Clinical Trial Page

Summary
EudraCT Number:2021-005071-40
Sponsor's Protocol Code Number:AVT03-GL-C01
National Competent Authority:Bulgarian Drug Agency
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2022-04-27
Trial results
A. Protocol Information
A.1Member State ConcernedBulgarian Drug Agency
A.2EudraCT number2021-005071-40
A.3Full title of the trial
A Randomized, Double-Blind, Parallel Design, Repeat Dose, 2-arm, Multicenter Study Comparing the Efficacy, Safety, Immunogenicity, and Pharmacokinetic Profiles of AVT03 and US-Prolia® in Postmenopausal Women with Osteoporosis, ALVOBOND
Рандомизирано, двойно-сляпо, с паралелен дизайн, с повтарящи се дози, двураменно, многоцентрово изпитване за сравняване на ефикасността, безопасността, имуногенността и фармакокинетичния профил на AVT03 и US-Prolia® при жени в постменопауза с остеопороза, ALVOBOND
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
A Randomized, Double-Blind, Parallel Design, Repeat Dose, 2-arm, Multicenter Study Comparing the Efficacy, Safety, Immunogenicity, and Pharmacokinetic Profiles of AVT03 and US-Prolia® in Postmenopausal Women with Osteoporosis, ALVOBOND
Рандомизирано, двойно-сляпо, с паралелен дизайн, с повтарящи се дози, двураменно, многоцентрово изпитване за сравняване на ефикасността, безопасността, имуногенността и фармакокинетичния профил на AVT03 и US-Prolia® при жени в постменопауза с остеопороза, ALVOBOND
A.3.2Name or abbreviated title of the trial where available
ALVOBOND
A.4.1Sponsor's protocol code numberAVT03-GL-C01
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorAlvotech Swiss AG
B.1.3.4CountrySwitzerland
B.3.1 and B.3.2Status of the sponsorCommercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAlvotech Swiss AG
B.4.2CountrySwitzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationAlvotech Swiss AG
B.5.2Functional name of contact pointSVP Clinical & Medical Affairs
B.5.3 Address:
B.5.3.1Street AddressThurgauerstrasse 54
B.5.3.2Town/ cityZurich
B.5.3.3Post codeCH-8050
B.5.3.4CountrySwitzerland
B.5.4Telephone number+41 44 3139560
B.5.5Fax number+41 44 313 95 70
B.5.6E-mail[email protected]
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation No
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product namedenosumab
D.3.2Product code AVT03
D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPSubcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNDenosumab
D.3.9.1CAS number 615258-40-7
D.3.9.2Current sponsor codeAVT03
D.3.9.4EV Substance CodeSUB29173
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number60
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product Yes
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 2
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name Prolia
D.2.1.1.2Name of the Marketing Authorisation holderAmgen Inc.
D.2.1.2Country which granted the Marketing AuthorisationUnited States
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameProlia
D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPSubcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNDenosumab
D.3.9.1CAS number 615258-40-7
D.3.9.4EV Substance CodeSUB29173
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number60
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product Yes
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Osteoporosis
Остеопороза
E.1.1.1Medical condition in easily understood language
Osteoporosis
Остеопороза
E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level PT
E.1.2Classification code 10031282
E.1.2Term Osteoporosis
E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
•To demonstrate clinical similarity of AVT03 and United States-licensed Prolia® (US-Prolia, hereafter referred to as Prolia) in terms of percent change from Baseline in bone mineral density (BMD) at 12 months
•To demonstrate clinical similarity of AVT03 and Prolia in terms of area under the percent change from Baseline in serum C telopeptide of type 1 collagen up to 6 months (AUEC0 6months of %Cfb sCTX 1). Note: This objective will be considered as primary for European Medicines Agency (EMA) submission only; for all other agencies, this objective will be considered as secondary.
E.2.2Secondary objectives of the trial
•To further compare clinical similarity of AVT03 and Prolia
•To assess and compare the safety of AVT03 with Prolia
•To assess and compare immunogenicity of AVT03 with Prolia
•To compare pharmacokinetic (PK) biosimilarity between AVT03 and Prolia
•To compare pharmacodynamic parameters between AVT03 and Prolia
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
1.Postmenopausal women with osteoporosis willing to sign an informed consent form and able to undergo protocol related procedures.
2.Age: ≥50 years.
