This study has been transitioned to CTIS with ID 2023-508350-26-00 check the CTIS register for the current data. Primary ObjectiveThe primary efficacy objective of the study is to assess the effect of garetosmab (10 mg/kg) versus placebo on the…
ID
Source
Brief title
Condition
- Bone disorders (excl congenital and fractures)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint:
The primary efficacy endpoint is the number of new HO lesions adjudicated as
positive based on CT at week 56.
Primary Safety Endpoint:
The primary safety endpoint is the incidence and severity of treatment emergent
adverse
events of special interest (AESIs) from baseline to week 56.
Secondary outcome
Secondary study parameters/outcome of the study (if applicable) (in Dutch):
Key Secondary Endpoint:
The key secondary endpoint is the number of clinician-assessed flare ups
through week 56.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
• The number of clinician-assessed flare-ups through week 28
• Occurrence of clinician-assessed flare-ups through weeks 28 and 56 (Yes/No)
• The number of patient-reported flare-ups through weeks 28 and 56
• Occurrence of patient-reported flare-ups through weeks 28 and 56 (Yes/No)
• Occurrence of new HO lesions adjudicated as positive based on CT at week 28
and 56 (Yes/No)
• Total volume of new HO lesions adjudicated as positive based on CT at weeks
28 and 56
• Number of new HO lesions adjudicated as positive based on CT at week 28
• Change from baseline in joint function assessment by physician to week 28 and
week 56 by the CAJIS
• Change from baseline in pulmonary function as assessed by spirometry at week
28 and week 56
• Change from baseline in disease severity to week 28 and week 56 by the PGIS
• Change since the start of the study in disease severity to week 28 and week
56 by the PGIC
• Change since the start of the study in disease severity to week 28 and week
56 by the CGIC
For patients continuing extended treatment, additional other secondary efficacy
endpoints are:
• Number of new HO lesions adjudicated as positive based on CT at week 84
• Occurrence of new HO lesions adjudicated as positive based on CT at
week 84 (Yes/No)
• Total volume of new HO lesions adjudicated as positive based on CT at
week 84
• The number of clinician-assessed flare-ups through week 84
• Occurrence of clinician-assessed flare-ups through week 84 (Yes/No)
Note: To ensure consistency of assessments, it is advised that the same
clinician
performs the clinician-assessed FOP flare-ups and CAJIS evaluations, at all
visits for the mentioned assessments for a given patient, whenever possible.
Background summary
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely
disabling, congenital genetic disease characterized by progressive multi-focal
heterotopic ossification (HO) of skeletal muscle, ligaments, tendons, and
fascia. Heterotopic ossification is the abnormal growth of bone in non skeletal
tissues. FOP is estimated to occur in approximately 1 in 0.63 to 1.86 million
individuals based on reports of diagnosed cases (Liljesthro*m, 2020). There are
approximately 800 confirmed cases of FOP globally. No ethnic, racial, gender,
or geographic predisposition has been reported. Palovarotene, a retinoic acid
receptor gamma (RAR*) selective agonist, is approved only in Canada for the
reduction of HO in adults and children >8 years for females and >10 years for
males with FOP. Fibrodysplasia ossificans progressiva is caused by dominant
missense mutations in the intracellular domain of activin receptor type 1A
(ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor
which is expressed in many tissues of the body, including skeletal muscle and
cartilage (Huning, 2014). Although FOP is caused by a variety of such
mutations, the great majority of FOP patients carry the point mutation,
c.617G>A; p.R206H, which alters arginine (R) 206 to a histidine (H) (Huning,
2014). A significant breakthrough in the understanding of FOP occurred in 2015
when it was demonstrated that FOP-causing mutations of ACVR1 render this
receptor responsive to activin A and initiate signaling through the SMAD 1/5/8
pathway, akin to that obtained from osteogenic BMPs (Hatsell, 2015) (Hino,
2015). In contrast, when activin A engages wildtype ACVR1 receptors, it forms a
non-signaling complex, and as a result activin A antagonizes BMP pathway
signaling mediated by wild-type ACVR1(Aykul, 2020) (Hatsell, 2015). The
ACVR1[R206H] variant was subsequently expressed in a conditional inducible
mouse model of FOP. These mice developed progressive HO at anatomic locations
similar to those seen in patients with FOP, as detected by 18F-NaF PET/CT which
labeled active HO and volumetric CT (Hatsell, 2015) (Upadhyay, 2017).
