
Line graphs of the LSmean HRpQCT results (+/- SE) and change from baseline in HRpQCT results 
(+/- SE) will be presented. 
A descriptive summary will also be presented for the non-log transformed HRpQCT results for the 
Trabecular vBMD (radius) values,change from baseline and percentage change from baseline in 
HRpQCT by treatment group and OI type. 
For supportive evidence, the above analysis will be repeated on the mFAS, Non-restricted FAS in 
both versions and the PP population for HRpQCT results for the Trabecular vBMD (radius) and 
repeated for the bone strength on FEA for the FAS, Non-restricted FAS and PP population. 


 
 
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8.5.2.2 Dose Response Analysis 
The change from baseline LSMeans for the HRpQCT results for the Trabecular vBMD (radius) 
will further be analysed using the MCPMod methodology, using the following candidate models: 
 EMax (ED50 of 1.5 mg) 
 
 = 2) 
 Sigmoid EMax (ED50 of 1.5 mg and h=2.4) 
Parameter estimates and predicted values for each dose will be calculated for all models. This 
analysis will be repeated for the bone strength on FEA for supportive evidence. 
8.5.3 Analysis of secondary efficacy endpoint(s) 
The analysis of selected secondary efficacy endpoints will be performed on the FAS, mFAS, Non-
restricted FAS and PP populations. The remaining secondary endpoints will be analysed on the 
FAS Population only. 
8.5.3.1 Tr. vBMD (tibia) on HRpQCT 
Descriptive summary tables will be presented for HRpQCT results for the Tr. vBMD (tibia) 
,change from baseline and percentage change from baseline in Tr.vBMD (tibia) on HRpQCT 
results by treatment group and visit. 
The log transformed change from baseline in Tr.vBMD (tibia) on HRpQCT will be analysed via 
ANCOVA in the same manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see 
Section 8.5.2.1). This analysis will be conducted on the FAS, Non-restricted FAS, mFAS and PP 
populations. 
8.5.3.2 DXA BMD 
Descriptive summary tables will be presented for DXA Lumbar, Whole Body and Proximal femur 
BMD values and percentage change from baseline values by treatment group and visit. 
The percentage change from baseline in for DXA Lumbar, Whole Body and Proximal femur BMD 
will also be analysed via ANCOVA in the same manner as the change from baseline in Tr.vBMD 
(radius) on HRpQCT (see Section 8.5.2.1). This analysis will be conducted on the FAS, Non-
restricted FAS and PP populations. A similar analysis will be conducted on the associated DXA 
Lumbar, Whole Body and Proximal femur BMD change from baseline T-scores. 
8.5.3.3 Vertebral Assessments 
All vertebral endpoints will be analysed on the FAS Population and PP Population only. 
8.5.3.3.1 Vertebral Fractures 
For all vertebral assessments the X-ray scans will be used as source. 


 
 
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The number and proportion of patients with a new vertebral fracture and new or worsening 
vertebral fracture will be summarised by treatment group throughout the treatment period (at each 
visit).  In addition, a P-value for the comparison between each group will be provided using a Chi 
squared test. 
The total number of new vertebral fractures and new or worsening vertebral fractures per patient 
during the treatment period will be compared between each treatment group using a poisson 
regression model as described in section 8.5.1.  An estimate of the ratio of new vertebral fractures 
and new or worsening vertebral fractures between treatment groups will be presented together with 
a two-sided 95% confidence interval and P-value. 
For patients that have a vertebral fracture a shift table of the change in fracture grade will be 
presented. The number and percentage of patients with each level of change (from worst baseline 
grade to worst post-baseline grade) will be displayed. 
Finally the total sum of vertebral fracture grades will also be analyses via ANCOVA in the same 
manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see Section 8.5.2.1). 
8.5.3.3.2 Vertebral Height 
Vertebral height derived from 6-point quantitative morphometry will be summarized at 6 and 12 
months. The mean (across all vertebrae) Anterior, Mid and Posterior heights, HA/HP ratio and 
HM/HP ratio will be summarised descriptively. 
The maximum change from baseline in the HA/HP and the HM/HP ratio for fractured vertebrae 
will be analysed using ANCOVA in the same manner as the change from baseline in Tr.vBMD 
(radius) on HRpQCT (see Section 8.5.2.1). 
8.5.3.4 Bone Histomorphometry  
Changes in bone histomorphometry parameters will be analysed using ANCOVA in the same 
manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see Section 8.5.2.1) using 
the FAS population only. 
8.5.3.5 High Resolution peripheral Quantitative Computed Tomography 
(HRpQCT) 
Changes in baseline in the below HRpQCT parameters at each visit will be analysed using 
ANCOVA in the same manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see 
Section 8.5.2.1) across visits during the treatment period and follow-up period: 
 Total vBMD 
 Cortical vBMD 
 Bone volume fraction (BV/TV) 


