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    Summary
    EudraCT Number:2020-005999-36
    Sponsor's Protocol Code Number:HZNP-TEP-402
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-12-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-005999-36
    A.3Full title of the trial
    A Phase 3b/4, Double-masked, Randomized, International, Parallel-assignment, Multicenter Trial in Patients with Thyroid Eye Disease to Evaluate the Safety and Tolerability of Different Dosing Durations of Teprotumumab
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of thyroid eye disease with Teprotumumab infusions of varying treatment lenghts in a randomized clinical study to observe safety and tolerability
    A.3.2Name or abbreviated title of the trial where available
    TEPEZZA (teprotumumab-trbw) Post-Marketing Requirement
    A.4.1Sponsor's protocol code numberHZNP-TEP-402
    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 SponsorHorizon Therapeutics U.S.A., Inc.
    B.1.3.4CountryUnited States
    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 supportHorizon Therapeutics U.S.A. Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHorizon Therapeutics USA, Inc.
    B.5.2Functional name of contact pointMedical Director
    B.5.3 Address:
    B.5.3.1Street Address1 Horizon Way
    B.5.3.2Town/ cityDeerfield
    B.5.3.3Post codeIL 60015
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1504 251 4115
    B.5.6E-mailclinicaltrials@horizontherapeutics.com
    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 Yes
    D.2.1.1.1Trade name TEPEZZA
    D.2.1.1.2Name of the Marketing Authorisation holderHorizon Therapeutics U.S.A
    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 nameTEPROTUMUMAB
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTEPROTUMUMAB
    D.3.9.1CAS number 89957-37-9
    D.3.9.2Current sponsor codeHZN-001
    D.3.9.4EV Substance CodeSUB178558
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number48 to 50
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Thyroid Eye Disease (TED)
    E.1.1.1Medical condition in easily understood language
    Graves' ophthalmopathy
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10057889
    E.1.2Term Graves' ophthalmopathy
    E.1.2System Organ Class 100000004853
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The overall objective is to investigate the safety, tolerability and need for re-treatment of 3 different teprotumumab treatment durations in patients with Thyroid Eye Disease (TED).
    E.2.2Secondary objectives of the trial
    1. Change in proptosis measurement in the study eye
    2. Proptosis responder rate
    3. The overall responder rate
    4. Binocular diplopia responder rate
    5. Binocular diplopia resolution rate
    6. Change from Baseline in Graves’ Ophthalmopathy QoL quest appearance and visual functioning subscales
    7. Rate of flare at end of the Initial FU Period
    8. Time to proptosis response during the Initial Treatm. Period
    9. CAS:
    - % pts with a CAS of 0 or 1 who had active disease (CAS ≥3) at Baseline
    - % pts who improve on the following CAS items: Spontaneous orbital pain & gaze-evoked orbital pain
    10. Durab of complete response at the end of the Initial FU Period
    11. Durab of response at the last assessment in the Initial FU-Period
    12. % pts with at least 1TEAE assessed as Grade 3 or higher
    13. % pts with at least 1 post-baseline abnormal lab result of Grade 3 or higher
    14. Effect of teprotumumab the mean change from Baseline over time in serum biomarkers for pts with a Baseline CAS ≥3

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible patients must meet/provide all of the following criteria:
    1. Written informed consent.
    2. Male or female between the ages of 18 and 80 years, inclusive, at Screening.
    3. Initial diagnosis of TED within 7 years prior to Screening.
    4. Proptosis ≥3 mm from baseline (prior to diagnosis of TED), as estimated by treating physician, and/or proptosis >3 mm above normal for race and gender.
    5. Patients must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels <50% above or below the normal limits) at Screening. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the duration of the trial.
    6. Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the trial.
    7. Diabetic patients must have HbA1c ≤8.0% at Screening.
    8. Patients with a history of IBD (ulcerative colitis or Crohn’s disease) must be in clinical remission for at least 3 months, with no history of bowel surgery within 6 months prior to Screening and no planned surgery during the trial. Concomitant stable therapies for IBD without modifications in the 3 months prior to Screening are allowed.
    9. Women of childbearing potential (including those with an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for <12 months prior to Screening or not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum pregnancy test at Screening and negative urine pregnancy tests at all protocol-specified time points (i.e., prior to each dose and throughout the patient's participation in the Follow-up Period); patients who are sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of contraception during the trial, 1 of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started at least 1 full cycle prior to Baseline and continue for 180 days after the last dose of teprotumumab. Highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include implants, injectables, tubal ligation, combination oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner.
    10. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
    E.4Principal exclusion criteria
    Patients will be ineligible for trial participation if they meet any of the following criteria:
    1. Decreased best-corrected visual acuity due to optic neuropathy, as defined by a decrease in vision of
    2 lines on the Snellen chart, new visual field defect or color defect secondary to optic nerve involvement within the last 6 months.
