| Eligibility |
Inclusion Criteria:
1. Healthy males aged 28 - 65 years, both inclusive;
2. Body mass index (BMI) between 18 to < 30 kg/m2 and body weight of 60 - 90 kg (both
inclusive);
3. Subjects must give written informed consent before any assessment is performed and has
to understand the study and must be willing to follow and complete all the test
procedures;
4. Clinically acceptable physical exams and laboratory tests (blood hematology, blood
chemistry, coagulation, urinalysis) and no history or evidence of any clinically
significant medical disorder that would pose a risk to subject safety or interfere
with study evaluations or procedures;
5. Available for long term clinical assessments (36 weeks post-dose) for PK/PD and
immunogenicity assessments;
6. Subjects and their female partners who are of childbearing potential must be using 2
forms of birth control (1 of which is a highly effective method† and 1 must be a
barrier method‡) or abstain from sexual intercourse with a female partner (acceptable
only if it is the subject's usual form of birth control/lifestyle choice) starting at
Day -1 and throughout the study period and for at least 1 month after the end of EoS
Visit. A condom is required to be used also by vasectomized men to prevent delivery of
the drug via seminal fluid.
Highly effective forms of birth control include (i.e., less than 1% failure rate per year
when used consistently and correctly):
- hormonal contraception, i.e., oral, injectable or implantable hormonal contraceptives
for the female partner (Note: Not all oral contraception methods have a low failure
rate.).
- hormonal or non-hormonal intrauterine device (IUD), established IUD (loop) or
intrauterine system for the female partner.
- the subject has undergone effective surgical sterilization before he entered the
study.
- the subject's female partner has undergone effective surgical sterilization before the
subject entered the clinical trial and she is the sole sexual partner of the subject
during the study.
Acceptable methods of surgical sterilization are:
- Surgical bilateral oophorectomy for the female partner (with or without hysterectomy)
at least 6 weeks before the SCR Visit.
- Hysterectomy for the female partner at least 6 weeks before the SCR Visit.
- Bilateral tubal ligation for the female partner at least 6 weeks before the SCR Visit.
Barrier methods of birth control:
- Condom without spermicidal foam / gel / film / cream / suppository or fat- or
oil-containing lubricant.
- Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam / gel / film /
cream / suppository for the female partner.
Exclusion Criteria:
1. Subjects with prior exposure to denosumab (Prolia, Xgeva, or biosimilar denosumab);
2. Use of any other monoclonal antibodies or fusion proteins within the 3 months or 5
half-lives (whatever is longer) before the date of administration of the IMP;
3. Subjects being on a special diet or with significant weight loss from a weight
reduction diet (e.g., more than approx. 5 kg within 1 month) before the SCR Visit or
unwilling to maintain the same weight for the duration of the study;
4. Donation or loss of = 500 mL of blood within 8 weeks prior to dosing, or longer if
required by local regulation. Plasma donation within 28 days prior to dosing;
5. Diseases and conditions that affect bone metabolism e.g., osteoporosis,
hypo/hyper-parathyroidism (excluding isolated deviations of parathormone assessed as
not clinically significant); hypo-/hyperthyroidism, Cushing's syndrome, malabsorption
syndromes, rheumatoid arthritis, psoriatic arthritis, osteomalacia, bone fractures
within 6 months, or any contraindications to denosumab therapy;
6. Vitamin D deficiency (serum 25-hydroxy vitamin D < 20 ng/mL). For subjects with
vitamin D deficiency, a single attempt at oral replenishment with re-evaluation prior
to randomization is permitted (see Section 5.5);
7. Subjects with systolic blood pressure (SBP) = 140 mmHg or diastolic blood pressure
(DBP) = 90 mmHg and / or pulse < 50 or > 90 bpm (mean of triplicate measurements.