 
 
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 Peripheral to medullary trabecular bone density ratio (Met/Inn) 
 Trabecular thickness (TbTh) 
 Trabecular number (TbN) 
 Inhomogeneity 
 Cortical thickness 
 Cortical porosity  
 Cortical area (Ct.Ar) 
  Total Area (Tt.Ar) 
 Trabecular separation (Tb.Sp)  
 Trabecular area (Tb.Ar) 
Only patients in the open-label treatment arm will have assessments at Month 3 and as such at this 
visit no treatment comparison will be performed.  
Analyses will be performed on the FAS, mFAS and PP populations. 
8.5.3.6 Body composition  
Changes in baseline in the below body composition parameters at each visit will be analysed using 
ANCOVA in the same manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see 
Section 8.5.2.1): 
 Body height 
 Body weight  
 Body Mass Index (BMI)  
 Lean body mass 
 Fat body mass  
8.5.3.7 Bone Turnover Markers and Metabolic Biomarkers  
Changes in baseline in the below bone turnover markers and metabolic biomarkers (and their log 
transformed values) at each visit will be analysed using ANCOVA in the same manner as the 
change from baseline in Tr.vBMD (radius) on HRpQCT (see Section 8.5.2.1): 
 Parathyroid hormone [PTH] 
 Aminoterminal propeptide of type 1 procollagen [P1NP]  
 Carboxy-terminal propeptide of type 1 procollagen [P1CP]  
 Osteocalcin [OC] 


 
 
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 Bone-specific alkaline phosphatase [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-  
 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]) 
8.5.3.8 PROs and QoL 
All PRO and QoL analyses below will be performed on the FAS and Non-restricted FAS 
Populations. 
8.5.3.8.1 SF-12 
Changes from baseline in the norm-based 8 domains scores and 2 component score of the SF-12 at 
each visit during the treatment period will be analysed using ANCOVA in the same manner as the 
change from baseline in Tr.vBMD (radius) on HRpQCT (see Section 8.5.2.1). 
8.5.3.8.2 EQ-5D-5L 
Changes from baseline in the EQ-5D-5L index score and VAS score at each visit during the 
treatment period will be analysed using ANCOVA in the same manner as the change from baseline 
in Tr.vBMD (radius) on HRpQCT (see Section 8.5.2.1). 
8.5.3.8.3 OIQoL-A 
Changes from baseline in the OIQoL-A total score, pain subscale score and activity subscale score 
at each visit during the treatment period will be analysed using ANCOVA in the same manner as 
the change from baseline in Tr.vBMD (radius) on HRpQCT (see Section 8.5.2.1). 
8.5.3.9 Fractures 
All fracture analyses below will be performed on the FAS, Non-restricted FAS and PP populations 
utilising the X-day data. 
The number and proportion of patients with at least one new Peripheral, Vertebral, Non-Vertebral, 
Long-bone or any fracture will be summarised by treatment group and OI type at Month 12 and 
presented as the annualised fracture rate. In addition, each quarters fracture rate and the cumulative 
fracture rate by month will be presented. For each rate, a P-value for the comparison between each 
group will be provided using a Chi squared test. 
Graphs of the cumulative fracture rate by month will be presented.  


