This study has been transitioned to CTIS with ID 2024-510919-29-00 check the CTIS register for the current data. OBJECTIVES - Phase 2 (not to be conducted in NL):Phase 2 Primary Objective:- Identify a setrusumab dosing strategy in subjects with OI…
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint - Phase 2 (not to be conducted in NL):
- Percent change in serum P1NP from Baseline at Month 1
Primary Endpoint - Phase 3:
- Annualized rate of all radiographically-confirmed fractures, excluding
morphometric vertebral fractures (footnote a) and fractures of the fingers,
toes, face, and skull, during the double-blind (DB) Treatment Period.
________
Footnote:
a. Morphometric vertebral fractures are identified by a change from baseline in
the Genant semi-quantitative scoring based on an annual vertebral radiograph.
Secondary outcome
SECONDARY ENDPOINTS - Phase 2 (not to be conducted in NL):
(1) Serum setrusumab concentration at scheduled time points
(2a) Baseline-corrected AUEC for serum P1NP over a 1- and 2-month timeframe
(2b) Percent change from Baseline in bone turnover markers (P1NP and OCN) over
time
(3a) Change from Baseline in DXA lumbar spine BMD z-scores over time
(3b) Percent change from Baseline in DXA lumbar spine BMD over time
(4) Frequency, severity, and relationship to treatment of TEAEs, SAEs, and
AESIs
(5) Incidence of anti-setrusumab binding and neutralizing antibodies at
scheduled time points
SECONDARY ENDPOINTS - Phase 3:
(1a) Annualized rate of all radiographically-confirmed fractures, excluding
morphometric vertebral fractures (footnote a), but including fractures of the
fingers, toes, face and skull, during the DB Treatment Period
(1b) Annualized rate of all radiographically-confirmed fractures during the DB
Treatment Period
(2) Change from Baseline in DXA lumbar spine BMD z-score at 12 months
(3) Change from Baseline at 12 months for:
• POSNA-PODCI Sports/Physical Functioning and Pain/comfort
subscale scores for subjects <= 18 years of age at screening
• SF-36 PF and BP Domain Scales for subjects >= 18 years of
age at screening
(4) Frequency, severity, and relationship to treatment of TEAEs, SAEs, and
AESIs
(5) Incidence of binding and neutralizing anti-setrusumab antibodies at
scheduled time points
____________
Abbreviations:
AUEC, area under the effect curve;
AESI, adverse event of special interest;
BMD, bone mineral density;
DB, double-blind;
DXA, dual-energy X-ray absorptiometry;
OCN, osteocalcin;
OI, osteogenesis imperfecta;
P1NP, amino-terminal propeptide of type 1 procollagen;
PD, pharmacodynamic;
PK, pharmacokinetic;
SAE, serious adverse event;
TEAE, treatment-emergent adverse event
Background summary
[Protocol Amendment 3, 5.3. Rationale for Setrusumab in Osteogenesis Imperfecta]
Setrusumab is being investigated for the treatment of OI based on 1) the
serious unmet need for a treatment for OI, 2) the mechanism of action for
setrusumab that addresses the mechanism of disease for OI, and 3) previous
clinical experience with setrusumab suggesting a positive benefit risk profile
in patients with OI, supporting further development.
As described in Section 5.1 [of the protocol], there are no FDA- or
EMA-approved treatments for OI. Current treatment consists of a
multidisciplinary approach focusing on symptomatic relief, including
pharmacological intervention, physical therapy, occupational therapy,
orthopedic interventions, and follow-up by other subspecialists. Despite these
approaches, patients with OI have bone fragility and remain at elevated risk of
fractures, substantially impacting their daily living and quality of life.
Low bone mass and the resultant bone fragility in OI can be attributed to an
imbalance in bone resorption versus bone formation. Although bisphosphonates
are frequently used off-label in pediatric patients with OI, inhibition of bone
resorption with bisphosphonate treatment may not be adequate to restore
skeletal health in OI. Osteoanabolic therapies may be beneficial in pediatric
and adult patients by stimulating bone formation and increasing bone mass. One
of these potential approaches is through inhibition with sclerostin.