Inhibition of activin A with the neutralizing anti-activin A antibody
garetosmab blocked the development of new HO lesions and also resulted in
stasis or partial resorption of existing (but nascent) HO lesions. These
results suggested a fundamental role for activin A in the initiation and
progression of HO, and that an anti-activin A antibody might provide beneficial
clinical impact on HO in patients with FOP (Upadhyay, 2017). Recently,
experiments in the ACVR1[R206H] FOP mice have been extended to another
FOP-causing ACVR1 variant, R258G. This ACVR1[R258G] mouse model developed HO
much like the ACVR1[R206H] mouse model, and HO was again inhibited by
garetosmab. Hence, inhibition of activin A is a promising therapeutic approach
for halting HO in FOP, whether it arises as a result of the most common
FOP-causing variant of ACVR1, ACVR1[R206H], or any of the other FOP-causing
variants of ACVR1 reported to date. Garetosmab is a fully human monoclonal
antibody (mAb) that selectively binds activin A, AB, and AC, blocking their
ability to interact with their corresponding type I receptors and hence block
signaling. Garetosmab has been studied in 2 completed trials in healthy adult
subjects. R2477-HV-1525 was a first in human (FIH), double-blind,
placebo-controlled, single-ascending dose study in women of non-childbearing
potential (30 healthy subjects were exposed). R2477-1033-HV-1621 was a
randomized, double-blind, placebo-controlled, ascending-dose study to assess
the safety, tolerability, and pharmacodynamic (PD) effects of garetosmab alone
and in combination with trevogrumab (an anti-myostatin mAb) in healthy
postmenopausal women and healthy adult men (56 healthy subjects were exposed to
garetosmab alone or in combination with trevogrumab). The results of the
studies in healthy subjects showed that overall, garetosmab was well tolerated
with no significant safety findings observed. The clinical benefit of
garetosmab for the treatment of FOP was demonstrated in the phase 2,
double-blind, placebo-controlled, 28-week treatment study (LUMINA-1), followed
by 2 open label periods. While garetosmab did not have a significant effect on
the planned primary endpoint, total lesion activity (measuring a reduction in
the size and activity of pre-existing HO lesions), there was a striking
reduction in the number of new HO lesions as assessed by both 18F NaF PET and
CT in adult patients with FOP. These substantive and clinically meaningful
reductions were largely demonstrated by significant decreases in the incidence
and volume of new lesions after 28 weeks of treatment. Moreover, garetosmab
reduced the incidence of patient- and investigator reported flare-up events.
Results from the open-label period showed sustained efficacy with long-term
treatment through week 76. From a safety perspective, the majority of
treatment-emergent adverse events (TEAEs) were mild to moderate in severity.
Infusion reactions were balanced between treatment groups with no serious or
severe events. Notable imbalances in TEAEs included epistaxis, acne, madarosis
(thinning of the eyelashes or eyebrows), and a composite of skin infections
including abscesses, carbuncle, folliculitis, and furuncle. Additional
background information on the study drug and development program can be found
in the IB.
Study objective
This study has been transitioned to CTIS with ID 2023-508350-26-00 check the CTIS register for the current data.
Primary Objective
The primary efficacy objective of the study is to assess the effect of
garetosmab (10 mg/kg) versus placebo on the formation of new HO lesions from
baseline to week 56, as determined by low dose CT.
The primary safety objective of the study is to assess the safety and
tolerability of garetosmab (10 mg/kg, 3 mg/kg) versus placebo from baseline to
week 56.
