Setrusumab vs Bisphosphonates in Pediatric Subjects with Osteogenesis Imperfecta (Cosmic)

Start 17 Oct 2023 · Status Authorised, recruiting · 5 EU/EEA countries · 5 sites · Protocol UX143-CL314

Overview

Sponsor-declared trial summary

Phase Therapeutic confirmatory (Phase III)

Status Authorised, recruiting

Participants planned 68

Countries 5

Sites 5

osteogenesis imperfecta

Evaluate the effect of setrusumab vs intravenous bisphosphonates (IV-BP) on reduction in fracture rate, including morphometric vertebral fractures

Key facts

Sponsor: Ultragenyx Pharmaceutical Inc.
Participant type: Pediatric, Patients
Age range: 0-17 years
Gender: Male and Female
Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]
Trial duration: 17 Oct 2023 → ongoing
Decision date (initial): 2023-08-25
Transition trial: No
Low-intervention: No
Rare-disease indication: Yes
Vulnerable population: Yes
Funding sources: Ultragenyx Pharmaceutical Inc.

External identifiers

EU CT number: 2023-504196-24-00
ClinicalTrials.gov: NCT05768854

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

Evaluate the effect of setrusumab vs intravenous bisphosphonates (IV-BP) on reduction in fracture rate, including morphometric vertebral fractures

Secondary objectives 8

Evaluate the effect of setrusumab vs IV-BP on reduction in fracture rate, excluding morphometric vertebral fractures, but including fractures of the fingers, toes, face, and skull
Evaluate the systemic exposure of setrusumab
Assess the safety profile of setrusumab
Evaluate the immunogenicity of setrusumab
Evaluate the effect of setrusumab vs IV-BP on health-related quality of life by caregiver report
Evaluate the effect of setrusumab vs intravenous-bisphosphonates (IV-BP) on bone mineral density (BMD)
Evaluate the effect of setrusumab vs IV-BP on the reduction in fracture rate, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull
Evaluate the effect of setrusumab vs IV-BP on new radiographically confirmed fractures, including morphometric vertebral fractures

Conditions and MedDRA coding

osteogenesis imperfecta

Version	Level	Code	Term	System organ class
20.0	PT	10031243	Osteogenesis imperfecta	100000004850

Study design 4 periods

#	Title	Allocation	Blinding	Arms
1	Screening period Prospective subjects will have prior or current exposure to bisphosphonates but must be willing to receive either IV-BP or setrusumab as assigned by randomization. All prospective subjects must meet all screening criteria and be deemed eligible for study participation prior to randomization.	Not Applicable	None	all participants: Screening period
2	Randomization Subjects will be randomized 1:1 to either the setrusumab arm or the IV-BP arm. Randomization will be stratified by the number of fractures in the previous 2 years (≤ 4 fractures and no femur, tibia, or humerus fracture vs > 4 fractures or ≥ 1 femur, tibia, or humerus fracture).	Randomised Controlled	None	Arm 1: Setrusumab 20 mg/kg (intravenous, once a month) Arm 2: IV-BP (dose and dosing regimen will be determined by the Investigator)
3	Active controlled period Following randomization at the Baseline Visit, subjects will receive setrusumab by IV infusion once a month (QM) or receive IV-BP at a dose and dosing interval based on acceptable clinical practice, for up to 24 months during the Active-controlled Period. The minimum duration of the Active-controlled Period is 12 months. At the end of the Active-controlled Period, all subjects will complete a Final Visit, and enter the Extension Period. Subjects assigned to the IV-BP arm will transition to setrusumab.	Randomised Controlled	None	Arm 1: Setrusumab 20 mg/kg (intravenous, once a month) Arm 2: IV-BP (dose and dosing regimen will be determined by the Investigator)
4	Extension period During the Extension Period, all subjects will receive setrusumab for a minimum of 12 months or until setrusumab becomes commercially available in their respective country.	Not Applicable	None	Setrusumab: One arm only in the Setrusumab extension phase

Regulatory references

Scientific advice from competent authorities: European Medicines Agency
EMA paediatric investigation plan (PIP): EMEA-002169-PIP01-17
Plan to share IPD: No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

