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    Summary
    EudraCT Number:2021-003460-27
    Sponsor's Protocol Code Number:2021-12964
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-17
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-003460-27
    A.3Full title of the trial
    CXCR4-directed [68Ga]Ga-PentixaFor PET/CT vs AVS performance in a diagnoStic randomized Trial Ultimately comparing hypertenSion outcome in primary aldosteronism
    CXCR4-gerichte [68Ga]Ga-PentixaFor PET/CT vs AVS-prestaties in een diagnostisch gerandomiseerd onderzoek waarin hypertensie uitkomst bij primair aldosteronisme wordt vergeleken
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PET/CT scan with [68Ga]Ga-PentixaFor compared to adrenal vein sampling in a study to compare hypertension outcomes in patients with primary aldosteronism
    PET/CT scan met [68Ga]Ga-PentixaFor vergeleken met bijniervene sampling in een onderzoek om bloeddruk uitkomsten te vergelijken in patiënten met primair hyperaldosteronisme
    A.3.2Name or abbreviated title of the trial where available
    CASTUS
    A.4.1Sponsor's protocol code number2021-12964
    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 SponsorRadboudumc
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPentixaPharm
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportZonMW
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboudumc
    B.5.2Functional name of contact pointSecretary of Urology
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein Zuid 10
    B.5.3.2Town/ cityNIJMEGEN
    B.5.3.3Post code6525GA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+3124 363735
    B.5.5Fax number+31243541031
    B.5.6E-mailsecretariaat.uro@radboudumc.nl
    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 No
    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 name[68Ga]Ga-Pentixafor
    D.3.2Product code 9913
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSolution for infusion (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN[68Ga]Ga-PentixaFor
    D.3.9.1CAS number 1345698-96-5
    D.3.9.3Other descriptive namePENTIXAFOR GALLIUM GA-68
    D.3.9.4EV Substance CodeSUB196568
    D.3.10 Strength
    D.3.10.1Concentration unit MBq megabecquerel(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Aldosteronism
    Primair hyperaldosteronisme
    E.1.1.1Medical condition in easily understood language
    Primary Aldosteronism
    Primair hyperaldosteronisme
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10036692
    E.1.2Term Primary hyperaldosteronism
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To assess the concordance between [68Ga]Ga-PentixaFor PET/CT and AVS for identification and/or lateralization of APAs in patients with PA. (Step 1)
    -To assess non-inferiority in terms of clinical outcomes of [68Ga]Ga-PentixaFor PET/CT imaging vs. AVS in subtyping of patients with PA randomized to either [68Ga]Ga-PentixaFor PET/CT imaging or AVS confirmed by the surrogate Standard of Truth (SoT) daily defined doses (DDD) in patients after 6 months follow-up. (Step 2)
    - De overeenstemming tussen [68Ga]Ga-PentixaFor PET/CT en BVS te beoordelen voor identificatie en/of lateralisatie van APA's bij patiënten met PHA. (Stap 1)
    - Om de hoeveelheid antihypertensiva te beoordelen die na 6 maanden follow-up nodig is om de bloeddruk te normaliseren bij patiënten die zijn behandeld voor PHA volgens ofwel BVS of [68Ga]Ga-PentixaFor PET/CT. (Stap 2)
    E.2.2Secondary objectives of the trial
    Step1
    -Definitive quantitative criteria of [68Ga]Ga-PentixaFor uptake
    -In unilateral adrenalectomy, compare quantitative data in PET/CT imaging and CYP11B2 and CXCR4 staining
    -Outcomes based on PASO criteria
    Step2
    -Outcomes after adrenalectomy of [68Ga]Ga-PentixaFor PET/CT vs AVS in subtyping patients with PA by using PASO criteria