Secondary Objectives
Key Secondary Objectives
The key secondary objectives of the study are:
• To assess the effect of garetosmab 10 mg/kg versus placebo on the number per
patient of clinician assessed flare-up episodes to week 56
• To assess the effect of garetosmab (3 mg/kg) versus placebo on the formation
of new HO lesions from baseline to week 56 as determined by CT
• To assess the effect of garetosmab (3 mg/kg) versus placebo on the number per
patient of clinician assessed flare-up episodes to week 56
Secondary Objectives
All other secondary objectives will compare the 10 mg/kg dose group to the
placebo group and the 3 mg/kg dose group to the placebo group at week 28 and
week 56 unless otherwise specified.
Other secondary objectives of the study are:
• To assess the effect of garetosmab versus placebo on the occurrence of
clinician-assessed flare-up episodes
• To assess the effect of garetosmab versus placebo on the number per patient
of clinician assessed flare-up episodes to week 28
• To assess the effect of garetosmab versus placebo on the occurrence of
patient reported flare up episodes
• To assess the effect of garetosmab versus placebo on the number per patient
of patient reported flare-up episodes
• To assess the effect of garetosmab versus placebo in the proportion of
patients with new HO lesions as determined by CT
• To assess the effect of garetosmab versus placebo on volume of new HO lesions
as determined by CT
• To assess the effect of garetosmab versus placebo on the number of new HO
lesions per patient from baseline to week 28 as determined by CT
• To characterize the concentrations of total activin A
• To evaluate concentrations of garetosmab
• To assess the immunogenicity of garetosmab
• To assess the effect of garetosmab versus placebo in pulmonary function
assessed by pulmonary function tests
• To assess clinical outcomes (ie, joint function [Cumulative Analog Joint
Involvement Scale (CAJIS)]) at baseline and over time after the first dose of
garetosmab versus placebo
• To assess the effect of garetosmab versus placebo on patient's disease
severity assessed by the Patient Global Impression of Severity (PGIS)
• To assess the effect of garetosmab versus placebo on patient's change in
disease assessed by the Patient's Global Impression of Change (PGIC)
• To assess the effect of garetosmab versus placebo on clinician's change in
disease assessed by the Clinician's Global Impression of Change (CGIC)
• To assess the safety and efficacy of garetosmab beyond 12 months.
Exploratory Objectives
The exploratory objectives of the study are:
• To assess the effect of garetosmab versus placebo in the number of
pre-existing HO lesions that disappear as assessed by CT compared with baseline
• To assess, including but not limited to, biochemical markers of bone
formation, hypertrophic cartilage, inflammation, and activin A related ligands
at baseline and over time after the first dose of garetosmab
• To assess platelet function in patients treated with garetosmab via flow
cytometry
• To explore genetic associations with FOP or treatment response in an optional
genetics sub-study
• To assess the effect of garetosmab on lung volume
• To assess the EuroQol 5 dimensions questionnaire with a 3-level scale
(EQ-5D-3L) at baseline and over time after the first dose of garetosmab versus
placebo
• To assess quality of life at baseline (via Short-Form 36 [SF-36]) and over
time after the first dose of garetosmab versus placebo
• To explore the relationship of garetosmab concentration and the efficacy and
safety response
• To assess the effect of garetosmab on the duration of flare and severity
level of flare
Study design
R2477-FOP-2175 is a phase 3, randomized, multi-center, multinational,
parallel-group, placebo-controlled study to assess the efficacy of garetosmab
on the reduction of heterotopic bone formation, and its safety, tolerability,
and PK in FOP patients with active disease caused by any FOP-causing variant of
ACVR1. Approximately 66 patients will be enrolled 1:1:1 into the 3 parallel
arms of the study. The study consists of 4 periods and a Follow-up Safety Visit.
Screening Period: 4 weeks in duration (from study day -28 to day -1 [visit 1]).
All patients will undergo an informed consent process and screening procedures.