Male or female 2 to < 7 years of age at time of informed consent
Clinical diagnosis of OI Types I, III, or IV confirmed by identification of genetic mutation in COL1A1 or COL1A2
History of ≥ 1 fracture in the past 12 months, ≥ 2 fractures in the past 24 months, or ≥ 1 femur, tibia, or humerus fracture in the past 24 months
Any prior exposure to, or currently receiving, IV-bisphosphonate therapy for treatment of OI
Serum 25-hydroxyvitamin D level ≥ 20 ng/mL at the Screening visit. If 25- hydroxyvitamin D levels are below 20 ng/mL, the subject may be rescreened after a minimum of 14 days of vitamin D supplementation as directed by the Investigator

Exclusion criteria 15

Contraindication for the use of IV bisphosphonates based on clinical judgment of the Investigator
History of skeletal malignancies or bone metastases at any time
History of neural foraminal stenosis (except if due to scoliosis)
Clinical manifestations of Chiari malformation or basilar invagination. Presence of any other neurologic disease that has been clinically unstable within past 2 years requires review by the Medical Monitor.
History of or current uncontrolled concomitant diseases that may impact bone metabolism, such as hypo/hyperparathyroidism, abnormal thyroid function, nephrotic syndrome, or Stage IV/V renal disease
Any skeletal condition (other than OI) leading to bone deformity and/or increased risk of fractures, such as rickets, osteopetrosis, idiopathic juvenile osteoporosis, or skeletal dysplasia
History of known cardiovascular disease such as coronary artery anomaly, Kawasaki disease, myocarditis, cardiomyopathy, myocardial infarction, stroke, or thromboembolic disease. Individuals with other congenital or acquired cardiovascular disease necessitating echocardiogram require Medical Monitor review. Investigators should consider whether the potential benefits of treatment outweigh the potential risks in patients with cardiovascular risk factors such as confirmed arterial hypertension.
Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limit reference ranges after a recommended ≥ 4 hour fast, at Screening
Estimated glomerular filtration rate ≤ 35 mL/min/1.73 m2 at Screening
Prior treatment with growth hormone, denosumab, anti-sclerostin antibody, or other anabolic or anti-resorptive medications impacting the bone (other than bisphosphonates) at any time
History of external radiation therapy
Known hypersensitivity to setrusumab or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects
Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
Use of any investigational product or investigational medical device within 4 weeks or 5 half-lives (whichever is longer) of investigational drug prior to Screening, or during the study (per discretion of the Investigator in consultation with the Medical Monitor)
Concurrent participation in another clinical study without prior approval from the study Medical Monitor

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

Annualized rate of all radiographically-confirmed fractures, including morphometric vetrebral fractures at the primary analysis

Secondary endpoints 9

Annualized rate of radiographically-confirmed fractures, excluding morphometric vertebral fractures,but including fractures of the fingers, toes, face, and skull at the primary analysis
Change from baseline in Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI) Sports/Physical Functioning and Pain/Comfort subscale scores at the primary analysis
Serum setrusumab concentration at scheduled time points
Frequency, severity, and relationship to treatment of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs)
Incidence of binding and neutralizing anti-setrusumab antibodies at scheduled time points
Percent change from baseline in DXA BMD at the lumbar spine at the primary analysis
Annualized rate of all radiographically-confirmed fractures, excluding morphometric vertebral fractures and fractures of the fingers, toes, face, and skull, at the primary analysis
Change from baseline in dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) zscore at the lumbar spine at the primary analysis
Proportion of subjects experiencing new radiographically-confirmed fractures, including morphometric vertebral fractures, at the primary analysis

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Setrusumab

PRD10108414 · Product

Active substance: Setrusumab
Substance synonyms: BPS804, BPS-804, Human IgG2 lambda monoclonal antibody against human sclerostin
Other product name: fully human immunoglobulin G subclass 2 [IgG2] lambda anti-sclerostin neutralising monoclonal antibody
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INTRAVENOUS USE
Max daily dose: 20 mg/kg milligram(s)/kilogram
Max total dose: 480 mg/Kg milligram(s)/kilogram
Max treatment duration: 24 Month(s)
Authorisation status: Not Authorised
MA holder: ULTRAGENYX PHARMACEUTICAL INC.
Paediatric formulation: No
Orphan designation: No