 
 
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The time to first fracture will be analysed for each fracture category using Kaplan-Meier methods 
as per Section 8.5.1. As per Section 7.1.3 patients who do not have a facture will be censored at the 
date of completion/discontinuation of the treatment period for each category. 
Quartiles for the median time to event will be presented together with their 95% confidence 
intervals. A Kaplan-Meier plot will also be presented. Comparisons between treatment regimens 
will be performed by means of the log-rank test. 
8.5.4 Analysis of exploratory endpoint(s) 
All exploratory analyses below will be performed on the FAS only. 
8.5.4.1 Trabecular Bone Score (TBS) 
Changes from baseline in the TBS score at each visit during the treatment period will be analysed 
using ANCOVA in the same manner as the change from baseline in Tr.vBMD (radius) on 
HRpQCT (see Section 8.5.2.1). 
8.5.4.2 Auditory Function 
The audiometry score (Undetectable hearing loss, mild, moderate or severe) at each visit will be 
summarised descriptively by ear and treatment group.  
8.5.4.3 Bone formation 
Changes in baseline in the below bone formation parameters at each visit will be analysed using 
ANCOVA in the same manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see 
Section 8.5.2.1): 
 Normalised newly mineralised bone volume (MV/BV) 
 Normalised newly mineralised surface area (MS/BS) 
 Mineralised thickness (MTh) 
 Normalised formation patch number density (N.F. Patch/BV) 
 Formation patch volume (F.PatchVol.) 
 3D bone formation rate (3D BFR/BS) 
 3D mineral apposition rate (3D MAR) 
8.5.4.4 Bone Resorption 
Changes in baseline in the below bone resorption parameters at each visit will be analysed using 
ANCOVA in the same manner as the change from baseline in Tr.vBMD (radius) on HRpQCT (see 
Section 8.5.2.1): 
 Normalised newly eroded bone volume (EV/BV) 
  Normalised newly eroded surface area (ES/BS) 
  Erosion depth (ED) 


 
 
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  Normalised resorption cavity number density (N.R.Cav./BV) 
  Resorption cavity volume (R.Cav.Vol.) 
  3D bone resorption rate (3D BRR/BS) 
  3D mineral apposition rates (3D MRR) 
8.5.4.5 Follow-up Period Subgroup Analysis 
A subgroup analysis (descriptive statistics and associated ANCOVA analyses)  will be performed 
for HRpQCT, DXA, vertebral radiograph, CTX-1, and P1NP parameters at all follow-up visits by 
the administration of zoledronic acid during the follow-up period (none; at Month 12; at Month 
18). 
8.6 Safety analyses 
All definitions relative to safety endpoints are detailed in Section 7.1.4. 
All the safety analyses will be based on the Safety population and will be performed for all safety 
variables specified below. 
No statistical testing will be performed. 
8.6.1 Adverse events 
All AEs will be classified by SOC and PT according to the MedDRA Version 21.1 or higher.  
Details for imputing missing or partial start dates of adverse events are described in Section Error! 
Reference source not found.. 
All AE summaries will be generated by treatment period, follow-up period and overall (i.e 
including those that started in both the treatment period and follow-up period). 
Notes: 
 Two AEs with the same PT and classified in the same category (pre-treatment AE or 
 
 Where a patient has the same AE, based on preferred terminology, reported multiple 
times in the same category (pre-treatment AE or TEAE), the patient will only be 
counted once at the preferred terminology level in AE frequency tables. 
 Where a patient has multiple AEs within the same SOC in the same category (pre-
treatment AE or TEAE), the patient will only be counted once at the SOC level in AE 
frequency tables. 
 
 
 AEs where the causality is missing will be assumed to have Reasonable possibility of 
relatedness 


 
 
