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Pharmacokinetics, Safety and Tolerability Study of AVT04 to EU Approved and US Licensed Stelara (Ustekinumab)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04744363
Recruitment Status : Completed
First Posted : February 9, 2021
Last Update Posted : May 23, 2022
Sponsor:
Collaborator:
Iqvia Pty Ltd
Information provided by (Responsible Party):
Alvotech Swiss AG

Brief Summary:

Protocol Title:

A Phase 1, first-in-human, randomized, double-blind, single-dose, parallel-group, 3-arm study comparing the pharmacokinetic, safety, tolerability, and immunogenicity profiles of AVT04, EU approved Stelara®, and US-licensed Stelara® in healthy adult subjects

Short Title:

A first-in-human randomized, double-blind study to compare AVT04 with EU-approved Stelara and US-licensed Stelara as a single-dose subcutaneous injection in healthy adult subjects

Rationale:

Alvotech (hereafter, the Sponsor) is developing AVT04 globally as a proposed biosimilar to the reference product Stelara (ustekinumab) for subcutaneous (SC) use. This is a first-in-human (FIH) clinical study with AVT04. The study aims to demonstrate pharmacokinetic (PK) similarity of the proposed biosimilar test product AVT04 and the reference products EU approved Stelara and US-licensed Stelara, in addition to evaluating the safety and tolerability of AVT04, when administered as a single 45 mg/0.5 mL SC dose.


Condition or disease Intervention/treatment Phase
Psoriasis Drug: Stelara PFS Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 294 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A Phase 1, first-in-human, randomized, double-blind, single-dose, parallel-group, 3-arm study comparing the pharmacokinetic, safety, tolerability, and immunogenicity profiles of AVT04, EU approved Stelara®, and US licensed Stelara® in healthy adult subjects
Masking: Single (Investigator)
Masking Description: Blinded and unblinded site teams
Primary Purpose: Treatment
Official Title: Phase 1, FIH, Randomized, Double-blind, Single-dose, Parallel-group, 3-arm Study Comparing the PK, Safety, Tolerability, and Immunogenicity Profiles of AVT04, EU-approved Stelara®, and US-licensed Stelara® in Healthy Adult Subjects
Actual Study Start Date : May 25, 2021
Actual Primary Completion Date : March 19, 2022
Actual Study Completion Date : March 19, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Ustekinumab

Arm Intervention/treatment
Experimental: AVT04 45 mg SC
Single dose Pre-filled syringe to be injected subcutaneously into thigh or abdomen
Drug: Stelara PFS
Pre filled syringes filled with AVT04 and Stelara
Other Name: Ustekinumab

Active Comparator: US Stelara 45 mg SC
Single dose Pre-filled syringe to be injected subcutaneously into thigh or abdomen
Drug: Stelara PFS
Pre filled syringes filled with AVT04 and Stelara
Other Name: Ustekinumab

Active Comparator: EU Stelara 45 mg SC
Single dose Pre-filled syringe to be injected subcutaneously into thigh or abdomen
Drug: Stelara PFS
Pre filled syringes filled with AVT04 and Stelara
Other Name: Ustekinumab




Primary Outcome Measures :
  1. Area under the plasma concentration-time curve AUC0-inf [ Time Frame: From Baseline to day 92 ]
    Venous blood samples will be collected for measurement of Area under the plasma concentration-time curve (AUC 0-t) of AVT04, US Stelara EU Stelara

  2. Maximum serum concentration [ Time Frame: From Baseline to day 92 ]
    Venous blood samples will be collected for measurement of serum concentration of AVT04, EU Stelara, US Stelara


Secondary Outcome Measures :
  1. Ustekinumab serum concentration-time profile following single-dose administration [ Time Frame: From Baseline to day 92 ]
    Venous blood samples will be collected for measurement of serum concentration time profile of AVT04, US-Stelara EU Stelara

  2. The secondary PK parameters to be assessed are: AUC0-t [ Time Frame: From Baseline to day 92 ]
    Venous blood samples will be collected for measurement of the title measures of AVT04, US-Stelara EU Stelara