Comparator 20

Pamidronaatdinatrium Hospira 6 mg/ml concentraat voor oplossing voor infusie

PRD1167624 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: BE 237605
MA holder: HOSPIRA BENELUX BVBA
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pamidronate disodique Hospira 9 mg / ml solution à diluer pour perfusion

PRD1167576 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: BE 237614
MA holder: HOSPIRA BENELUX BVBA
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Zoledronate EG 5 mg/100 ml solution pour perfusion

PRD5769278 · Product

Active substance: Zoledronic Acid
Substance synonyms: ZOLEDRONATE
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA08 — ZOLEDRONIC ACID
Marketing authorisation: 2018010086
MA holder: EUROGENERICS N.V./S.A.
MA country: Luxembourg
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

NERIXIA 25 mg soluzione iniettabile

PRD375820 · Product

Active substance: Neridronate Sodium
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: INFUSION
Max daily dose: 25 d day
Max total dose: 600 d day
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA — BISPHOSPHONATES
Marketing authorisation: 035268010
MA holder: ABIOGEN PHARMA S.P.A.
MA country: Italy
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Aclasta 5 mg solution for infusion

PRD10109489 · Product

Active substance: Zoledronic Acid
Substance synonyms: ZOLEDRONATE
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA08 — ZOLEDRONIC ACID
Marketing authorisation: EU/1/05/308/001
MA holder: SANDOZ PHARMACEUTICALS D.D.
MA country: Norway
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Aclasta 5 mg solution for infusion

PRD10109487 · Product

Active substance: Zoledronic Acid
Substance synonyms: ZOLEDRONATE
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA08 — ZOLEDRONIC ACID
Marketing authorisation: EU/1/05/308/001
MA holder: SANDOZ PHARMACEUTICALS D.D.
MA country: Liechtenstein
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Zoledronate EG 4 mg/100 ml solution pour perfusion

PRD5781028 · Product

Active substance: Zoledronic Acid
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA08 — ZOLEDRONIC ACID
Marketing authorisation: 2018010085
MA holder: EUROGENERICS N.V./S.A.
MA country: Luxembourg
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pamidronate Disodium 3 mg/ml Sterile Concentrate

PRD1173800 · Product

Active substance: Pamidronate Disodium
Substance synonyms: DISODIUM PAMIDRONATE
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: PL 04515/0118
MA holder: HOSPIRA UK LTD
MA country: XI
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

PAMIFOS-90, 90 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji

PRD2697807 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: 9380
MA holder: VIPHARM S.A.
MA country: Poland
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

PAMIFOS-30, 30 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji

PRD2773206 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: 9378
MA holder: VIPHARM S.A.
MA country: Poland
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

NERIXIA 100 mg concentrato per soluzione per infusione

PRD375819 · Product

Active substance: Neridronate Sodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 25 d day
Max total dose: 600 d day
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA — BISPHOSPHONATES
Marketing authorisation: 035268022
MA holder: ABIOGEN PHARMA S.P.A.
MA country: Italy
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pamidronaatdinatrium Hospira 9 mg/ml concentraat voor oplossing voor infusie

PRD1167625 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: BE 237614
MA holder: HOSPIRA BENELUX BVBA
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

PAMIDRONATE DE SODIUM HOSPIRA 9 mg/ml, solution à diluer pour perfusion

PRD1169046 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: 34009 381 699 5 9
MA holder: PFIZER HOLDING FRANCE
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pamidronate disodique Hospira 3 mg / ml solution à diluer pour perfusion

PRD1167574 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: BE 237596
MA holder: HOSPIRA BENELUX BVBA
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

PAMIDRONATE DE SODIUM HOSPIRA 6 mg/ml, solution à diluer pour perfusion

PRD1169045 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: 34009 381 698 9 8
MA holder: PFIZER HOLDING FRANCE
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Aclasta 5 mg solution for infusion

PRD10109345 · Product

Active substance: Zoledronic Acid
Substance synonyms: ZOLEDRONATE
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA08 — ZOLEDRONIC ACID
Marketing authorisation: EU/1/05/308/001
MA holder: SANDOZ PHARMACEUTICALS D.D.
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

PAMIFOS-60, 60 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji

PRD2773207 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: 9379
MA holder: VIPHARM S.A.
MA country: Poland
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pamidronate disodique Hospira 6 mg / ml solution à diluer pour perfusion

