| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Chronic Plaque-type Psoriasis |
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| E.1.1.1 | Medical condition in easily understood language |
| Moderate to Severe Chronic Plaque-type Psoriasis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037153 |
| E.1.2 | Term | Psoriasis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the therapeutic equivalence of AVT04 compared to EU-approved Stelara® (EU-Stelara) in the treatment of moderate to severe chronic plaque psoriasis (PsO). |
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| E.2.2 | Secondary objectives of the trial |
•To compare the safety, tolerability, and immunogenicity of AVT04 and EU Stelara in the treatment of moderate to severe chronic PsO.
•To compare steady-state pharmacokinetics of AVT04 and EU Stelara.
•To compare efficacy of AVT04 and EU Stelara in patients with moderate to severe chronic PsO.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patient has signed the informed consent form (ICF) and documentation as required by relevant competent authorities and is able to understand and adhere to the visit schedule and study requirements.
2.Patient is male or female, aged 18 to 75 years old, inclusive, at time of Screening.
3.Patient has had moderate to severe chronic PsO for at least 6 months.
4.Patient has involved body surface area ≥10%, PASI ≥12, and static Physician′s Global Assessment (sPGA) ≥3 (moderate) at Screening and at BL.
5.Patient has had stable psoriatic disease for at least 2 months (ie, without significant changes as defined by the investigator or designee) prior to Screening.
6.Patient is a candidate for systemic therapy because the patient has had a previous failure, inadequate response, intolerance, or contraindication to at least 1 systemic antipsoriatic therapy including, but not limited to, methotrexate, cyclosporine, psoralen plus ultraviolet light A (PUVA), and ultraviolet light B (UVB).
7.Patient has a negative QuantiFERON test for tuberculosis (TB) during Screening.
Note: Patients with an indeterminate QuantiFERON test are allowed if they have all of the following:
a.No evidence of active TB on chest radiograph within 3 months prior to the first dose of study drug.
b.Documented history of adequate prophylaxis initiation prior to receiving study drug in accordance with local recommendations.
c.No known exposure to active TB after most recent prophylaxis.
d.Asymptomatic at Screening and BL.
Investigators should check with the medical monitor before enrolling such patients.
8.Patient is naïve to ustekinumab therapy, approved or investigational.
9.Female patients are eligible to participate if they are NOT pregnant (with negative serum pregnancy test at Screening [refer to Appendix 14.5]), not breastfeeding, and at least ONE of the following conditions applies:
a.If a women of childbearing potential (WOCBP) -
i.agrees to use a highly effective method of contraception (Appendix 14.5) consistently and correctly from Screening (signing the ICF) until at least 15 weeks after investigational product (IP) administration or
ii.whose career, lifestyle, or sexual orientation precludes sexual intercourse with a male partner or
iii.having sexual intercourse exclusively with a sterile male partner
b.If not a WOCBP (non-WOCBP), defined as:
i.Surgically sterile (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, as confirmed by review of the patient’s medical records, medical examination, or medical history interview), or
ii.Postmenopausal (defined as no menses for 12 months without an alternative medical cause). A high follicle stimulating hormone [FSH] level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy [HRT]. Female patients on HRT and whose menopausal status is in doubt will be required to use 1 of the non-estrogen hormonal highly effective contraception methods (refer to Appendix 14.5) from Screening (signing the ICF) until at least 15 weeks after IP administration if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment
Note: Nonsterilized male patients with female partners of childbearing potential are eligible to participate if they agree to ONE of the following from Screening (signing the ICF) until at least 15 weeks after IP administration:
a.Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
b.Agree to use a male condom and have their partner use a contraceptive method with a failure rate of <1% per year as described in Appendix 14.5 when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
c.Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. In addition, male patients must refrain from donating sperm from Screening (signing the ICF) until at least 15 weeks after IP administration.
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| E.4 | Principal exclusion criteria |
1.Patient diagnosed with psoriatic arthritis,erythrodermic psoriasis,pustular psoriasis,guttate psoriasis,medication-induced psoriasis,other skin conditions,or other systemic autoimmune disorder at the time of the Screening Visit that would interfere with evaluations of the effect of the study drug on psoriasis.
2.Patient has prior use of any of the following medications within specified time periods or will require use during the study:
a.Topical medications within 2 weeks of BL visit (except low- to mid-potency topical corticosteroids on face,eyes,scalp,palms,soles,and genital area;only).
b.PUVA phototherapy and/or UVB phototherapy within 4 weeks prior to the BL visit.
c.Nonbiologic psoriasis systemic therapies (eg, cyclosporine,methotrexate,and acitretin) within 4 weeks prior to the BL visit.
d.Any systemic steroid in the 4 weeks prior to the BL visit.
e.Investigational agent(s) within 90 days or 5 half-lives (whichever is longer) before BL visit.
f.Other systemic biologics within 90 days or 5 half lives (whichever is the longer) before BL visit.
g.Any therapeutic agent targeting interleukin (IL)-12, IL-17 or IL-23 at any time (eg, Secukinumab,Briakinumab,Guselkumab,Ixekizumab,and Brodalumab).
Refer to the protocol table in Exclusion criteria for specified washout periods for products listed.
