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    Summary
    EudraCT Number:2019-004873-17
    Sponsor's Protocol Code Number:NBI-74788-CAH3003
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-30
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2019-004873-17
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont (NBI-74788) in Adult Subjects with Classic Congenital Adrenal Hyperplasia, Followed by Open-Label Treatment
    Estudo aleatorizado, duplamente cego e controlado por placebo, para avaliar a segurança e eficácia do Crinecerfont (NBI-74788) em indivíduos adultos com hiperplasia suprarrenal congênita clássica, seguido de tratamento em regime aberto
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of safety and efficacy of NBI-74788 in Classic Congenital Adrenal Hyperplasia
    Estudo da segurança e eficácia do NBI-74788 em hiperplasia adrenal congênita clássica
    A.4.1Sponsor's protocol code numberNBI-74788-CAH3003
    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 SponsorNeurocrine Biosciences, 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 supportNeurocrine Biosciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAccelsiors CRO and Consultancy Services Ltd
    B.5.2Functional name of contact pointRegulatory Unit
    B.5.3 Address:
    B.5.3.1Street Address103 Haros Str.
    B.5.3.2Town/ cityBudapest
    B.5.3.3Post code1222
    B.5.3.4CountryHungary
    B.5.4Telephone number+3612990091
    B.5.5Fax number+3612990096
    B.5.6E-mailregulatory@accelsiors.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2194
    D.3 Description of the IMP
    D.3.1Product nameCrinecerfont
    D.3.2Product code NBI-74788
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCrinecerfont
    D.3.9.1CAS number 752253-39-7
    D.3.9.2Current sponsor codeNBI-74788
    D.3.9.4EV Substance CodeSUB197132
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Classic Congenital Adrenal Hyperplasia (CAH)
    Hiperplasia Suprarrenal Congénita Clássica
    E.1.1.1Medical condition in easily understood language
    Congenital adrenal hyperplasia (CAH) is a group of rare inherited endocrine disorders characterized by a deficiency of one of the enzymes needed to make specific hormones.
    A hiperplasia adrenal congênita (HAC) é um grupo de distúrbios endócrinos hereditários raros, caracterizados por uma deficiência de uma das enzimas necessárias para produzir hormônios específicos.
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10010323
    E.1.2Term Congenital adrenal hyperplasia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the efficacy of Crinecerfont (100 mg twice daily [bid]), compared with placebo, in reducing daily glucocorticoid dosage while maintaining adrenal androgen control.
    • To evaluate the efficacy of Crinecerfont, compared with placebo, in reducing adrenal steroid levels following an initial 4-week treatment period.
    • To evaluate the effect of Crinecerfont, compared with placebo, on clinical endpoints associated with supraphysiologic glucocorticoid dosing.
    • To evaluate plasma concentrations of Crinecerfont and metabolites.
    • To assess the safety and tolerability of Crinecerfont.
    • To evaluate an alternate dosing regimen of crinecerfont in subjects who have not reduced their glucocorticoid dose by Month 12.
    •Avaliar a eficácia de crinecerfont (100 mg duas vezes ao dia, [bid]), em comparação com o placebo, na redução da dosagem de glicocorticoide diária, mantendo o controlo dos andrógenos adrenais.
    •Avaliar a eficácia de crinecerfont, em comparação com o placebo, na redução dos níveis de esteroides adrenais iniciais após um período de tratamento de 4 semanas.
    •Avaliar o efeito de crinecerfont, em comparação com o placebo, em parâmetros de avaliação clínicos associados à administração de glicocorticoides suprafisiológicos.
    •Avaliar as concentrações plasmáticas de crinecerfont e metabólitos.
    •Avaliar a segurança e a tolerabilidade de crinecerfont.
    •Avaliar um regime de dosagem alternativo de crinecerfont em participantes que não apresentaram redução da dose de glicocorticoides até ao mês 12.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subjects must provide written informed consent.
    • Be a female or male at least 18 years of age.
    • Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency.
    • Be on a stable, supraphysiologic glucocorticoid dose regimen that has been stable for at least 1 month prior to screening.