PRD1167575 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 60 mg/h milligram(s)/hour
Max total dose: 1440 mg/h milligram(s)/hour
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: BE 237605
MA holder: HOSPIRA BENELUX BVBA
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pamidronate disodique Hospira 3 mg / ml solution à diluer pour perfusion

PRD1167573 · Product

Active substance: Pamidronate Disodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA03 — PAMIDRONIC ACID
Marketing authorisation: BE 237587
MA holder: HOSPIRA BENELUX BVBA
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Zoledronate EG 5mg/100ml Infusionslösung

PRD4881390 · Product

Active substance: Zoledronic Acid
Substance synonyms: ZOLEDRONATE
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INFUSION
Max daily dose: 5 mg milligram(s)
Max total dose: 120 mg milligram(s)
Max treatment duration: 24 Month(s)
Authorisation status: Authorised
ATC code: M05BA08 — ZOLEDRONIC ACID
Marketing authorisation: BE507795
MA holder: EUROGENERICS N.V./S.A.
MA country: Belgium
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ultragenyx Pharmaceutical Inc.

Sponsor organisation: Ultragenyx Pharmaceutical Inc.
Address: 60 Leveroni Court Suite 200
City: Novato
Postcode: 94949-5746
Country: United States

Scientific contact point

Organisation: Ultragenyx Pharmaceutical Inc.
Contact name: Functional contact point: Medical Information

Public contact point

Organisation: Ultragenyx Pharmaceutical Inc.
Contact name: Functional contact point name: Ultragenyx trial information group

Third parties 14

Organisation	City, country	Duties
Clinical Outcomes Solutions LLC ORG-100045476	Tucson, United States	Other
Icon Clinical Research Limited ORG-100008322	Dublin 18, Ireland	Code 5, Data management
Labcorp Central Laboratory Services LP ORG-100032236	Indianapolis, United States	Laboratory analysis
EPL Archives GmbH ORG-100046845	Darmstadt, Germany	Other
Almac Clinical Technologies LLC ORG-100043036	Souderton, United States	Code 14
Advarra Inc. ORG-100045827	Columbia, United States	Other
Eresearchtechnology Inc. ORG-100013039	Philadelphia, United States	Other
Oracle Corp. ORG-100007842	Redwood City, United States	Data management
Nordic Bioscience A/S ORG-100009315	Herlev, Denmark	Laboratory analysis
Cytel Inc. ORG-100042560	Waltham, United States	Other
Bioclinica Inc. ORG-100033079	Princeton, United States	Other
Primevigilance Limited ORG-100027742	Guildford, United Kingdom	Code 8
Drug Development Solutions Limited ORG-100045894	Ely, United Kingdom	Laboratory analysis
Yprime LLC ORG-100042888	Malvern, United States	E-data capture

Locations

5 EU/EEA countries · 5 investigational sites

By country

Country	MS status	Planned subjects	Sites
France	Ended	5	1
Germany	Ended	5	1
Italy	Ongoing, recruitment ended	5	1
Netherlands	Ongoing, recruitment ended	5	1
Poland	Ongoing, recruitment ended	7	1
Rest of world Brazil, Canada, United States	—	41	—

Investigational sites

France

1 site · Ended

Assistance Publique Hopitaux De Paris

Institut Imagine, 149 Rue De Sevres, 75015, Paris

Germany

1 site · Ended

University Hospital Cologne AöR

Center for Rare Skeletal Diseases in Childhood and Adolescence, Kerpener Strasse 62, Lindenthal, Cologne

Italy

1 site · Ongoing, recruitment ended

Azienda Ospealiero Universitaria Policlinico Umberto I

Maternal and Child and UroGynecological Sciences, Viale Del Policlinico 155, 00161, Rome

Netherlands

1 site · Ongoing, recruitment ended

University Medical Center Utrecht

University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht

Poland

1 site · Ongoing, recruitment ended

SPZOZ CSK Uniwersytetu Medycznego w Lodzi

Klinika Pediatrii, Patologii Noworodka i Chorob Metabolicznych Kosci, ul. Sporna 36/50, 91-738, Lodz

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country	Trial start	Trial end	Recruitment start	Recruitment end
France	2024-01-02	2025-06-24	2024-01-02	2024-05-03
Italy	2024-02-16		2024-02-16	2024-05-03
Netherlands	2024-01-03		2024-01-03	2024-05-03
Poland	2023-10-17		2023-10-17	2024-05-03