Screening procedures may be conducted over multiple days.
Double-Blind Treatment Period (DBTP): 56 weeks in duration (from study
day 1 [visit 2] to week 56 [visit 17]). All patients will be randomized to
doubleblind treatment with garetosmab 10 mg/kg, garetosmab
3 mg/kg, or placebo.
Extended Treatment Period (ETP): 28+ weeks in duration (study week 56+ [visit
17+]) for those who choose to continue double-blind treatment. Patients who
complete the DBTP and elect to extend double-blind treatment continue until the
last global patient completes week 84.
Observation Period: 28+ weeks in duration (study week 56+ [visit 17+]) for
those who choose to discontinue from double-blind treatment. Patients who
complete the DBTP and elect to go unblinded and stop treatment will be followed
to assess survival and any pertinent safety events (ie, severe bleeding) since
the last contact. The Observation Period will continue until the last global
patient completes their last study visit. Patients will not receive treatment
and may participate in other studies.
Follow-Up Safety Visit: 30 weeks from the last dose administered (study week
84+ [visit 24+]) for all patients who receive treatment, except for patients
who are unblinded that were treated with placebo (placebo-treated patients
unblinded at week 56 [visit 17] do not participate in the Follow-Up Safety
Visit). Consists of a safety follow-up visit 30 weeks after the last study drug
administration.
Efficacy assessments will include whole body CT for HO lesions, assessment of
flare-ups, CAJIS, pulmonary function tests, change in disease severity, and
quality of life (EuroQol 5 dimensions questionnaire with a 3-level scale
[EQ5D-3L] and Short-Form 36 [SF-36]).
Safety assessment will include adverse events (AEs), vital signs, physical
examination, Electrocardiograms (ECGs), serum and urine laboratory testing, ear
nose, and throat (ENT) consultation, coagulation parameters, platelet flow
cytometry, and menstrual cycle history.
Patients who participated in the phase 2, R2477-FOP-1623 study (LUMINA-1) can
enroll if they meet the inclusion criteria and do not meet the exclusion
criteria.
Intervention
Study Drug: Garetosmab is supplied as a liquid drug product and will be
administered intravenous (IV) in this study.
Dose/Route/Schedule: Patients will receive either garetosmab IV (10 mg/kg)
every 4 weeks (Q4W), garetosmab IV (3 mg/kg) Q4W, or matching placebo Q4W.
Placebo Route/Schedule: Placebo to match garetosmab is supplied as a liquid
solution without the monoclonal antibody (or the protein).
Study burden and risks
Potential benefit of this study and a summary of the safety and efficacy data
from LUMINA-1 are described previously in Section 1 and the IB. Because
patients with FOP suffer from a severe, debilitating, and ultimately fatal
genetic disease, it is proposed that the potential benefit of garetosmab in
reducing HO activity outweighs any potential risks previously outlined.
Five deaths were reported in the open-label period of LUMINA-1. The sponsor
investigated these events extensively, and the majority of these deaths appear
consistent with common causes of death in patients with FOP, and with the life
expectancy in patients with FOP of similar age and disease severity as measured
by the clinical staging of FOP developed by Pignolo et al (Pignolo, 2018).
Thus, a clear relationship to treatment was not identified. However, as these
deaths occurred in the absence of a placebo group in the open-label period of
the LUMINA-1 study, the possibility of an association cannot be excluded.
Therefore, this phase 3 study has been designed to further evaluate the
benefit-risk profile of garetosmab in adult patients with FOP. This study will
include an extended 1-year placebo arm which will allow for controlled
assessment of safety, while the addition of inclusion/exclusion criteria will
restrict the population to those with lower likelihood of morbidity and
mortality due to the disease itself (ie, lower CAJIS and less disability), and
allow the sponsor to better determine the relationship of study drug to adverse
events. In addition, the ETP will allow the sponsor to understand better the
long-term safety profile of garetosmab.
Specific safety considerations and risk mitigation strategies for the study are
described in the sections below. These measures will be described in the
informed consent form (ICF).