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An overall summary of AEs will be provided. The total number of events and number and 
proportion of patients experiencing any AEs, TEAEs, AEs related to study medication, SAEs, 
SAEs related to study medication, severe AEs, AEs leading to permanent discontinuation of study 
treatment and AEs leading to death will be tabulated for each treatment group and overall.  
Additionally, TEAEs, related TEAEs, serious TEAEs, related SAEs, severe TEAEs, AEs leading to 
permanent discontinuation of study treatment and AEs leading to death will be summarised by 
SOC and PT for each treatment group and overall (number and percentage of patients experiencing 
at least one AE per PT as well as the number of observed events per PT). All TEAEs will also be 
summarised separately by maximum severity grade for each SOC and PT and by relationship to 
study medication for each SOC and PT.  
The frequency and incidence of TEAEs will be presented by system organ class and preferred term 
for each treatment group (number and percentage of participants experiencing at least 1 AE per 
preferred term as well as the number of observed events per preferred term).  
Infusion site reactions will be tabulated and summarised by treatment group and overall. 
All AE tables will be presented on both the pooled and the non-pooled version of the Safety 
population. 
All AEs will be presented in full in a comprehensive listing including patient number, treatment 
regimen, intensity, seriousness, actions taken, outcome, causality, onset/stop and duration. Details 
of all TEAEs of special interest, SAEs, AEs leading to permanent discontinuation of study 
treatment and AEs leading to death will be listed separately. 
8.6.1.1 Adverse Events of Special Interest 
The AESIs for setrusumab are:  
  Fractures 
  Cardiovascular events 
The frequency and incidence of all treatment emergent AESIs will be presented by system organ 
class and preferred term for each treatment group.  
8.6.2 Clinical laboratory evaluations 
Haematology, blood chemistry and urinalysis assessment will be conducted at Screening, Baseline, 
Months 1, 2, 3, 6, 9 and 12/EOT during the treatment period and months 14,18 and 24 during the 
follow-up period.   
Clinical laboratory data will be reported in Standard International (SI) units. Descriptive statistics 
will be presented for quantitative laboratory parameters for each treatment group and time-point. 
Similarly, changes from Baseline will be summarised.  


 
 
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Values outside the normal range will be categorised as H (above the normal range) or L (below the 
data listings. 
Line graphs of mean calcium values (+/- SE) and change from baseline in calcium (+/- SE) will be 
presented. 
Serum pregnancy test results and Follicle-stimulating hormone and estradiol assessments recorded 
at screening will be listed only. 
8.6.2.1 Liver Function 
The number and proportion of patients with laboratory values for liver function and enzymes of 
clinical concern as follows will be presented descriptively by treatment group: 
Parameter 
Level for clinical concern 
ALT 
> 1.5 times the upper limit of the 
normal range (ULN) 
> 2xULN 
> 3xULN 
> 5xULN 
> 10xULN 
AST 
> 1.5xULN 
> 2xULN  
> 3xULN 
> 5xULN 
> 10xULN 
Bilirubin Total 
> 2xULN 
> 3xULN 
ALT/AST and Bilirubin Total 
ALT/AST> 3xULN and Bilirubin 
Total> 2xULN 
(assessments to occur at the same 
visit) 
 
8.6.3 Vital signs 
Vital signs will be performed at each planned visit during the treatment period and at months 14, 18 
and 24 during the follow-up period. 
Descriptive statistics (observed values and changes from baseline) will be presented for each 
treatment group and time-point for vital sign measurements (body temperature, respiratory rate 
(RR), pulse rate, systolic blood pressure, diastolic blood pressure, weight and BMI).  
A data listing of vital signs for patients will be provided. 


 
 
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8.6.4 Physical examinations 
All physical examination data and abnormalities will be listed by patient and body system. 
8.6.5 Electrocardiograms 
Single 12-lead ECG will be obtained at Screening, Months 6 and 12/EOT during the treatment 
period and Month 14 during the follow-up using an ECG machine that automatically calculates the 
heart rate (HR) and measures PR, QRS, QT and QTc intervals. 
Descriptive statistics will be presented for the 12-lead ECG measurements for each treatment group 
and time-point. Similarly, changes from baseline will be summarised.  
In addition, the overall ECG interpretation will be summarised by presenting the number and 
percentage of patient
treatment 
group and time-point.  
A data listing of all ECG measurements will be provided. 
8.6.6 Heath Economics 
The number of patients that required hospitalisation during the treatment period and follow-up 
period will be summarised descriptively. In addition the duration of hospitalisation, the unit to 
which the patient was admitted and the reason for hospitalisation during will be summarised 
descriptively by treatment group.  
8.7 Other analysis 
8.7.1 PK  
Setrusumab concentrations will be summarised on the PK population by descriptive statistics by 
treatment group and time-point, and including the geometric mean and coefficient of variation. 
A graphical representation of the setrusumab concentrations distribution using mean plots (mean 
and SD) will be provided over time per setrusumab dose-level on the PK population. All 3 dose-
levels will be plotted on the same graph. 
8.7.2 DMC 
An independent, unblinded external DMC will periodically review accumulating safety data.  This 
will include data evaluation of accumulating unblinded safety data of Setrusumab. Full details of 
composition, operational aspects, and data to be reviewed and recommendation of the DMC is 
provided in a separate DMC charter and DMC SAP. 
8.7.3 Interim Analysis 
There is no formal interim analysis planned, however the primary efficacy analysis and study 
unblinding will be performed when all data up to Month 12 has been collected. Given the study has 