    • If treated with fludrocortisone, dose should be stable for at least 1 month prior to screening
    with an upright plasma renin activity (PRA) during screening that is not greater than ULN on
    the subject’s usual sodium intake. If PRA is >ULN, the subject must have systolic blood
    pressure >100 mmHg, without orthostatic hypotension, and with serum sodium and
    potassium in the normal range.
    • Female subjects of childbearing potential with fertile male partners must agree to use
    contraception consistently from screening until the final study visit or 30 days after the last
    dose of study drug, whichever is longer. A female who is not of childbearing potential must
    meet one of the following:
    Postmenopausal
    Permanent sterilization procedure
    • Male subjects must agree to use contraception consistently from screening until 90 days after the last dose of study drug.
    1. Os participantes devem facultar o formulário de consentimento informado por escrito.
    2. Devem ser indivíduos do sexo masculino ou feminino com 18 anos de idade, no mínimo.
    3. Ter um diagnóstico clinicamente confirmado de deficiência de 21-hidroxilase clássica CAH.
    4. Deve estar num regime de dose estável, suprafisiológico de glicocorticoide que tenha sido estável por pelo menos 1 mês antes da seleção.
    5. Se tratado com fludrocortisona, a dose deve ser estável por pelo menos 1 mês antes da seleção com uma atividade de renina plasmática ascendente (PRA) que não está acima do LSN durante a seleção na ingestão habitual de sódio por parte do participante. Se a PRA é > LSN, o participante deve ter tensão arterial sistólica de >100 mmHg, sem hipotensão ortostática, e com sódio sérico e potássio sérico dentro do intervalo normal.
    6. Os participantes do sexo feminino em idade fértil com um parceiro fértil, devem concordar em usar contraceção de forma consistente desde a seleção até à consulta de final do estudo ou 30 dias após a última dose do medicamento do estudo, o que for mais longo. Uma mulher que não esteja em idade fértil deve cumprir uma dos seguintes:
    - Estar em pós-menopausa
    - Procedimento de esterilização permanente
    7. Os participantes do sexo masculino devem concordar em usar contraceção forma consistente desde a seleção até 90 dias após a última dose do medicamento do estudo.
    E.4Principal exclusion criteria
    • Have a known or suspected diagnosis of any of the other forms of classic CAH including 11-β-hydroxylase deficiency, 17-α-hydroxylase deficiency, 3-β-hydroxysteroid dehydrogenase deficiency, P450 side-chain cleavage deficiency, or P450 oxidoreductase deficiency.
    • Have a history of bilateral adrenalectomy, hypopituitarism, or other condition requiring
    chronic therapy with oral glucocorticoids, or requiring chronic therapy with inhaled
    glucocorticoids that based on dose and hormone profile the investigator deems would yield
    significant systemic exposure interfering with study endpoints.
    • Have a clinically significant medical condition or chronic disease (including history of neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine disease [excluding CAH]) that in the opinion of the investigator would preclude the subject from participating in and completing the study or that could confound interpretation of study outcome.
    • History of malignancy, unless successfully treated with curative intent and considered to be cured.
    • Have a known history of clinically concerning cardiac arrhythmia (including long QT syndrome) or prolongation of screening (pre-treatment) QT interval corrected for heart rate using Fridericia’s correction (QTcF) of >450 msec (males) or >470 msec (females).
    • Known sensitivity (ie, hypersensitivity) or allergy to any corticotropin-releasing hormone (CRH) receptor antagonist.
    • Have evidence of chronic renal or liver disease Used any active investigational drug within 30 days or 5 half-lives (whichever is longer) before screening, or plans to use an investigational drug (other than the study drug) during the study.
    • Females who are pregnant or lactating.
    • Are using any excluded concomitant medication and cannot discontinue use of these
    medications for the duration of the study (also refer to Section 9.9.1):
    • Orally administered glucocorticoids for indications other than CAH.
    • Strong inducers of CYP3A4 or CYP2B6 except topically administered medications.
    • Medications that affect cortisol or glucocorticoid metabolism (eg, phenytoin, mitotane,
    phenobarbital, strong CYP3A4 inhibitors such as ketoconazole, clarithromycin,
    cholestyramine, certain antivirals) except topically administered medications.
    • Aromatase inhibitors (eg, anastrozole, letrozole, testolactone).