3.Female subject is postmenopausal according to 1 of the following criteria:
a.Spontaneous amenorrhea for ≥12 consecutive months
b.Biochemical criteria of menopause, follicle-stimulating hormone, >40 IU/L except surgically sterile
c.Having had bilateral oophorectomy ≥6 weeks prior to Screening
4.Body Mass Index: 18.5-32.0 kg/m2
5.A baseline dual-energy x-ray absorptiometry scan with a T score less than or equal to -2.5 and greater than or equal to -4.0 at the lumbar spine (LS) (L1 to L4), total hip, and/or femoral neck.
Note: If the left hip cannot be scanned (eg, due to left hip replacement, etc), right hip can be scanned instead. However, it is required to always scan the same hip.
6.At least 2 consecutive evaluable lumbar vertebrae and at least 1 evaluable hip.
7.Willing to receive calcium plus vitamin D supplements.
8.No history or evidence of a clinically significant disorder, condition, or disease that, in the opinion of the Investigator, would pose a risk to subject safety.
9.Resting supine systolic blood pressure of ≤150 mmHg and diastolic blood pressure of ≤90 mmHg. Other vital signs showing no clinically relevant deviations according to the Investigator’s judgment.
10.12-lead electrocardiogram (ECG) recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the Investigator.
11.Subject smokes <10 cigarettes per day within 3 months of Screening. Note: It is strongly recommended that subjects do not smoke during their participation in the study.
12.Recommended to abstain from alcohol from 48 hours prior to study drug administration, and 24 hours prior to study visits.
E.4Principal exclusion criteria
1.Evidence of clinically relevant pathology, especially prior diagnosis of bone disease, or any uncontrolled condition that will affect bone metabolism such as, but not limited to: osteogenesis imperfecta, hyperparathyroidism, hyperthyroidism, hypothyroidism, osteomalacia, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, current flare-up of osteoarthritis and/or gout, active malignancy, renal disease (defined as creatinine clearance <50 mL/min as calculated by Cockcroft-Gault formula), Paget's disease of the bone, recent bone fracture (within 6 months), and malabsorption syndrome. For causes of secondary osteoporosis, please see Appendix 14.2.
2.History and/or presence of 1 severe or more than 1 moderate vertebral fractures confirmed by x-ray.
3.History of hip fracture.
4.Presence of active healing fractures.
5.Previous treatment with denosumab and previous use of the following medications:
a.Intravenous bisphosphonates, fluoride, or strontium ranelate within 5 years prior to Screening
b.Oral bisphosphonates used for >3 years cumulative use, and any dose within 12 months of Screening
c.Parathyroid hormone (PTH) or PTH derivatives, eg, teriparatide and selective estrogen receptor modulators eg, raloxifene within 1 year of Screening
d.Calcitonin within 6 months of Screening
e.Other bone metabolism drugs: administration of any of the following treatments within the last 3 months,
i.anabolic steroids or testosterone
ii.glucocorticoids (>5 mg/day prednisone or equivalent for >10 days)
iii.systemic hormone replacement therapy
iv.tibolone
v.calcitriol
vi.anticonvulsants (except benzodiazepines)
vii.heparin
viii.systemic use of ketoconazole, androgens, adrenocorticotropic hormone (ACTH), cinacalcet or any cathepsin K inhibitor (eg, odanacatib), aluminium, lithium, protease inhibitors, methotrexate, gonadotropin releasing hormone agonists
6.Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures (eg, tooth extraction, dental implants, oral surgery in the past 6 months), periodontal, and/or pre-existing dental disease requiring therapy.
7.Evidence of hypo/hypercalcemia at Screening.
8.Known vitamin D deficiency (25-hydroxy vitamin D level <20 ng/mL [50 nmol/L]) after supplementation at Screening.
9.Known intolerance to calcium or vitamin D supplement.
10.Any current active infections, including localized infections, or any recent history (within 1 week prior to study drug administration) of active infections or a history of recurrent or chronic infections.
11.Presence of known current infection with hepatitis B or presence of positive serology – ie, hepatitis B surface antigen and or core antigen, hepatitis C virus antibody or human immunodeficiency virus at Screening.
12.Haematology and chemistry laboratory results outside the reference ranges, which are clinically significant, and, in the opinion of the Investigator or designee, could cause this study to be detrimental to the subject.
13.Donation of more than 500 mL of blood within the 8 weeks prior to study drug administration.
14.Hypersensitivity to denosumab or its constituents.