 
 
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been powered at Month 12 and there will not be multiple comparisons, there is no requirement to 
adjust the Type I error rate.   
Due to hierarchical nature of the primary end-point, the complexity of the data and timelines 
involved, Mereo has implemented a two-stage data transfer into the study database for the primary 
analysis. The initial transfer will include the majority of study data analysis including a lock and 
transfer of the clinical database and transfer of the primary end-point Tb. vBMD, the second 
transfer will include finite analysis (FEA) data from the HRpQCT, audited PK data and ADA data. 
An analysis and unblinding of Sponsor will be completed on the first dataset  at this point the 
database will be locked and no further data manipulation will be completed. The vendors 
completing the data analysis for the second transfer will remain blinded to patient treatment 
allocation by nature that this information is retained at ICON Plc additionally the FEA is a 
computed model process and the PK and ADA a fully validated assay which cannot be influenced 
by any full or partial unblinding. The data transfers will be completed into the clinical database 
with no further data manipulation for the existing data. 
The Clinical Study report (CSR) will be prepared based upon the results of the primary analysis. 
8.7.4 Follow-up Analysis 
The data collected during the off treatment follow-up will be separately analysed and published in 
an addendum to the CSR. 
 
9 
 
Not applicable. 
 
 
 
 
 
 


 
 
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10 
 
1. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96  adopted 
March 1998). 
 
 


 
 
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11 
 
Appendix A  SF12 
The calculation of the SF12 V2.0 norm-based domain and component score is a 3 step process: 
1) Reverse score / recalibrate item scores 
2) Compute transformed raw scale domain scores (0-100) 
3) Convert transformed raw scale domain scores to norm-based domain/component scores 
Step 1: Reverse Score / Recalibrate Item Scores 
Question 1: In General, Would you say your health is: 
Response to Question 1 Scoring 
Excellent 
5.0 
Very Good 
4.4 
Good 
3.4 
Fair 
2.0 
Poor 
1.0 
 
Question 2: Does you health limit you in: 
a) Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling or playing golf 
b) Climbing several flights of stairs 
Response to Question 2a/2b Scoring 
No, not limited at all 
3.0 
Yes, limited a little 
2.0 
Yes, limite da lot 
1.0 
 
Question 3: How much of the time have you had any of the following result of your physical health: 
a) Accomplished less than you would like 
b) Were limited in the kind of work or other activities 
Response to Question 3a/3b Scoring 
None of the time 
5.0 
A little of the time 
4.0 
Some of the time 
3.0 


 
 
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Most of the time 
2.0 
All of the time 
1.0 
 
Question 4: How much of the time have you had any of the following problems with your work or other 
regular daily activities as a result of any emotional problems: 
a) Accomplished less than you would like 
b) Were limited in the kind of work or other activities 
Response to Question 4a/4b Scoring 
None of the time 
5.0 
A little of the time 
4.0 
Some of the time 
3.0 
Most of the time 
2.0 
All of the time 
1.0 
 
Question 5: How much did pain interfere with your normal work: 
Response to Question 5 Scoring* 
Not at all 
5.0 
A little bit 
4.0 
Moderately 
3.0 
Quite a bit 
2.0 
Extremely 
1.0 
* Scores are reversed from reported numeric values 
 