    -Reproducibility of [68Ga]Ga-PentixaFor PET/CT
    -Intra- and inter-reader agreement of [68Ga]Ga-PentixaFor PET/CT for subtyping
    -Inter-observer agreement of [68Ga]Ga-PentixaFor PET/CT between imaging centers
    -In unilateral adrenalectomy, compare quantitative data in PET/CT imaging and CYP11B2 and CXCR4 staining
    -Cost effectiveness analysis of AVS versus [68Ga]Ga-PentixaFor PET/CT
    -Quality of life of [68Ga]Ga-PentixaFor PET/CT versus AVS
    -Rate of inconclusive results or failure of subtype diagnosis by [68Ga]Ga-PentixaFor PET/CT or AVS
    -Safety and intolerability
    -Image quality of [68Ga]Ga-PentixaFor PET/CT imaging
    Stap1
    -Definitieve kwantitatieve criteria voor [68Ga]Ga-PentixaFor opname
    -Bij unilaterale adrenalectomie, vergelijken kwantitatieve data van PET/CT-beeldvorming tussen CYP11B2- en CXCR4-kleuring
    -Uitkomstmaten na adrenalectomie op basis van PET/CT vs BVS subtypering door gebruik te maken van de PASO criteria
    Stap2
    -Uitkomstmaten na adrenalectomie op basis van PET/CT vs BVS subtypering door gebruik te maken van de PASO criteria
    -Reproduceerbaarheid van PET/CT
    -Intra- en interbeoordelaarsbetrouwbaarheid van PET/CT
    -Interbeoordelaarsbetrouwbaarheid van PET/CT tussen beeldvormingscentra
    -Bij unilaterale adrenalectomie, vergelijken kwantitatieve data van PET/CT-beeldvorming tussen CYP11B2- en CXCR4-kleuring
    -Kosteneffectiviteitsanalyse van BVS vs PET/CT
    -Kwaliteit van leven bij PET/CT vs BVS
    -Aantallen inconclusieve resultaten / falen tot subtyperen van BVS en PET/CT
    -Veiligheid en intolerabiliteit
    -Beeldkwaliteit van PET/CT

    (PET/CT = [68Ga]Ga-PentixaFor PET/CT)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - The patient has a diagnosis of primary aldosteronism, confirmed by an elevated aldosterone/rennin ratio (ARR) and an intravenous salt-loading test (according to the Endocrine Society guidelines)(1)
    - Patients who fall in the “grey area” according to the Endocrine Society guidelines (1), will be discussed with all site investigators before inclusion to reach consensus on the diagnosis before inclusion.
    - Age over 18 years at time of consent
    - Signed informed consent

    E.4Principal exclusion criteria
    - Refusal by the patients to undergo AVS, [68Ga]Ga-PentixaFor PET/CT, CT, or adrenalectomy
    - Suspicion of familial hyperaldosteronism type 1 (FH-1), type 2 (FH-2), type 3 (FH-3), or type 4 (FH-4)
    - Suspicion of adrenocortical carcinoma
    - Severe comorbidity potentially interfering with treatment or health-related quality of life
    - Requirement of medication interfering with the study protocol
    - Any medical condition present that in the opinion of the investigator will affect patients’ clinical status.
    - Pregnancy or lactation
    • Estimated glomerular filtration rate (eGFR) < 40 ml/min/1.73m²
    E.5 End points
    E.5.1Primary end point(s)
    Step 1: Primary end point is a concordance between [68Ga]Ga-PentixaFor PET/CT and AVS of at least 50%
    Step 2: [68Ga]Ga-PentixaFor PET/CT results in less than 1 daily defined doses compared to AVS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Step 1: We evaluate the concordance after the [68Ga]Ga-PentixaFor PET/CT and AVS is performed
    Step 2: We will evaluate the daily defined doses after 6 months of follow-up
    E.5.2Secondary end point(s)
    Step 1:
    1. To establish definitive quantitative criteria of [68Ga]Ga-PentixaFor uptake in unilateral and bilateral PA for SUVs, liver-to-lesion ratio and lesion-to-contralateral ratio.
    2. In patients who receive unilateral adrenalectomy, compare quantitative data in PET/CT imaging between immunohistochemically (CYP11B2 and CXCR4 staining) diagnosed multinodular hyperplasia and solitary adenomas.