    • Ter um diagnóstico conhecido ou suspeito de qualquer uma das outras formas clássicas de HAC, incluindo deficiência de 11-β-hidroxilase, deficiência de 17-α-hidroxilase, deficiência de 3-β-hidroxisteróide desidrogenase, deficiência de clivagem da cadeia lateral P450 ou deficiência de oxidoredutase P450 .
    • 2. Ter um historial de adrenalectomia bilateral, hipopituitarismo, ou outro quadro clínico que exija terapêutica crónica com glicocorticoides , ou que requerem terapia crônica com glicocorticóides inalados que, dependendo da dose e do perfil hormonal considerado pelo investigador, produziriam uma exposição sistêmica significativa que interfere nos desfechos do estudo.
    • Ter uma condição médica clinicamente significativa ou doença crônica (incluindo histórico de má absorção neurológica, hepática, renal, cardiovascular, gastrointestinal, má absorção significativa, hematológica, pulmonar, psiquiátrica ou endócrina [exceto HAC]) que, na opinião do investigador, impediria o sujeito de participar e concluir o estudo ou que possa confundir a interpretação do resultado do estudo.
    • História de malignidade, a menos que seja tratada com sucesso com intenção curativa e considerada curada.
    • Tem um histórico conhecido de arritmia cardíaca (incluindo síndrome do QT longo) ou prolongamento do rastreamento (pré-tratamento), intervalo QT corrigido para a freqüência cardíaca usando a correção de Fridericia (QTcF) de> 450 mseg (homens) ou> 470 mseg (mulheres) )
    • Sensibilidade conhecida (isto é, hipersensibilidade) ou alergia a qualquer antagonista do receptor do hormônio liberador de corticotropina (CRH).
    • Tenha evidências de doença renal ou hepática crônica. Usou qualquer medicamento em investigação ativo dentro de 30 dias ou 5 semi-vidas (o que for maior) antes da triagem ou planeja usar um medicamento em investigação (que não seja o medicamento do estudo) durante o estudo.
    • Mulheres grávidas ou amamentando.
    • Estiver a usar qualquer um dos medicamentos concomitantes excluídos (consulte a Secção 0) e não puderem interromper o uso desses medicamentos por toda a duração do estudo.
    • Glicocorticóides administrados por via oral para outras indicações além da HAC.
    • Fortes indutores de CYP3A4 ou CYP2B6, exceto medicamentos administrados topicamente.
    • Medicamentos que afetam o metabolismo do cortisol ou dos glicocorticóides (por exemplo, fenitoína, mitotano, fenobarbital, inibidores fortes do CYP3A4, como cetoconazol, claritromicina, colestiramina, certos antivirais), exceto medicamentos administrados topicamente.
    E.5 End points
    E.5.1Primary end point(s)
    • Percent change from baseline in glucocorticoid daily dose (in hydrocortisone equivalents adjusted for BSA [mg/m2/day]) at Week 24.
    • Variação percentual da linha de base na dose diária de glicocorticóide (em equivalentes de hidrocortisona ajustados para BSA [mg / m2 / dia]) na semana 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    Semana 24
    E.5.2Secondary end point(s)
    - Change from baseline in serum androstenedione at Week 4.
    - Achievement of a reduction in glucocorticoid daily dose to physiologic levels Week 24.
    - Changes from baseline in HOMA-IR, weight, and fat mass at Week 24.
    - Alteração da linha de base na androstenediona sérica na semana 4.
    - Realização de uma redução da dose diária de glicocorticóide para os níveis fisiológicos Semana 24.
    - Alterações da linha de base no HOMA-IR, peso e massa gorda na semana 24.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 4 and Week 24
    Semana 4 e semana 24
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 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 Yes
    E.8.1.7.1Other trial design description
    open-label period
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    United States
    Austria
    France
    Poland
    Sweden
    Bulgaria
    Netherlands
    Spain
    Czechia
    Germany
    Greece
    Italy
    Belgium
    Portugal
    United Kingdom
    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
    Última Visita Último Sujeito
    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
    E.8.9.2In all countries concerned by the trial years4
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 165
    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)
    Subjects will return to previous standard of care treatment.
    Os indivíduos retornarão ao padrão anterior de tratamento.
    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 Decision2020-09-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-12
    P. End of Trial
    P.End of Trial StatusOngoing
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