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Serious breach SB-85412

Sponsor became aware: 2025-05-28
Date of breach: 2025-05-28
Submission date: 2025-07-10
Member states concerned: France, Germany, Italy, Netherlands, Poland
Categories: Protocol
Areas impacted: Subject safety, Data reliability or robustness
Benefit-risk balance changed: No
Description: Dr. Rush’s site incurred repeated protocol non-compliances including numerous, consecutive missed monthly visits and missed radiographs for suspected fractures for the 3 subjects randomized to IV-BP in Study UX143-CL314. During the study, the site was subjected to a total of 8 monitoring visits (04 May 2023, 23 January 2024, 01 April 2024, 29 May 2024, 15 August 2024, 14 October 2024, 15 January 2025, 05 May 2025). A For-Cause Audit, conducted on 27-28 August 2024 resulted in Corrective and Preventive Actions (CAPAs).

The CAPAs included:

• The site received clarification about protocol interpretation from the Ultragenyx Medical Director,
• The site received guidance from local IRB regarding protocol deviations that did occur,
• Protocol deviation logs were updated,
• As a preventative action, the site study coordinator committed to ensuring protocol deviations are submitted to the IRB and added to the Investigator Site File.

Following the CAPAs, Dr. Rush failed to complete CAPAs and continued to not comply with the approved protocol, failed to document and explain deviations, failed to provide proof of completed site training, and failed to ensure proper monitoring of the study, all of which violate the agreements outlined in the signed FDA Form 1572.
Based on the above, Ultragenyx made the decision to close the site on 28 May 2025 for both studies UX143-CL301 and UX143-CL314, and assessed the repeated non-compliances described above as a Serious Breach on 02 June 2025 for Study UX143-CL314 due to potential impact on overall data reliability from this site and potential safety impact for subjects in the BP arm, who missed numerous, consecutive study visits.
Sponsor actions: Actions that will be taken to address the serious breach:
• Dr. Rush will be notified of the closure of his site on 04 June 2025.
• All 7 active subjects (across both studies) will be contacted and given the opportunity to transfer to another suitable site as soon as possible to continue their study participation and treatment. Subjects who consent to the transfer will be transferred with appropriate travel and lodging assistance provided.
• Data Monitoring Committee will be notified immediately and debriefed about this case on 10 June 2025.
• Ultragenyx will conduct a sensitivity analysis to assess impact to Study UX143-CL314 data from Dr. Rush’s site and the results of the sensitivity analysis will be provided within the future MAA.

Organisation	City	Country	Type
Children's Mercy Hospitals And Clinics	Kansas City	United States	Clinical investigator