3.Patient has received live or attenuated vaccines during the 4 weeks prior to BL visit or has the intention of receiving a live or attenuated vaccine during the study.
Note: Inactivated (non-live and non-attenuated) vaccines are allowed.
4.Patient has an underlying condition (including, but not limited to metabolic,hematologic,renal,hepatic,pulmonary,neurologic,endocrine,cardiac,infectious,or gastrointestinal) which significantly immunocompromises the patient and/or places the patient at unacceptable risk for receiving an immunomodulatory therapy.
5.Patient has a planned surgical intervention during the duration of the study except those related to the underlying disease and which will not put the patient at further risk or hinder the patient′s ability to maintain compliance with study drug and the visit schedule.
6.Patient has an active infection or history of infections as follows:
a.Any active infection (including Severe Acute Respiratory Syndrome-Coronavirus-2 infection)
i.For which non-systemic anti-infectives were used within 4 weeks prior to BL visit.
Note: patients receiving topical antibiotics for facial acne do not need to be excluded.
ii.Which required hospitalization/quarantine or systemic anti-infective within 8 weeks prior to BL visit.
b.Recurrent or chronic infections or other active infection that,in the opinion of the investigator or designee, might cause this study to be detrimental to the patient.
c.Invasive fungal infection or mycobacterial infection.
d.Opportunistic infections, such as listeriosis, legionellosis, or pneumocystis.
7.Patient is positive for human immunodeficiency virus, hepatitis C virus antibody, hepatitis B surface antigen, and/or hepatitis B core antibody.
8.Patient has severe progressive or uncontrolled, clinically significant disease that in the judgment of the investigator or designee renders the patient unsuitable for the study.
9.Patient has a history of malignancy within 5 years except for adequately treated cutaneous squamous or basal cell carcinoma, in situ cervical cancer or in situ breast ductal carcinoma.
10.Patient has active neurological disease such as multiple sclerosis,Guillain-Barré syndrome,ptic neuritis,transverse myelitis,or history of neurologic symptoms suggestive of central nervous system demyelinating disease.
11.Patient has moderate to severe heart failure(New York Heart Association class III/IV).
12.Patient has uncontrolled diabetes mellitus type 1 or 2 in the judgement of the investigator.
13.Patient has a history of hypersensitivity to the active substance or to any of the excipients of EU Stelara or AVT04.
14.Patient has evidence (as assessed by the investigator or designee using good clinical judgment) of alcohol or drug abuse or dependency at the time of Screening, for the 5 years prior to Screening, or during the study.
15.Patient is unable to follow study instructions and comply with the protocol in the opinion of the investigator or designee.
16.Patient has a history of clinically significant hematological abnormalities, including cytopenia (eg,thrombocytopenia,leukopenia).
17.Patient has a laboratory abnormality that could cause this study to be detrimental to the pat. The following laboratory abnormalities should be excluded:
a.Hemoglobin <9 g/dL
b.Platelet count <100,000/mm³
c.White blood cell count <3000 cells/mm³
d.AST and/or ALT that is persistently ≥2 × the upper limit of normal.(Persistently indicates at least on 2 occasions separated by a number of days,per the rescreening procedure)
e.Creatinine clearance <50 mL/min(Cockcroft-Gault formula)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent improvement in PASI from BL to Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints
•PASI 50, 75, 90, and 100 response rates at Weeks 4, 8, 12, 16, 28, 40 (EoT), and 52 (EoS).
•Percent improvement in PASI from BL to Week 4, 8, 16, 28, 40 (EoT), and 52 (EoS).
•Area under the effect curve for PASI from BL through Week 12.
•Proportion of patients achieving sPGA responses of clear (0) or almost clear (1) at Weeks 4, 8, 12, 16, 28, 40 (EoT), and 52 (EoS).
•Change in Dermatology Life Quality Index scores from BL to Weeks 12, 28, 40 (EoT), and 52 (EoS).
•Change in percentage body surface area affected by chronic PsO from BL to Weeks 4, 8, 12, 16, 28, 40 (EoT), and 52 (EoS).
Safety endpoints
•Frequency, type and severity of treatment-emergent adverse events including adverse drug reactions.
•Frequency and severity of injection site reactions (ISRs).
•Routine safety parameters, including laboratory safety, vital sign measurements, 12-lead electrocardiogram (ECG) results, chest X ray, and physical examination findings.
Pharmacokinetic endpoint
•Serum trough concentrations at steady-state.
Immunogenicity endpoint
•Proportion of patients with ADAs at Weeks 4, 12, 16, 28, 40 (EoT), and 52 (EoS).
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints
• PASI: Weeks 4, 8, 12, 16, 28, 40, and 52.
• sPGA: at Weeks 4, 8, 12, 16, 28, 40, and 52.
• Dermatology Life Quality Index: Weeks 12, 28, 40, and 52.
• Body surface area affected by chronic PsO: Weeks 4, 8, 12, 16, 28, 40, and 52.
Safety endpoints
• Frequency.
Pharmacokinetic endpoint
• Serum trough concentrations at steady-state.
Immunogenicity endpoint
• Anti-drug antibodies: at Weeks 4, 12, 16, 28, 40, and 52.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Georgia |
| Ukraine |
| Estonia |
| Poland |
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| E.8.7 | Trial 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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