  3. Adverse Events [ Time Frame: From screening to day 92 ]
    The safety parameters to be assessed include AEs, clinical laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis and urine microscopy), vital signs, ECG, physical examination findings, and injection site reactions

  4. Immunogenicity assessments include ADAs and NAbs [ Time Frame: From screening to day 92 ]
    Formation of neutralizing antibodies measured through a validated system

  5. The secondary PK parameters to be assessed are: Tmax [ Time Frame: From screening to day 92 ]
    Venous blood samples will be collected for measurement of the title measures of AVT04, US-Stelara EU Stelara

  6. The secondary PK parameters to be assessed are: Kel [ Time Frame: From Screening to day 92 ]
    Venous blood samples will be collected for measurement of the title measures of AVT04, US-Stelara EU Stelara

  7. The secondary PK parameters to be assessed are: t1/2 [ Time Frame: From Screening to day 92 ]
    Venous blood samples will be collected for measurement of the title measures of AVT04, US-Stelara EU Stelara

  8. The secondary PK parameters to be assessed are: Vz/F [ Time Frame: From screening to day 92 ]
    Venous blood samples will be collected for measurement of the title measures of AVT04, US-Stelara EU Stelara

  9. The secondary PK parameters to be assessed are: CL/F [ Time Frame: From Screening to day 92 ]
    Venous blood samples will be collected for measurement of the title measures of AVT04, US-Stelara EU Stelara


Other Outcome Measures:
  1. The inflammatory cytokine biomarkers to be assessed include: IFN-γ, IL-22, IL-17, IL-5, IL-13, and IL-10 [ Time Frame: From screening to day 92 ]
    Venous blood samples will be collected to assess the cytokine biomarkers



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Subjects are eligible to be included in the study only if all of the following criteria apply at any time starting from Screening up to Day 1 prior to IP administration:

  1. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol.
  2. Male or female subjects.
  3. Subjects must be 18 to 55 years old inclusive, at the time of signing the ICF.
  4. Have a body weight of 60.0 to 90.0 kg (inclusive) and body mass index (BMI) of 18.5 to 30.0 kg/m2 (inclusive).
  5. For Japanese subjects only Is a second-generation Japanese person living abroad and both parents and grandparents are of Japanese origin, OR Was born in Japan and both parents and grandparents are of Japanese origin.
  6. Medical history without major pathology, according to the PI's judgment.
  7. Resting supine systolic blood pressure (BP) of ≤140 mm Hg and diastolic BP of ≤90 mm Hg; other vital signs showing no clinically relevant deviations according to the PI's judgment.
  8. Computerized (12-lead) electrocardiogram (ECG) recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the PI.
  9. Glycated hemoglobin (HbA1c) ≤42 mmol/mol.
  10. Clinical safety laboratory results are within the reference ranges or showing no clinically relevant deviations as judged by the PI.
  11. Have a negative urine drug screen (opiates, methadone, cocaine, amphetamines [including ecstasy and methamphetamines], cannabinoids, barbiturates, and benzodiazepines) and a negative alcohol breath test.
  12. Tested negative for TB, hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBc), anti-hepatitis C virus (HCV) antibodies, and anti-human immunodeficiency virus (HIV) 1/2 antibodies at Screening.
  13. Nonsmoker or occasional smoker, ie, smokes ≤10 cigarettes (or equivalent of tobacco- or nicotine containing products) per week within 3 months of Screening, and ability and willingness to refrain from smoking during confinement at the study site.
  14. Ability and willingness to abstain from alcohol from 48 hours prior to drug administration, during confinement at the study site until discharge, and 24 hours prior to ambulatory visits.
  15. Female subjects are eligible to participate if they are not pregnant (see Appendix 3), not breastfeeding, and at least ONE of the following conditions applies:

    1. Is not a woman of childbearing potential (WOCBP), defined as:

      Surgically sterile (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, as confirmed by review of the subject's medical records, medical examination, or medical history interview), or 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]. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). Female subjects on HRT and whose menopausal status is in doubt will be required to use 1 of the non estrogen hormonal highly effective contraception methods (Appendix 3) from Screening (signing the ICF) until at least 13 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.