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 97 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Type	Title	Version
Protocol (for publication)	D1_Collection Prioritization Requirements	N/A
Protocol (for publication)	D1_Patient ID Card Template	3.0
Protocol (for publication)	D1_Protocol Amendment 2 Admin Memo_FP	N/A
Protocol (for publication)	D1_Protocol Clarification Memo_Drug Definitions	N/A
Protocol (for publication)	D1_Protocol Clarification Memo_Enrollment Weight Limit	N/A
Protocol (for publication)	D1_Setrusumab_Blood Volumes by Visit	N/A
Protocol (for publication)	D1_Study Protocol	3.0
Protocol (for publication)	D4_Event Diary_English	1.0
Protocol (for publication)	D4_Event Diary_French	1.0
Protocol (for publication)	D4_Event Diary_German	1.0
Protocol (for publication)	D4_Event Diary_Italian	1.0
Protocol (for publication)	D4_OPFT Handheld__French	1.0
Protocol (for publication)	D4_OPFT Handheld_English	1-0
Protocol (for publication)	D4_OPFT Handheld_German	1-0
Protocol (for publication)	D4_OPFT Handheld_Italian	1.0
Protocol (for publication)	D4_POSNA_English	1-0
Protocol (for publication)	D4_POSNA_French	1.0
Protocol (for publication)	D4_POSNA_German	1-0
Protocol (for publication)	D4_POSNA_Italian	1.0
Protocol (for publication)	D4_Training questionnaire_English	1.0
Protocol (for publication)	D4_Training questionnaire_French	1.0
Protocol (for publication)	D4_Training questionnaire_German	1.0
Protocol (for publication)	D4_Training questionnaire_Italian	1.0
Recruitment arrangements (for publication)	K1_Handbook	1.0
Recruitment arrangements (for publication)	K1_HCP Study Card	1.0
Recruitment arrangements (for publication)	K1_Parent Absence Note	1.0
Recruitment arrangements (for publication)	K1_Passport	1.0
Recruitment arrangements (for publication)	K1_Patient Card	1.0
Recruitment arrangements (for publication)	K1_Recruit and Informed Consent Procedure	1
Recruitment arrangements (for publication)	K1_Recruit and Informed Consent Procedure_FP	1
Recruitment arrangements (for publication)	K1_Recruit-ICF process	N/A
Recruitment arrangements (for publication)	K1_Recruit-ICF process	1.0
Recruitment arrangements (for publication)	K1_Schedule of Events	1.0
Recruitment arrangements (for publication)	K2_Handbook	1.0
Recruitment arrangements (for publication)	K2_Handbook	1.0
Recruitment arrangements (for publication)	K2_Handbook_FP	1
Recruitment arrangements (for publication)	K2_HCP Study Card	1
Recruitment arrangements (for publication)	K2_HCP Study Card	1.0
Recruitment arrangements (for publication)	K2_HCP Study Card_FP	1
Recruitment arrangements (for publication)	K2_Parent Absence Note	1.0
Recruitment arrangements (for publication)	K2_Parent Absence Note	1.0
Recruitment arrangements (for publication)	K2_Parent Absence Note_FP	1
Recruitment arrangements (for publication)	K2_Passport	1.0
Recruitment arrangements (for publication)	K2_Passport	1.0
Recruitment arrangements (for publication)	K2_Passport_FP	1
Recruitment arrangements (for publication)	K2_Patient Card	1.0
Recruitment arrangements (for publication)	K2_Patient Card_FP	1
Recruitment arrangements (for publication)	K2_Recruit_Patient Card	1
Recruitment arrangements (for publication)	K2_Recruit-ICF process	N/A
Recruitment arrangements (for publication)	K2_Recruitment Patient Card	1.0
Recruitment arrangements (for publication)	K2_Schedule of Events	1.0
Recruitment arrangements (for publication)	K2_Schedule of Events	1.0
Recruitment arrangements (for publication)	K2_Schedule of Events_FP	1
Recruitment arrangements (for publication)	K2_Ultragenyx Cosmic ITA Certificate_FP	N/A
Subject information and informed consent form (for publication)	L1_Assent 6_en_FP	2.0
Subject information and informed consent form (for publication)	L1_Assent 6_FP	2.0
Subject information and informed consent form (for publication)	L1_Clincierge_PFD_Data Protection Notice_en_FP	1.0
Subject information and informed consent form (for publication)	L1_Clincierge_PFD_Data Protection Notice_FP	1
Subject information and informed consent form (for publication)	L1_IT_SIS-ICF_Certificate of translation_redacted	N/A
Subject information and informed consent form (for publication)	L1_OptICF Appendix_Caregiver Interview_en_FP	1.0
Subject information and informed consent form (for publication)	L1_OptICF Appendix_Caregiver Interview_FP	1
Subject information and informed consent form (for publication)	L1_P-G Privacy Form_en_FP	2.0
Subject information and informed consent form (for publication)	L1_P-G Privacy Form_FP	2.0
Subject information and informed consent form (for publication)	L1_Parent-Guardian ICF_en_FP	4.0
Subject information and informed consent form (for publication)	L1_Parent-Guardian ICF_FP	4.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_Assent	2.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_Assent 3-less than 7	1.1
Subject information and informed consent form (for publication)	L1_SIS-ICF_Assent_girls at puberty	1.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_Girls at puberty	1.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_opt Caregiver	2.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_opt FBR	2.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_Optional Appendix	1
Subject information and informed consent form (for publication)	L1_SIS-ICF_Parent	2.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_Parent	4.1
Subject information and informed consent form (for publication)	L1_SIS-ICF_Parent_FP	6.0
Subject information and informed consent form (for publication)	L1_SIS-ICF_Parents Guardian	3.1
Subject information and informed consent form (for publication)	L2_Clincierge Data Protection Notice	1.0
Subject information and informed consent form (for publication)	L2_Clincierge Data Protection Notice_en	1.0
Subject information and informed consent form (for publication)	L2_Clincierge Data Protection Notice_nl	1.0
Subject information and informed consent form (for publication)	L2_Clincierge_Data Protection Notice	2.0
Subject information and informed consent form (for publication)	L2_SIS-ICF_Assent 5-less 7	2.1
Subject information and informed consent form (for publication)	L4_Clincierge_Data Protection Notice	1
Summary of Product Characteristics (SmPC) (for publication)	G2_aclasta_SmPC_Dutch	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_aclasta_SmPC_English	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_aclasta_SmPC_France	n
Summary of Product Characteristics (SmPC) (for publication)	G2_aclasta_SmPC_German	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_aclasta_SmPC_Italian	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_aclasta_SmPC_Polish	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_Nerixia_SmPC_Italian	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_Pamidronaatdinatrium_SmPC_Dutch	N/A
Summary of Product Characteristics (SmPC) (for publication)	G2_Pamifos_SmPC_Polish	N/A
Synopsis of the protocol (for publication)	D1_Synopsis_Abbreviated_Dutch	3.0
Synopsis of the protocol (for publication)	D1_Synopsis_Abbreviated_English	3.0
Synopsis of the protocol (for publication)	D1_Synopsis_Abbreviated_French	3.0
Synopsis of the protocol (for publication)	D1_Synopsis_Abbreviated_German	2.0
Synopsis of the protocol (for publication)	D1_Synopsis_Abbreviated_Italian	3.0
Synopsis of the protocol (for publication)	D1_Synopsis_Abbreviated_Polish	3.0