Question 6: How much of the time during the past 4 weeks: 
a) Have you felt calm and peaceful 
b) Did you have a lot of energy 
c) Have you felt downhearted and depressed 
Response to Question 6a/6b Scoring* 6c Scoring 
None of the time 
1.0 
5.0 
A little of the time 
2.0 
4.0 


 
 
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Some of the time 
3.0 
3.0 
Most of the time 
4.0 
2/0 
All of the time 
5.0 
1.0 
* Scores are reversed from reported numeric values 
Question 7: How much of the time has your physical health or emotional problems interfered with your 
social activities: 
Response to Question 7 Scoring* 
None of the time 
5.0 
A little of the time 
4.0 
Some of the time 
3.0 
Most of the time 
2.0 
All of the .time 
1.0 
 
Step 2: Compute transformed raw scale scores 
The 8 domain raw scale scores are calculated by first summing the responses for all items in that 
particular domain (see below table), then converting the score to a transformed 0-100 scale using 
the below formula: 
SF-12v2 Scale 
Sum items Lowest, highest 
possible 
raw 
scores  
Possible raw score 
range 
Physical Functioning (PF) 2a,2b 
2,6 
4 
Role Physical (RP) 
3a,3b  
2,10 
8 
Bodily Pain (BP) 
5 
1,5 
4 
General Health (GH) 
1 
1,5 
4 
Vitality (VT) 
6b 
1,5 
4 
Social Functioning (SF) 
7 
1,5 
4 
Role Emotional (RE) 
4a,4b 
2,10 
8 
Mental Health (MH) 
6a,6c 
2,10 
8 
   
 


 
 
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Transformed Scale =        Actual raw summed score - lowest possible raw score    * 100 
                                                                Possible raw score range 
 
Step 3: Convert transformed raw scale domain scores to norm-based domain scores 
To convert the transformed raw scale domain scores (as per step 2) to norm domain scores: 
1) Firstly Z-scores for each domain must be calculated using the formulas below (based upon 
1998 general US population): 
PF_Z = (PF  81.18122) / 29.10558 
RP_Z = (RP  80.52856) / 27.13526 
BP_Z = (BP  81.74015) / 24.53019 
GH_Z = (GH  72.19795) / 23.19041 
VT_Z = (VT  55.59090) / 24.84380 
SF_Z = (SF  83.73973) / 24.75775 
RE_Z = (RE  86.41051) / 22.35543 
MH_Z = (MH  70.18217) / 20.50597 
PCS_Z= (PF_Z * 0.42402) + (RP_Z * 0.35119) + (BP_Z * 0.31754) + (GH_Z * 0.24954) 
+ (VT_Z * 0.02877) + (SF_Z * -0.00753) + (RE-Z * -0.19206) + (MH_Z * -0.22069) 
MCS_Z= (PF_Z * -0.22999) + (RP_Z * -0.12329) + (BP_Z * -0.09731) +                      
(GH_Z * -0.1571) + (VT_Z * 0.23534) + (SF_Z * 0.26876) + (RE_Z *0.43407) + 
(MH_Z * 0.48581) 
2) Secondly norm-based scores are calculated by multiplying each Z-score by 10 and adding 
the resulting product to 50 
e.g for Norm-Based PF = 50 + (PF_Z *10) 
 
 
 


 
 
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Appendix B  EQ-5D-5L 
To calculate the EQ-5D-5L Index score, firstly each response will be converted to a score of 1-5: 
Mobility Response 
Scoring 
I have no problems in walking about 
1 
I have slight problems in walking about 
2 
I have moderate problems in walking about 
3 
I have severe problems in walking about 
4 
I am unable to walk about 
5 
Self-Care Response 
 
I have no problems washing or dressing myself 
1 
I have slight problems washing or dressing myself 
2 
I have moderate problems washing or dressing myself 
3 
I have severe problems washing or dressing myself 
4 
I am unable to washing or dressing myself 
5 
Usual Activities 
 
I have no problems doing my usual activities 
1 
I have slight problems doing my usual activities 
2 
I have moderate problems doing my usual activities 
3 
I have severe problems doing my usual activities 
4 
I am unable to doing my usual activities 
5 
Pain / Discomfort 
 