    2. Is a WOCBP who agrees to use a highly effective method of contraception (Appendix 3) consistently and correctly from Screening (signing the ICF) until at least 13 weeks after IP administration.
  16. Nonsterilized male subjects 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 13 weeks after IP administration:

    1. 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.
    2. Agree to use a male condom and have their partner use of a contraceptive method with a failure rate of <1% per year as described in Appendix 3 when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
    3. Male subjects 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.
  17. In addition, male subjects must refrain from donating sperm from Screening (signing the ICF) until at least 13 weeks after IP administration.

Exclusion Criteria:

Subjects are excluded from the study if any of the following criteria apply at any time starting from Screening up to Day 1 prior to IP administration:

  1. Have a history of relevant drug and/or food allergies.
  2. Have a history of hypersensitivity to Stelara, AVT04, or their constituents.
  3. Have a known history of previous exposure to IL-12 and/or IL-23 inhibitors.
  4. Have any past or concurrent medical conditions that could potentially increase the subject's risks or that would interfere with the study evaluation, procedures, or study completion. Examples of these include medical history with evidence of clinically relevant pathology (eg, malignancies or demyelinating disorders).
  5. Presence of chronic obstructive pulmonary disease. Childhood asthma is allowed.
  6. Presence of type 1 or 2 diabetes mellitus.
  7. Have a known history of active or latent TB, except for subjects with documented and complete adequate treatment of TB or initiation (>1 month) of adequate prophylaxis of latent TB, with an isoniazid-based regimen.
  8. Have resided or traveled in regions where tuberculosis and mycosis are endemic within 90 days before Screening, or who intend to visit such a region during the study period or within 3 months (12 weeks) after dosing.
  9. Any current active infections, including localized infections, or any recent history (within 1 week prior to study drug administration) of active infections (including severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] based on a positive COVID-19 polymerase chain reaction [PCR] nasopharyngeal swab test), cough or fever, or a history of recurrent or chronic infections.
  10. Participation in a clinical study with an IP within 60 days or 5 half-lives of that IP (if known), whichever is longer, prior to IP administration in the current study.
  11. Treatment with nontopical medications (including over-the-counter [OTC] medications and herbal remedies such as St. John's Wort extract) within 7 days or 5 half lives of the drug (whichever is longer) prior to IP administration, with the exception of multivitamins, vitamin C, food supplements and a limited amount of acetaminophen (up to 2 g in 24 hours, but <1 g in 4 hours) or ibuprofen (<1.2 g per day), which may be used throughout the study.
  12. Have received live vaccines during the past 4 weeks before Screening or have the intention to receive vaccination during the study period or within 13 weeks after dosing.
  13. Donation of more than 500 mL of blood within 8 weeks prior to drug administration.
  14. History of alcohol abuse (with an average intake exceeding 10 drinks/week for women and 15 drinks/week for men: 1 drink = 360 mL of beer, 150 mL of wine, or 45 mL of spirits) or drug addiction (including soft drugs like cannabis products).
  15. Any persons who are:

    1. An employee of the study site, Investigator, contract research organization (CRO) or Sponsor;
    2. A first-degree relative of an employee of the study site, the Investigator, CRO, or the Sponsor.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04744363


Locations
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Australia
Nucleus Network
Brisbane, Australia
Nucleus Network Melbourne
Melbourne, Australia, 3004
New Zealand
ACS
Auckland, New Zealand, 1010
CCST
Christchurch, New Zealand, 8011
Sponsors and Collaborators
Alvotech Swiss AG
Iqvia Pty Ltd
Investigators
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Study Director: Paul Duijzings, MSc Program Lead
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Responsible Party: Alvotech Swiss AG
ClinicalTrials.gov Identifier: NCT04744363    
Other Study ID Numbers: AVT04-GL-101
First Posted: February 9, 2021    Key Record Dates
Last Update Posted: May 23, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Psoriasis
Skin Diseases, Papulosquamous
Skin Diseases
Ustekinumab
Dermatologic Agents