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    The EU Clinical Trials Register currently displays   42159   clinical trials with a EudraCT protocol, of which   6934   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2018-003809-26
    Sponsor's Protocol Code Number:MK-3475-905
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-05
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2018-003809-26
    A.3Full title of the trial
    A Randomized Phase 3 Study Evaluating Cystectomy with Perioperative Pembrolizumab and Cystectomy with Perioperative Enfortumab Vedotin and Pembrolizumab versus Cystectomy Alone in Participants who are Cisplatin-Ineligible or Decline Cisplatin with Muscle-Invasive Bladder Cancer (KEYNOTE-905/EV-303)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 trial of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab for cisplatin-ineligible participants with MIBC
    A.4.1Sponsor's protocol code numberMK-3475-905
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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 supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form 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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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) Yes
    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 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 Padcev (Enfortumab Vedotin)
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma US, 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 nameEnfortumab Vedotin
    D.3.4Pharmaceutical form Powder 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 INNENFORTUMAB VEDOTIN
    D.3.9.3Other descriptive nameENFORTUMAB VEDOTIN
    D.3.9.4EV Substance CodeSUB185524
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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
    Muscle-invasive Bladder Cancer (MIBC)
    E.1.1.1Medical condition in easily understood language
    Participants with muscle-invasive urothelial carcinoma who are ineligible for cisplatin-based chemotherapy
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10022877
    E.1.2Term Invasive bladder cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To compare pathologic complete response (pCR) rates between Arm A (preoperative pembrolizumab and radical cystectomy plus pelvic lymph node dissection [RC+PLND]) and Arm B (RC+PLND) and between Arm C (preoperative enfortumab vedotin in combination with pembrolizumab and RC+PLND) and Arm B
    2. To compare EFS between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND) and between Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and RC+PLND) and Arm B.
    E.2.2Secondary objectives of the trial
    1. To compare OS between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND) and between Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and RC+PLND) and Arm B.
    2. To assess DFS in participants from Arm A (perioperative pembrolizumab and RC+PLND), Arm B (RC+PLND), and Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and RC+PLND) who are disease free after surgery.
    3. To compare the rates of pDS between Arm A and Arm B and between Arm C and Arm B.
    4. To evaluate the safety and tolerability of perioperative pembrolizumab with RC+PLND and perioperative enfortumab vedotin in combination with pembrolizumab with RC+PLND.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Have a histologically confirmed diagnosis of urothelial carcinoma (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology to be confirmed by BICR (central pathology and/or imaging):
    * T1 disease (eligible only with N1 disease) and T2 disease will be confirmed by central pathology review and T3, T4a, N0 and N1 disease will be confirmed by central imaging review.
    * Participants with mixed histology are eligible provided the urothelial component is ≥50% as noted above (participants whose tumors contain predominant [≥50%] plasmacytoid variant are not eligible).
    * Participants whose tumors contain any neuroendocrine histology are not eligible.
    * UCs not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible. UCs invading into the prostatic stroma with no histologic muscle invasion is allowed, provided that the extent of disease is confirmed via imaging.
    -Have clinically nonmetastatic bladder cancer (N≤1M0) determined by imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR
    -Be deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines
    -Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria OR be eligible for treatment with cisplatin (by NOT meeting at least one of the following criteria) but decline treatment with cisplatin-based chemotherapy:
    *Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method Modification of Diet of Renal Disease (MDRD) equationsor measured by 24-hour urine collection)
    *ECOG Performance Status 2
    *CTCAE v.4 Grade ≥2 audiometric hearing loss
    *NYHA Class III heart failure
    -Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days [+ 14 days] prior to study enrollment [ICF signed]) that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression assessment.
    Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
    -Must have an ECOG performance status of 0, 1, or 2
    -Demonstrate adequate organ function (all screening labs should be performed within 14 days prior to randomization)
    -Participant is male or female at least 18 years of age, at the time of signing the informed consent
    -Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of enfortumab vedotin:
    *Refrain from donating sperm
    PLUS:
    *Must agree to use contraception unless confirmed to be azoospermic.
    If the male participants are receiving pembrolizumab only or undergoing surgery only, there are no contraception requirements
    *Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    -A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
    *Is not a WOCBP
    OR
    *Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 120 days after the last dose of pembrolizumab and 180 days after the last dose of enfortumab vedotin, whichever comes last, and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    *A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention.
    *The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    *Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    -The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
    E.4Principal exclusion criteria
    -Has a known additional non-urothelial malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization.
    -Participants with ≥ N2 disease or metastatic disease (M1) as identified by imaging.
    -Has received any prior systemic treatment, chemoradiation, and / or radiation therapy for MIBC or NMIBC.
    -Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    -Has received prior systemic anticancer therapy including investigational agents (including enfortumab vedotin or other MMAE-based ADCs) within 3 years prior to randomization.
    -Has received any prior radiotherapy to the bladder.
    -Has received a partial cystectomy of the bladder to remove any NMIBC or MIBC.
    -Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
    -Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
    -Has ongoing sensory or motor neuropathy Grade 2 or higher
    -Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency
    -Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
    -Has known severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20).
    -Has active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator
    -Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
    -Has a history of uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
    -Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
    -Has an active infection (viral, bacterial, or fungal) requiring systemic therapy. Participants may be rescreened once after resolution of the infection
    -Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    -Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as detectable HCV RNA via qualitative nucleic acid testing) infection
    -Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
    -Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    -Has had an allogenic tissue/solid organ transplant
    E.5 End points
    E.5.1Primary end point(s)
    1. Pathological Complete Response (pCR) Rate
    2. Event-Free Survival (EFS)

    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 5.7 years
    2. Up to approximately 7.7 years
    E.5.2Secondary end point(s)
    1. Overall Survival (OS)
    2. Disease-Free Survival (DFS)
    3. Pathologic Downstaging (pDS) Rate
    4. Number of Participants Experiencing an Adverse Event (AE)
    5. Number of Participants Discontinuing Study Treatment due to an AE
    6. Number of Participants Experiencing Perioperative Complications
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 8.4 years
    2. Up to approximately 7.7 years
    3. Up to approximately 5.7 years
    4. Up to approximately 8.4 years
    5. Up to approximately 1 year
    6. Up to approximately 1 year

    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Cystectomy
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA105
    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
    Australia
    Belgium
    Canada
    Denmark
    France
    Germany
    Hungary
    Ireland
    Israel
    Italy
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    Sweden
    Thailand
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 years7
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months10
    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: 418
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 418
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 438
    F.4.2.2In the whole clinical trial 836
    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)
    The subjects will be treated per standard of care post participation in the study.
    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 Decision2019-05-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-02
    P. End of Trial
    P.End of Trial StatusOngoing
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