I have no pain or discomfort 
1 
I have slight pain or discomfort 
2 
I have moderate pain or discomfort 
3 
I have severe pain or discomfort 
4 
I have extreme pain or discomfort 
5 
Anxiety / Depression 
 
I am not anxious or depressed 
1 
I am slightly anxious or depressed 
2 
I am moderately anxious or depressed 
3 
I am severely anxious or depressed 
4 
I am extremely anxious or depressed 
5 


 
 
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The score from each domain will then be converted to a deduction from full health (using EQ-5D-5l value set 
for England) and aggregated to form the index score:   
Full health (11111) =  
 
Mobility level 1 (No problems): 
Mobility level 2 (Slight):  
Mobility level 3(Moderate): 
Mobility level 4 (Severe): 
Mobility level 5 (Unable) 
 
Self-care level 1 (No problems): 
Self-care level 2 (Slight): 
Self-care level 3 (Moderate): 
Self-care level 4 (Severe): 
Self-care level 5 (Unable) 
 
Usual activities 1 (No problems): 
Usual activities 2 (Slight): 
Usual activities 3 (Moderate): 
Usual activities 4 (Severe): 
Usual activities 5 (Unable): 
 
Pain/discomfort 1 (No pain): 
Pain/discomfort 2 (Slight): 
Pain/discomfort 3 (Moderate): 
Pain/discomfort 4 (Severe): 
Pain/discomfort 5 (Extreme): 
 
Anxiety/depression 1 (No Anxiety) 
Anxiety/depression 2 (Slight): 
Anxiety depression 3 (Moderate): 
Anxiety/depression 4 (Severe): 
Anxiety/depression 5 (Extreme): 
1.000 
 
0 
0.058 
0.076 
0.207 
0.274 
 
0 
0.050 
0.080 
0.164 
0.203 
 
0 
0.050 
0.063 
0.162 
0.184 
 
0 
0.063 
0.084 
0.276 
0.335 
 
0 
0.078 
0.104 
0.285 
0.289 
 
For example, the index score for a patient with health state 23245 is calculated as follows: 
Full Health =1 
Mobility deduction = 0.058 
Self-care deduction= 0.080 
Usual Activity deduction = 0.050 
Pain/discomfort deduction = 0.276 
Anxiety / depression deduction = 0.289 
Index Score = 1  (0.058 + 0.080 + 0.050 + 0.276 + 0.289) = 0.247 
 
 
 


 
 
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Appendix C  OIQoL-A 
Introduction and Item Scoring 
The OIQoL-A consists of 37 items; however, the first 4 items are informational only and are not 
included in the scoring.  Therefore, up to 33 items (Q5-Q37) are included in the total score. 
Thirteen items are numerical rating scales (NRS) scored between 0 and 10, and the remainder are 
categorical items scored betwee
and therefore may not be included in the total score. The scoring of individual items is summarized 
in the table below. 
Items 
Response scale 
Scoring 
Q 5, 6, 7 
Q 9, 10, 11 
Q 14 
Q 15, 16, 17 
11-point NRS 
(0-10) 
0-10 
Q 8, 12, 18 
11 points NRS (0-100%) 
0-10 
Q13 
5-point Likert scale: 
 
0-4 
Q 19-25 
Q 34-37 
5-
No 
difficulty
 
0-4 
Q 26 
Not applicable
included  
0-4 or Missing 
Q27-33 
5-
Never
 
0-4 
 
Total Score Calculation (0-100) 
The total score is calculated on a 0-100 scale, where higher scores indicate a greater (negative) 
total score calculation is based on 33 items as follows:  
((Q37/4)*(1/33))]*100 
data forms, the denominator weighting for each item should be the total number of completed, 
scored items. However, if more than 20% of the items on the instrument have missing data, the 
total score should not be calculated and should be considered missing.  


 
 
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Pain Subscale 
T
will be used to evaluate pain severity.  
Impact on Activities of Daily Living (ADL)  
Items #19-26 comprise the ADL domain, so that the subscale score is based on a total of 7 or 8 
 
[
 
 
[(Q19/4)*(1/7
25/4)*(1/7))]*100 
Similarly if more than 20% of the items on the instrument have missing data, the ADL subscale 
score should not be calculated and should be considered missing.