Sclerostin, a small protein produced by osteocytes, inhibits canonical Wnt
signaling, and thereby suppresses osteoblast differentiation and bone formation
(Poole et al., 2005). Sclerostin levels have been found to be absent or low in
several rare, genetic skeletal disorders that present with high BMD and low
fracture risk, such as sclerosteosis and van Buchem disease. This has led to
the concept that inhibiting sclerostin and thereby increasing bone formation
may be useful for the treatment of disorders such as OI that are characterized
by bone fragility and increased risk of fractures. Anti-sclerostin antibodies
have been shown to stimulate osteoblast bone formation and improve trabecular
and cortical bone mass in multiple mouse models of OI, with effects that were
generally similar across growing and skeletally mature mice. In a murine model
of Type III OI (oim/oim), anti*sclerostin antibody therapy was also shown to
reduce the number of fractures (Cardinal et al., 2019). The anti-sclerostin
antibody, romosozumab is approved for use in women with post-menopausal
osteoporosis, in whom the increases in bone mass corresponded to significant
reductions in fracture risk (Cosman et al., 2016).
As described in Section 5.2 [of the protocol], across 5 Phase 1 or 2 studies,
setrusumab increased serological markers of bone anabolism and lumbar spine BMD
in healthy post-menopausal women with low BMD; and increased markers of bone
formation, bone strength indices at peripheral bone sites, and lumbar spine BMD
in patients with OI. Setrusumab also demonstrated an acceptable safety profile
in these studies. Available nonclinical data support the evaluation of
setrusumab safety and efficacy in pediatric and adult patients with OI. The
underlying disease pathology of OI is similar in children and adults, though
fracture rates in OI patients are highest during childhood, similar
improvements in bone mass and reductions in fracture risk are expected across
ages. The rationale for the use of setrusumab in children and adults with OI is
to facilitate bone building and decrease the risk of fractures and
fracture-related sequelae.
[Protocol Amendment 3, 7.1.3. Rationale for Study Design, extract from 'Phase
3-specific Rationale']
Based on its mechanism of action of increasing BMD and bone formation as
demonstrated in adults with OI, it is hypothesized that setrusumab treatment
will reduce fractures over time in the proposed study population.
Study objective
This study has been transitioned to CTIS with ID 2024-510919-29-00 check the CTIS register for the current data.
OBJECTIVES - Phase 2 (not to be conducted in NL):
Phase 2 Primary Objective:
- Identify a setrusumab dosing strategy in subjects with OI
Phase 2 Secondary Objectives:
- Evaluate the PK of setrusumab doses in subjects with OI
- Determine the PD effects of setrusumab on bone formation and turnover markers
- Evaluate the effect of setrusumab on lumbar spine BMD (bone mineral density)
- Evaluate the safety profile of setrusumab for the treatment of subjects with
OI
- Evaluate the immunogenicity of setrusumab for the treatment of subjects with
OI
OBJECTIVES - Phase 3:
Phase 3 Primary Objective:
- Evaluate the effect of setrusumab vs placebo on reduction in fracture rate,
excluding morphometric vertebral fractures and fractures of the fingers, toes,
face, and skull
Phase 3 Secondary Objectives:
- Evaluate the effect of setrusumab vs placebo on reduction in fracture rate
- Evaluate the effect of setrusumab vs placebo on lumbar spine BMD
- Evaluate the effect of setrusumab vs placebo on functional assessments and
patient-/caregiver-reported health-related quality of life, including pain
- Evaluate the effect of setrusumab vs placebo on clinical outcome assessments
including subject-/caregiver-reported assessments of physical function, pain,
and health-related quality of life
- Assess the safety profile of setrusumab
- Evaluate the immunogenicity of setrusumab for the treatment of subjects with
OI
Study design
UX143-CL301 is an operationally seamless Phase 2/3 study that consists of a
randomized single blind, Phase 2 dose-evaluation phase and a Phase 3
double-blind (DB), placebo-controlled phase to evaluate the efficacy and safety
of setrusumab in OI subjects 5 to < 26 years of age. Phase 2 and Phase 3
consist of separate and distinct subject cohorts, and data will be analyzed
separately in the primary analysis for each phase (refer to protocol, Section
11).