Application history

13 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2023-04-28	Netherlands	Acceptable with conditions 2023-08-21	2023-08-21
2	NON SUBSTANTIAL MODIFICATION	NSM-1	2023-08-29	Netherlands	Acceptable with conditions 2023-08-21	2023-08-29
3	NON SUBSTANTIAL MODIFICATION	NSM-2	2023-11-15	Netherlands	Acceptable with conditions 2023-08-21	2023-11-15
4	NON SUBSTANTIAL MODIFICATION	NSM-3	2023-11-20	Netherlands	Acceptable with conditions 2023-08-21	2023-11-20
5	SUBSTANTIAL MODIFICATION	SM-1	2023-11-22	Netherlands	Acceptable 2024-03-11	2024-03-11
6	NON SUBSTANTIAL MODIFICATION	NSM-4	2024-03-18			2024-03-18
7	SUBSTANTIAL MODIFICATION	SM-3	2024-09-09	Netherlands	Acceptable 2024-11-11	2024-11-12
8	SUBSTANTIAL MODIFICATION	SM-4	2025-01-14	Netherlands	Acceptable 2025-03-03	2025-03-03
9	SUBSTANTIAL MODIFICATION	SM-5	2025-08-08	Netherlands	Acceptable 2025-09-22	2025-09-24
10	NON SUBSTANTIAL MODIFICATION	NSM-5	2025-11-13		Acceptable 2025-09-22	2025-11-13
11	SUBSTANTIAL MODIFICATION	SM-7	2025-11-14	Netherlands	Acceptable 2026-02-03	2026-02-05
12	NON SUBSTANTIAL MODIFICATION	NSM-6	2026-02-12	Netherlands	Acceptable 2026-02-03	2026-02-12
13	SUBSTANTIAL MODIFICATION	SM-8	2026-03-03	Netherlands	Acceptable 2026-04-28	2026-04-30

Setrusumab vs Bisphosphonates in Pediatric Subjects with Osteogenesis Imperfecta (Cosmic)

Overview

Key facts

External identifiers

Trial design

Main objective

Secondary objectives 8

Conditions and MedDRA coding

Study design 4 periods

Regulatory references

Eligibility criteria

Inclusion criteria 5

Exclusion criteria 15

Endpoints

Primary endpoints 1

Secondary endpoints 9

Investigational products

Test 1

Comparator 20

Sponsors and contacts

Ultragenyx Pharmaceutical Inc.

Scientific contact point

Public contact point

Third parties 14

Locations

By country

Investigational sites

Country notifications

Oversight and notifications

Serious breaches 1 · Art. 52 CTR

Results and documents

Documents 97 files

Application history

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