Subjects with pulse rate between 45 and 50 bpm (inclusive) may be enrolled provided
they have a normal thyroid function, no clinical symptoms associated with the
bradycardia and no apparent signs of other diseases causing bradycardia (e.g.,
cardiovascular disease);
8. Subjects with abnormal ECGs (QTcF > 450 ms, signs of ischemia, sinus tachycardia
[heart rate, HR > 90] or sinus bradycardia [HR < 50], ventricular conduct delay [QRS >
120 ms] or others) which, in the judgment of the Investigator or any of the
Sub-Investigators, may be clinically relevant. Subjects with heart rate between 45 and
50 bpm (inclusive) may be enrolled provided they have a normal thyroid function, no
clinical symptoms associated with the bradycardia and no apparent signs of other
diseases causing bradycardia (e.g., cardiovascular disease). Potential cardiovascular
disease resulting in bradycardia should be excluded by further investigations on the
discretion of the Investigator;
9. Any clinically relevant laboratory findings that, in the opinion of the Investigator,
would preclude inclusion in the trial; subjects with creatinine above Upper Limit of
Normal (ULN) or liver enzymes (alanine aminotransferase [ALT], aspartate
aminotransferase [AST]) 1.5-fold above ULN will be excluded;
10. Subject presents with any psychiatric disorder, which may prevent the subject from
completing the study or interfere with the interpretation of the study results;
11. Subjects with current or a history of clinically significant (or "serious") skin
infections or skin disorders;
12. Subject has a history or presence of anemia or coagulopathy;
13. Significant changes in physical activity during the 6 months before IMP administration
or constant levels of intense physical exercise;
14. Positive test results for hepatitis B surface antigen (HbsAg), anti-hepatitis B core
(anti-HBc) antibodies indicative of active hepatitis, optionally Hepatitis B surface
antibody (anti-HBS), hepatitis A virus antibodies (immunoglobulin M [IgM]), hepatitis
C virus (HCV) antibodies and / or human immunodeficiency virus (HIV) type-1 and / or
type-2 antibodies at the SCR Visit;
15. Use of any prescription drug or any over-the-counter (OTC) drug within the 2 weeks (or
less than 5 x the half-life of that medication, whichever is longer) including herbal
supplements, or prescribed/ non-prescribed marijuana derivatives before the date of
administration of the IMP (excluding localized use not intended to have systemic
action and occasional use of paracetamol of up to 2 g per day), which, in the judgment
of the Investigator or Sub-Investigators, may affect participation in this clinical
study. Vitamins, minerals and nutritional supplements may be taken at the discretion
of the Investigator;
16. Prior use of any medications that may affect bone turnover within 12 months of IMP
administration and for the duration of the study. This includes medications such as,
but not limited to: bisphosphonates, fluoride, or selective estrogen receptor
modulator, such as ralaxofene, calcitonin, strontium, parathyroid hormone or
derivatives, supplemental vitamin D [> 1000 IU/day], except for the potential vitamin
D replenishment after SCR, glucocorticosteroids, anabolic steroids, calcitriol,
diuretics. Current use of anti-angiogenic drugs;
17. Receiving or has received any investigational drug (or is currently using an
investigational device) within 60 days before receiving IMP, or at least 10 times the
respective elimination half-life (whichever period is longer) and for the duration of
the study;
18. Men with partners who are pregnant or planning to become pregnant while the subject is
on study until through at least 1 month after the end of the study;
19. Intent to donate sperm during the study through at least 1 month after the end of the
study;
20. Unwilling or unable to limit alcohol consumption throughout the course of the study.
Alcohol is prohibited 24 hours prior to each visit in the clinical and throughout
confinement. Alcohol is also limited to no more than 168 g pure alcohol per week (10 g
pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%])
during the outpatient period.;
21. Positive urine screen for alcohol and/or drugs with a high potential for abuse at SCR
or Day -1;
22. Any other condition that might reduce the chance of obtaining data required by
protocol or that might compromise the ability to give truly informed consent and/or
comply with study procedures;
23. Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental
procedures (e.g., tooth extraction, dental implants, oral surgery in the past 6
months), or planned invasive dental procedure during the study; poor oral hygiene,
periodontal, and/or pre-existing dental disease;
24. Subject with known hypersensitivity to denosumab or any monoclonal /or polyclonal
antibodies or previously received denosumab treatment or to any of the excipients of
the IMPs;
25. Known allergies, hypersensitivity, or intolerance to protein-based therapies or to any
ingredients (including excipients) of the additional medication (vitamin D, in case
replenishment is given) or with a history of any significant drug allergy (e.g.,
anaphylaxis, hepatotoxicity, immune-mediated thrombocytopenia or anemia) including
latex;
26. Corrected serum calcium of < Lower Limit of Normal (LLN) or > ULN at SCR;
27. Individuals with history of tuberculosis or diagnosed with active or latent
tuberculosis by interview or interferon-gamma release assay;
28. Vaccinations must be completed 6 weeks prior to dosing in case multiple vaccinations
are required and no further vaccinations until the EoS. COVID-19 related vaccinations
should not be done within at least 3 weeks prior to SCR and until 3 weeks after
dosing. COVID-19 vaccinations should not be done or be planned from 2 days before or
on the same day as any ambulatory visits;
29. Participants who smoke more than 10 cigarettes per day or consume equivalent nicotine
substitutes, including e-cigarettes or inability to refrain from smoking during the
in-house period;
30. Any disease or condition that in the opinion of Investigator, may affect the patient
safety or the study results;
31. Subject has a positive test result for SARS-CoV-2 in RT-PCR testing before
randomization;
32. Subject has clinical signs and symptoms consistent with COVID-19, e.g., fever, dry
cough, dyspnea, sore throat, fatigue or confirmed infection by appropriate laboratory
test within the last 30 days prior to SCR or on admission;
33. Subject who had severe course of COVID-19 (i.e., hospitalization, extracorporeal
membrane oxygenation (ECMO), and/or mechanically ventilated);
34. Vulnerable subjects (i.e., persons under any administrative or legal supervision or
persons kept in detention);
35. Subjects who are employees of Sponsor, clinical research organization (CRO) or who is
the Investigator or any Sub-Investigator, research assistant, pharmacist, study
coordinator, other site staff or relative thereof directly involved in the conduct of
the clinical study;
36. Subjects who are not able to read, speak and understand the German language.
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