In Phase 2, subjects will be randomized 1:1 to receive 20 or 40 mg/kg
setrusumab intravenously once a month (QM); subjects and Investigators will be
blinded to setrusumab dose. The Phase 2 primary analysis will evaluate
pharmacokinetics (PK), pharmacodynamic (PD) and safety data from the early part
of Phase 2 to determine the dosing strategy for initiation of Phase 3 and the
Phase 2 open-label Treatment Extension Period. After a dosing strategy has been
determined, a separate cohort of subjects will be randomized 2:1 into Phase 3
to receive setrusumab or placebo throughout the double-blind (DB),
placebo-controlled period, after which subjects will transition to the
open-label Treatment Extension Period. After initiation of Phase 3, the two
phases will be conducted in parallel to the end of the study. An optional
substudy will be conducted in approximately 10 subjects (>= 8 years) consisting
of a bone biopsy following at least 12 months of setrusumab exposure to
investigate the impact of setrusumab on bone histomorphology.
Intervention
Interventions (footnote a)
SETRUSUMAB
---------------------
Dose Formulation: 160 mg lyophilized powder for solution
Unit Dose Strength(s)/Dosage Level(s):
- Phase 2 (not in NL): 20 mg/kg or 40 mg/kg through the Phase 2 primary
analysis; 20 mg/kg (footnote b)
- Phase 3: 20 mg/kg (footnote b)
Route of Administration: IV infusion over 60 minutes (footnote c)
Use: Experimental
Frequency: Once a month (QM)
PLACEBO
--------------
Dose Formulation: Dextrose / glucose 5% solution in water
Unit Dose Strength(s)/Dosage Level(s): N/A
Route of Administration: IV infusion over 60 minutes (footnote c)
Use: Placebo comparator
Frequency: Once a month (QM)
_________
Footnotes:
a. During Phase 2 and Phase 3, subjects may receive supplementation with
calcium and vitamin D, if needed, as directed by the treating physician.
b. 20 mg/kg is the selected dosing strategy for Phase 3 and Phase 2 open-label
extension period (OLE); all Phase 2 subjects transition to 20 mg/kg after the
last Phase 2 subject completes the Month 6 study visit. Dose selection took
into consideration all PD, PK, safety, and available BMD data through Month 2,
including the primary endpoint of percent change from Baseline in serum P1NP at
Month 1.
c. The infusion rate may be adjusted to extend the infusion time (eg, based on
subject*s history with any infusions), and/or the infusion interrupted or
discontinued for clinical safety concerns (eg, infusion-related reaction) at
any time at the discretion of the Investigator.
Study burden and risks
The potential benefits of setrusumab are based on initial efficacy results seen
in clinical trials....
The potential risks of setrusumab are based on nonclinical studies and results
seen in clinical trials.
The study has been carefully designed to minimize potential risks of treatment
with setrusumab (details are given in the Protocol, 5.5. Risk Minimization).
During the design of this clinical study, efforts were made to minimize burden
on subjects during the study (details are given in the Protocol, 5.6. Measures
Taken to Minimize Subject Burden).
Potential risks and benefits are detailed in the protocol:
5.4. Potential Risks and Benefits
5.4.1. Potential Benefits
5.4.2. Potential Risks
5.4.2.1 Nonclinical Summary
5.4.2.2. Potential Clinical Risks
The 'Benefit Risk Conclusion' is provided in the protocol, Section 5.4.3.:
Taking into account measures to minimize risk to subjects in this study
(protocol, Section 5.5), the potential risks in association with setrusumab are
justified by the anticipated benefits that may be afforded to subjects with OI.