A risk-benefit statement with respect to the overall development program is
provided in the IB.
Old Saw Mill River Road 777
Tarrytown NY 10591
US
Old Saw Mill River Road 777
Tarrytown NY 10591
US
Listed location countries
Age
Inclusion criteria
1. Male or female 18 years or older at screening
2. Clinical diagnosis of Fibrodysplasia Ossificans Progressiva (FOP) [(based on
findings of congenital malformation of the great toes, episodic soft tissue
swelling, and/or progressive Heterotopic Ossification (HO)]
3. Confirmation of FOP diagnosis with documentation of Type I activin A
receptor (ACVR1) FOP causing mutation
4. FOP disease activity within 1 year of screening visit. FOP disease activity
is defined as pain, swelling, stiffness, or other signs and symptoms associated
with FOP flare-ups; or worsening of joint function, or radiographic progression
of HO lesions (increase in size or number of HO lesions) with/without being
associated with flare-up episodes
5. Willing and able to undergo CT imaging procedures and other procedures as
defined in the protocol
6. Willing and able to comply with clinic visits and study-related procedures
7. Provide informed consent signed by study patient or legally acceptable
representative
8. Able to understand study-related questionnaires
Exclusion criteria
A patient who meets any of the following criteria will be excluded from the
study:
1. CAJIS score at screening >19
2. Patient has significant concomitant illness or history of significant
illness such as but not limited to cardiac, renal, rheumatologic, neurologic,
psychiatric, endocrine, metabolic, or lymphatic disease, that in the opinion of
the study investigator might confound the results of the study or pose
additional risk to the patient by their participation in the study
3. Previous history or diagnosis of cancer (exceptions: localized
basal/squamous cell cancer
that has been successfully excised; in situ cervical cancer)
4. Severely impaired renal function defined as estimated glomerular filtration
rate <30 mL/min/1.73 m^2 calculated by the Modification of Diet in Renal
Disease equation
(1 retest is allowed)
5. Uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >9% at screening (1
retest is allowed)
6. History of poorly controlled hypertension, as defined by:
a. Systolic blood pressure >=180 mm Hg or diastolic blood pressure >=110 mm Hg at
the screening visit
b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood
pressure of 100 mm Hg to 109 mm Hg at the screening visit, AND a history of
end-organ damage (including history of left-ventricular hypertrophy, heart
failure, angina, myocardial infarction, stroke, transient ischemic attack,
peripheral arterial disease, end-stage renal disease, and moderate-to-advanced
retinopathy [hemorrhages or exudates, papilledema])
7. Known history of cerebral vascular malformation
8. Cardiovascular conditions such as New York Heart Association class III or IV
heart failure, cardiomyopathy, intermittent claudication, myocardial
infarction, or acute coronary syndrome within 6 months prior to screening;
symptomatic ventricular cardiac arrhythmia (Note: sinus dysrhythmia,
asymptomatic block or well-controlled atrial fibrillation with normal resting
ventricular rate are not exclusion criteria.)
9. History of severe anemia requiring transfusion
10. Patients who are on concomitant antiplatelet therapy (eg, clopidogrel),
anticoagulants (eg, warfarin, heparin, factor Xa inhibitor, or thrombin
inhibitors) in the last 30 days or within 5 half-lives of the therapy,
whichever is longer. Low-dose acetylsalicylic acid (aspirin <=100 mg or <=150
mg/day, based on local practice) is acceptable.
(NOTE: low doses of heparin for flushing of catheters will be permitted.)