    3. To assess biochemical and clinical outcomes based on PASO criteria (2)

    Step 2:
    4. To asses biochemical and clinical outcomes after adrenalectomy of [68Ga]Ga-PentixaFor PET/CT imaging vs AVS in subtyping patients with PA by using the PASO criteria for clinical and biochemical outcome measures (complete, partial or absent)
    5. To evaluate reproducibility of [68Ga]Ga-PentixaFor PET/CT by comparison of two [68Ga]Ga-PentixaFor PET/CT scans with an interval of 1-14 days in the first 10 patients undergoing [68Ga]Ga-PentixaFor PET/CT.
    6. To assess intra- and inter-reader agreement of [68Ga]Ga-PentixaFor PET/CT for subtyping for each imaging center.
    7. To analyze inter-observer agreement of [68Ga]Ga-PentixaFor PET/CT between the imaging centers in terms of subtyping.
    8. In patients who receive unilateral adrenalectomy, compare quantitative data in PET/CT imaging between immunohistochemically (CYP11B2 and CXCR4 staining) diagnosed multinodular hyperplasia and solitary adenomas.
    9. To perform cost effectiveness analysis of AVS versus [68Ga]Ga-PentixaFor PET/CT management.
    10. To evaluate quality of life as assessed by EQ-5D-5L questionnaire and the Short Form health survey (SF36) of [68Ga]Ga-PentixaFor PET/CT versus AVS management
    11. Determination of the rate of inconclusive results and/or failure of subtype diagnosis by [68Ga]Ga-PentixaFor PET/CT imaging or AVS.
    12. To assess safety and intolerability.
    13. To assess image quality of [68Ga]Ga-PentixaFor PET/CT imaging
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. After the lateralization results of AVS of the last included patient is known.
    2. After the pathology results of the last included patient is reported.
    3 + 4 + 9 + 10 + 11. After the last included patients finished the last visit
    5. After PET/CT imaging results of both PET/CTs in the first 10 patients are known.
    6 + 7 + 13. After all PET/CT imaging results are known
    8. After the pathology results of the last included patient is reported.
    12. After the last included patients finished the last visit and after every adverse event
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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 Yes
    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) Yes
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Two-step trial
    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
    Bijniervene sampling
    Adrenal vein sampling
    E.8.2.4Number of treatment arms in the trial2
    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 concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Step 1: If a concordance of >50% is reached after the 25th patient, the first step will end and we will continue to the randomized diagnostic trial.
    If the concordance of 50% or higher is not reached after patient 41, step 1 will end and we will not perform the randomized diagnostic trial.
    Step 2: Last visit of the last subject (after 6 months of follow-up)
    Stap 1: Bij een concordantie van 50% of hoger na 25 patiënten, zal de eerste stap stoppen en zullen we doorgaan naar stap 2, de gerandomiseerde diagnostische trial.
    Wanneer de concordantie van 50% of hoger na 41 patienten niet gehaald wordt, zal stap 1 stoppen en zullen wij de gerandomiseerde diagnostische trial in stap 2 niet uitvoeren.
    Stap 2: Laatste bezoek van de laatste proefpersoon (na 6 maanden follow-up)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 228
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 228
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state228
    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)
    Patient can receive another treatment based on the PET/CT results compared to AVS (antihypertensive drugs or adrenalectomy). In CASTUS step 1, a concordance of more than 50% was reached and therefore the added risk for patients is negligible.
    Patiënten krijgen mogelijk een andere behandeling (medicamenteuze behandeling met antihypertensiva of adrenalectomie) op basis van de uitslagen van de [68Ga]Ga-PentixaFor PET/CT dan bij de uitslagen van de bijniervene sampling. In CASTUS stap 1 is een concordantie bereikt van meer dan 50%, waardoor we verwachten dat het toegevoegde risico voor patiënten verwaarloosbaar is.
    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 Decision2022-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-14
    P. End of Trial
    P.End of Trial StatusOngoing
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