Leveroni Court 60
Novato CA 94949
US
Leveroni Court 60
Novato CA 94949
US
Listed location countries
Age
Inclusion criteria
1. Males and females 5 to < 26 years of age at time of informed consent
2. Diagnosis of OI Type I, III, or IV as confirmed by identification of
pathogenic or likely pathogenic genetic variants in COL1A1 or COL1A2. If a
variant of uncertain significance is identified, then clinical presence of the
expected phenotype can be used to confirm the diagnosis.
3. >= 1 fracture in the past 12 months, >= 2 fractures in the past 24 months, or
>= 1 tibia, femur, or humerus fracture in the past 24 months
4. Serum 25-hydroxyvitamin D >= 20 ng/mL at the Screening Visit. If
25-hydroxyvitamin D levels are below 20 ng/mL, 25-hydroxyvitamin D testing can
be repeated after a minimum of 14 days of vitamin D supplementation as directed
by the treating physician
5. Willing to not receive bisphosphonate therapy during the study
6. From the period following informed consent to 60 days after the last dose of
study drug, females of childbearing potential and fertile males must consent to
use highly effective contraception. If female, agree not to become pregnant. If
male, agree not to father a child or donate sperm
7. Willing and able to provide informed consent for subjects >= 18 years of age,
or provide assent (if possible) and have a legally authorized representative
provide informed consent, after the nature of the study has been explained and
prior to any research-related procedures
8. Willing to provide access to medical records for the collection of
radiographic data, fracture data, growth data, and disease history
9. Must, in the opinion of the Investigator, be willing and able to complete
all aspects of the study, adhere to the study visit schedule, and comply with
the assessments
Exclusion criteria
1. For Phase 2 subjects only, a history of major bone surgery within the
previous 6 months prior to Screening or planned major bone surgery for the
first 3 months of the study
2. History of skeletal malignancies or bone metastases at any time
3. History of neural foraminal stenosis (except if due to scoliosis)
4. Clinically unstable manifestations of Chiari malformation or basilar
invagination within the past 2 years. Presence of any other neurologic disease
that has been clinically unstable within past 2 years requires review by the
Medical Monitor.
5. History of or uncontrolled concomitant diseases such as
hypo/hyperparathyroidism, Paget*s disease, abnormal thyroid function, thyroid
disease or other endocrine disorders or conditions that could affect bone
metabolism
6. Rickets or any skeletal condition (other than OI) leading to bone
deformities and/or increased risk of fractures
7. History of stroke, myocardial infarction, TIA, or angina. Investigators
should consider whether the potential benefits of treatment outweigh the
potential risks in patients with other cardiovascular risk factors such as
hypertension, hyperlipidemia, familial hyperlipidemia, family history of
premature ischemic cardiovascular disease, smoking, diabetes mellitus, and
metabolic syndrome.
8. Hypocalcemia, defined as serum calcium levels below the age-adjusted normal
limits after a >= 4 hour fast
9. Estimated glomerular filtration rate < 29 mL/min/1.73 m2
10. Prior treatment with the following:
a. Teriparatide, growth hormone, or other bone anabolic or anti-resorptive
medications within 6 months of the first dose of study drug (Month 0)
b. Denosumab within 24 months of the first dose of study drug (Month 0)
c. Romosozumab at any time
11. Documented alcohol and/or drug abuse within 12 months prior to dosing or
evidence of such abuse, as determined by the Investigator
12. 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
13. Known hypersensitivity to setrusumab or its excipients that, in the
judgment of the Investigator, places the subject at increased risk for adverse
effects
14. History of external radiation therapy
15. Pregnant or breastfeeding or planning to become pregnant (self or partner)
at any time during the study
16. Use of any investigational product or investigational medical device within
4 weeks or 5 half-lives of investigational drug (whichever is longer) prior to
Screening, or during the study (per discretion of the Investigator in
consultation with the Medical Monitor)
17. Concurrent participation in another clinical study without prior approval
from the Investigator in consultation with the Medical Monitor
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-510919-29-00 |
| EudraCT | EUCTR2021-006597-23-NL |
| ClinicalTrials.gov | NCT05125809 |
| CCMO | NL83275.041.23 |