11. Patients with a history of severe, non-traumatic bleeding requiring
transfusion or hospitalization for hemodynamic compromise (eg, severe nose
bleeds requiring hospitalization, nasal packing or cauterization, menstrual
bleeding that is prolonged/heavy)
12. Patients with a known pre-existing medical history of a bleeding diathesis
(eg, hemophilia A, von Willebrand*s Factor deficiency, platelet count <=20×10^9/
L)
13. Ongoing significant viral illness or pneumonia within 2 weeks of screening
14. History of severe respiratory compromise requiring oxygen, respiratory
support (eg, bilevel positive airway pressure [biPAP] or continuous positive
airway pressure [CPAP]), or a history of aspiration pneumonia requiring
hospitalization
15. Known history of recent epididymitis (within 6 months of screening) or
sexually transmitted diseases affecting urogenital organs
16. Prior use in the past year and concomitant use of bisphosphonates
17. Concurrent participation in another interventional clinical study or a
non-interventional study with radiographic measures or invasive procedures (eg,
collection of blood or tissue samples). Participation in the FOP Connection
Registry or other studies in which patients complete study questionnaires is
allowed
18. Treatment with another investigational drug, denosumab, imatinib or
isotretinoin in the last 30 days or within 5 half-lives of the investigational
drug, whichever is longer
19. Known hypersensitivity to garetosmab or any of its excipients
20. Positive serum human chorionic gonadotropin (hCG)/urine pregnancy test at
the screening/baseline visit
21. Members of the clinical site study team and/or his/her immediate family,
unless prior approval granted by the sponsor
22. Patients who are committed to an institution by virtue of an order issued
either by the judicial or the administrative authorities
23. Has received a COVID-19 vaccination (initial series or booster) within 1
week of planned start of study medication or for which the planned COVID-19
vaccinations would not be completed 1 week prior to start of study drug
24. Pregnant or breastfeeding women
25. Women of childbearing potential (WOCBP)* who are unwilling to practice
highly effective contraception or undergo pregnancy tests prior to the initial
dose, during the study, and for at least 30 weeks after the last dose. Highly
effective contraceptive measures include:
a. stable use of combined (estrogen- and progestogen-containing) hormonal
contraception (oral) associated with inhibition of ovulation initiated 2 or
more menstrual cycles prior to screening,
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS),
c. bilateral tubal ligation/occlusion,
d. vasectomized partner (provided that the male vasectomized partner is the
sole sexual partner of the WOCBP study patient and that the vasectomized
partner has obtained medical assessment of surgical success for the procedure),
e. and/or sexual abstinence *,*
Pregnancy testing and contraception are required for WOCBP.
Pregnancy testing and contraception are not required for women who are
post-menopausal or permanently sterile.
*WOCBP are defined as women who are fertile following menarche until becoming
postmenopausal, unless permanently sterile. Permanent sterilization methods
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A
postmenopausal state is defined as no menses for 12 months without an
alternative medical cause. A high FSH level in the postmenopausal range may be
used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy. However, in the absence of 12
months of amenorrhea, a single FSH measurement is insufficient to determine the
occurrence of a postmenopausal state. The above definitions are according to
the Clinical Trial Facilitation Group (CTFG) guidance.
* 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 drugs. The reliability of sexual abstinence needs to
be evaluated in relation to the duration of the clinical trial and the
preferred and usual lifestyle of the patient.
* Periodic abstinence (calendar, symptothermal, post-ovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
method (LAM) are not acceptable methods of contraception. Female condom and
male condom should not be used together.
26. Male patients with WOCBP partners* who are not willing to use condoms with
WOCBP partners to prevent potential fetal exposure, during the study, and for
30 weeks after the last dose. Sperm donation is prohibited during the study and
for 30 weeks after the last dose of study drug.
*Male patients with WOCBP partners will be asked to inform and ensure their
female partners to use highly effective contraception measures * to prevent
pregnancy.
* Vasectomy with medical assessment of surgical success and sexual abstinence *
are considered highly effective contraception measures.
* 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 drugs. The reliability of sexual abstinence needs to
be evaluated in relation to the duration of the clinical trial and the
preferred and usual lifestyle of the pat
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 | CTIS2023-508350-26-00 |
| EudraCT | EUCTR2022-000880-40-NL |
| ClinicalTrials.gov | NCT04577820 |
| CCMO | NL81750.018.22 |