    2. Corneal decompensation unresponsive to medical management.
    3. Decrease in proptosis of ≥2 mm in the study eye between Screening and Baseline.
    4. Prior orbital irradiation, orbital decompression or strabismus surgery.
    5. Planned eyelid surgery during the course of the trial.
    6. Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal or estimated glomerular filtration rate ≤30 mL/min/1.73m2 at Screening.
    7. Use of any steroid (intravenous, oral, steroid eye drops) for the treatment of TED or other conditions within 3 weeks prior to Screening. Steroids cannot be initiated during the trial. Exceptions include topical and inhaled steroids, as well as steroids used to treat infusion reactions.
    8. Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of teprotumumab or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of teprotumumab. Use of any other non-steroid immunosuppressive agent within 3 months prior to the first infusion of teprotumumab.
    9. Any previous treatment with teprotumumab, including previous enrollment in this trial or participation in a prior teprotumumab trial.
    10. Treatment with any monoclonal antibody within 3 months prior to Screening.
    11. Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results.
    12. Use of an investigational agent for any condition within 60 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.
    13. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
    14. Pregnant or lactating women.
    15. Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the patient.
    16. Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions to monoclonal antibodies.
    17. Human immunodeficiency virus, untreated or positive viral load for hepatitis C or hepatitis B infections.
    18. Any other condition that, in the opinion of the Investigator, would preclude inclusion in the trial.
    19. After 150 patients with a CAS <3 at Baseline have been randomized, an additional exclusion criterion will apply: CAS <3 at Baseline.
    E.5 End points
    E.5.1Primary end point(s)
    - The percentage of patients who experience at least 1 TEAE and the percentage of patients who experience at least 1 treatment-emergent AESI during treatment with teprotumumab.
    - The percentage of patients who receive re-treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the whole study
    E.5.2Secondary end point(s)
    1. Mean change from Baseline in proptosis measurement in the study eye.
    2. Proptosis responder rate (percentage of patients with a ≥2-mm reduction from Baseline in proptosis in the study eye, without deterioration [≥2-mm increase] of proptosis in the fellow eye).
    3.The overall responder rate (percentage of patients with ≥2-point reduction in CAS AND ≥2-mm reduction in proptosis from Baseline in the study eye, provided there is no corresponding deterioration [≥2 point/mm increase] in CAS or proptosis in the fellow eye).
    4. The binocular diplopia responder rate (percentage of patients with baseline binocular diplopia >0 who have a reduction of ≥1 grade).
    5. The binocular diplopia resolution rate (percentage of patients with baseline binocular diplopia >0 who have no binocular diplopia).
    6. Mean change from Baseline in the GO-QoL questionnaire appearance and visual functioning sub-scales.
    7. Rate of flares at the end of the Initial Follow-up Period.
    8. Time to proptosis response from the first infusion until the end of the Initial Treatment Period.
    9. CAS:
    - Proportion of patients with a CAS ≥3 at Baseline who have a CAS of 0 or 1 at the end of the Initial Treatment Period
    - Proportion of patients who improve on individual questions on the CAS for
    - spontaneous orbital pain
    - gaze-evoked orbital pain.
    10. Proportion of patients with complete response at the end of the Initial Follow-up Period, as defined by durability of complete response.
    11. Proportion of patients with response at the last assessment in the Initial Follow-up Period, as defined by durability of response at the last assessment in the Initial Follow-up Period.
    12. Mean change from Baseline over time in disease biomarkers for patients with a Baseline CAS ≥3.
    All other endpoints, except the time to proptosis response, rate of flares at the end of the Initial Follow-up Period, durability of complete response and durability of response at the last assessment in the Initial Follow-up Period, will be assessed by randomized cohort at the end of the Initial Treatment Period, at the end of the Initial Follow-up Period. For patients who require re-treatment, the same endpoints will be estimated at the end of the 24-week Re-treatment Period.
    Safety and Tolerability Endpoints
    1. Incidence of TEAEs, SAEs, TEAEs resulting in premature discontinuation of treatment and treatment-emergent AESIs (infusion reactions, hyperglycemia, hearing impairment, new onset IBD and exacerbation of IBD).
    2. Incidence of ≥Grade 3 TEAEs.
    3. Incidence of ≥Grade 3 laboratory evaluations, in which CTCAE grading is available.
    4. The results of best-corrected visual acuity.
    PK and ADA Endpoints
    1. Peak and trough concentrations of teprotumumab.
    2. ADA incidence and titers.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline; Week 12 and Week 24 and Week 48 (for the cohort 3)
    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 No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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
    Tolerability
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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
    Germany
    Italy
    Spain
    United Kingdom
    United States
    France
    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 years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    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: 252
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 300
    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)
    Standard of Care
    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 Decision2022-02-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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