15.A recent history of major surgery including spine surgery due to disc herniation, spinal stenosis, or similar condition within 3 months prior to randomization.
16.History or presence of malignancy within 5 years (with the exception of successfully treated basal cell carcinoma).
17.Inability to communicate or cooperate with the Investigator because of language difficulties or poor mental development or incapacitation.
18.A history (within the previous 3 years) or evidence of alcohol or drug abuse (including soft drugs like cannabis products).
19.Vaccination with a live vaccine with the exception of flu vaccine within the previous month. Coronavirus disease 2019 vaccination is not considered an exclusion criterion.
20.Any other condition which in the view of the Investigator is likely to interfere with the study or put the subject at risk.
21.Current participation or history of participation in an investigational trial in the last 30 days or 5 half-lives - whichever is longer.
E.5 End points
E.5.1Primary end point(s)
Percent change from Baseline in LS BMD at 12 months
Area under the percent change from Baseline in serum C-telopeptide of type 1 collagen up to 6 months (AUEC0 6months of %Cfb sCTX 1). Note: This endpoint will be considered as primary for EMA submission only; for all other agencies, this endpoint will be considered as secondary.
E.5.1.1Timepoint(s) of evaluation of this end point
12 months
E.5.2Secondary end point(s)
Efficacy endpoint
•Percent change from Baseline in LS BMD at 6 and 18 months
•Percent change from Baseline in hip and femoral neck BMD at 6, 12, and 18 months
•Incidence of new morphometric vertebral fractures at 12 and 18 months
Pharmacodynamic endpoint
•Percent change from Baseline in sCTX-1 at 3, 6, 9, 12, and 18 months
Safety endpoints
•Incidence, nature, and severity of adverse events including adverse drug reactions
•Frequency and severity of injection site reactions
•Frequency and severity of findings in routine safety parameters, including clinical laboratory assessments (hematology, clinical biochemistry, coagulation, urinalysis, and urine microscopy), vital signs, ECG, and physical examination
Immunogenicity endpoint
•Frequency and titer of anti-drug antibodies and frequency of neutralizing antibodies against AVT03 and Prolia at predose and Day 30, Day 90, Day 180, Day 270, Day 365 (Month 12), Month 15, and Month 18 (EoS) after treatment.
Pharmacokinetic endpoint
•Serum trough concentration of AVT03 and Prolia
E.5.2.1Timepoint(s) of evaluation of this end point
Efficacy endpoint - 6, 12 and 18 months.
Pharmakodynamic endpoint - 3, 6, 9, 12 and 18 months.
Immunogenicity endpoint - day 30, day 90, day 180, day 270, day 365, month 15, month 18.
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic Yes
E.6.7Pharmacodynamic Yes
E.6.8Bioequivalence No
E.6.9Dose response No
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others Yes
E.6.13.1Other scope of the trial description
Immunogenicity
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other No
E.7.1.3.1Other trial type description
E.7.2Therapeutic exploratory (Phase II) No
E.7.3Therapeutic confirmatory (Phase III) Yes
E.7.4Therapeutic use (Phase IV) No
E.8 Design of the trial
E.8.1Controlled Yes
E.8.1.1Randomised Yes
E.8.1.2Open No
E.8.1.3Single blind No
E.8.1.4Double blind Yes
E.8.1.5Parallel group Yes
E.8.1.6Cross over No
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) Yes
E.8.2.2Placebo No
E.8.2.3Other Yes
E.8.2.3.1Comparator description
Prolia
E.8.2.4Number of treatment arms in the trial2
E.8.3 The trial involves single site in the Member State concerned No
E.8.4 The trial involves multiple sites in the Member State concerned Yes
E.8.4.1Number of sites anticipated in Member State concerned3
E.8.5The trial involves multiple Member States Yes
E.8.5.1Number of sites anticipated in the EEA15
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA Yes
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
Bulgaria
Czechia
Georgia
Poland
South Africa
E.8.7Trial has a data monitoring committee No
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years2
E.8.9.1In the Member State concerned months4
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years2
E.8.9.2In all countries concerned by the trial months4
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 400
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 76
F.2 Gender
F.2.1Female Yes
F.2.2Male No
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations No
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception No
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state30
F.4.2 For a multinational trial
F.4.2.1In the EEA 401
F.4.2.2In the whole clinical trial 476
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
None
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2022-06-24
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2022-09-05
P. End of Trial
P.End of Trial StatusOngoing