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    Summary
    EudraCT Number:2016-002240-17
    Sponsor's Protocol Code Number:ATR-101-301
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-03-06
    Trial results View 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 ConcernedUK - MHRA
    A.2EudraCT number2016-002240-17
    A.3Full title of the trial
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for the Treatment of Cushing’s Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of ATR-101 for the Treatment of Cushing’s Syndrome
    A.4.1Sponsor's protocol code numberATR-101-301
    A.5.4Other Identifiers
    Name:US IND NumberNumber:129885
    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 SponsorMillendo Therapeutics, 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 supportMillendo Therapeutics, inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address26-28 Hammersmith Grove
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW6 7HA
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44208563 5902
    B.5.6E-mailregsubmissions@medpace.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameATR-101
    D.3.4Pharmaceutical form Tablet
    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 INNNevanimibe hydrochloride
    D.3.9.1CAS number 133825-81-7
    D.3.9.2Current sponsor codeATR-101, PD 132301-2
    D.3.9.3Other descriptive nameATR-101; CI-984
    D.3.9.4EV Substance CodeSUB185323
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number250 to 500
    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 Yes
    D.3.11.13.1Other medicinal product typeATR-101 is a selective Acyl-CoA: cholesterol acyltransferase 1 (ACAT1) inhibitor
    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 placeboTablet
    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
    endogenous Cushing’s syndrome
    E.1.1.1Medical condition in easily understood language
    Endogenous Cushing’s syndrome occurs when a person makes too much cortisol. Usually, the cause is a growth in the pituitary gland, but growth can be in other parts of the body like the adrenal glands.
    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 SOC
    E.1.2Classification code 10014698
    E.1.2Term Endocrine disorders
    E.1.2System Organ Class 10014698 - Endocrine disorders
    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 and safety of orally-administered ATR-101 in adults with endogenous Cushing’s syndrome
    E.2.2Secondary objectives of the trial
    • To evaluate the changes in adrenal steroids and adrenal steroid intermediates
    • To evaluate the change in adrenocorticotropic (ACTH)
    • To evaluate the change in metabolic syndrome-related parameters, including fasting glucose, insulin, lipid panel, blood pressure and body mass index (BMI)
    • To assess the safety and tolerability of ATR-101
    • To determine the pharmacokinetics (PK) of ATR-101 and its major metabolites
    • To evaluate the PK/pharmacodynamic (PD) relationships of ATR-101
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of signed and dated informed consent prior to any study-specific procedures
    2. Men and women 18-80 years of age (inclusive) at screening
    3. Subjects must have a confirmed diagnosis of endogenous Cushing’s syndrome as evidenced by
    baseline UFC 1.3 to 10 × ULN (mean of all 24-hr UFC levels obtained during the screening period within 28 days of enrolment into the open-label dose-escalation period) AND documentation at any time of ONE of the following three criteria:
    • For subjects with a diagnosis of pituitary Cushing’s syndrome, either:
    − Magnetic resonance imaging (MRI) confirmation of pituitary adenoma (greater than or equal to 0.6 cm), OR
    − For subjects with a pituitary microadenoma less than 0.6 cm, bilateral inferior petrosal sinus sampling (BIPSS) showing an ACTH gradient > 2 before or > 3 after corticotropin-releasing hormone (CRH) or desmopressin (DDAVP) stimulation, OR
    − For subjects who have had prior pituitary surgery: histopathology confirming an ACTH-staining adenoma
    • For subjects with a diagnosis of adrenal Cushing’s syndrome: MRI or computed tomography (CT) of the adrenal glands showing an adrenal tumor
    • For subjects with a diagnosis of ectopic ACTH as the cause of their Cushing’s syndrome: ACTH-dependent Cushing’s syndrome and either:
    − MRI showing no pituitary adenoma, OR
    − MRI showing only a small pituitary adenoma (< 0.6 cm) AND a negative BIPSS, OR
    − For subjects who have had prior pituitary surgery: histopathology that is negative for an ACTH-staining adenoma
    4. Subjects with a history of prior pituitary surgery must be at least 3 months post-surgery at the time of the screening visit
    5. Body mass index (BMI) between 18 and 60 kg/m2, inclusive, at screening
    6. Female subjects must be postmenopausal > 2 years OR must have been permanently surgically sterilized (bilateral salpingectomy or tubal occlusion) > 2 years OR male partner(s) has had a vasectomy > 2 years OR must consent to use two permitted medically-acceptable methods of contraception throughout the study during any sexual intercourse with a male partner. Permitted medically-acceptable methods of birth control for this study include oral contraceptives, contraceptive implants, Depo-Provera®, contraceptive patch, vaginal ring, male condom, female condom, spermicide, diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, or an intrauterine device (IUD) that does not contain steroid hormones; IUDs must have been in place for at least 28 days prior to first dose of study drug.
    E.4Principal exclusion criteria
    1. Pseudo-Cushing’s syndrome, cyclic Cushing’s syndrome or current iatrogenic Cushing’s syndrome
    2. Subjects who are considered candidates for surgical treatment of Cushing’s syndrome, unless it is clearly
    documented that the subject has refused such surgery or that surgery cannot be scheduled for at least the
    anticipated duration of the study
    3. Normal late night salivary cortisol value during screening, unless the subject’s history clearly demonstrates that he or she does not have pseudo-Cushing’s or cyclic Cushing’s. If the subject has a normal late night salivary cortisol, and the PI feels the subject does not have pseudo-Cushing’s or cyclic Cushing’s, the subject may be enrolled with approval of the medical monitor
    4. Normal 24-hr UFC during screening (this would be suggestive of cyclic Cushing’s)
    5. Radiotherapy of the pituitary within 6 months prior to or during screening
    6. For subjects with pituitary Cushing’s syndrome, any compression of the optic chiasm or the presence of a tumor within 2 mm of the optic chiasm on the most recent pituitary MRI prior to or during screening
    7. Use of or medical requirement for any of the following medications within the timeframes specified below prior to collection of the first 24-hr UFC during Screening and throughout study participation:
    • Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
    • Pituitary-directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARĪ³ agonists (rosiglitazone or pioglitazone): 4 weeks
    • Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
    • Octreotide (immediate release formulation): 1 week
    • Pasireotide: 4 weeks
    • Mitotane: 26 weeks
    • Mifepristone: 3 weeks
    8. Uncontrolled diabetes mellitus, as evidenced by HbA1c > 9.0% at screening
    9. Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 mmHg during screening. Note: if appropriate, subjects may have blood pressure medications adjusted and blood pressure reassessed at an unscheduled visit prior to Visit T1.
    10. Any history of gastric or small intestinal surgery or any current disease that causes malabsorption. Note: irritable bowel syndrome is acceptable for inclusion
    11. Alcohol or substance abuse (cocaine, amphetamines and/or opioids) within the year prior to screening
    12. Abnormal laboratory values as per the guidelines listed below or any other clinically significant, unexplained laboratory abnormality according to the Investigator:
    Serum ALT or AST > 3 × ULN
    • Serum total bilirubin > 1.5 × ULN
    • Serum creatinine > 1.5 × ULN
    • Glomerular filtration rate < 60 mL/min/1.73m^2
    13. Pregnant, breast-feeding, having conceived within the 6 months prior to screening, or having an intent to become pregnant during the study period
    14. QTc > 470 msec on electrocardiogram at screening (subjects with a single QTc > 470 msec may have 2 additional ECGs taken during screening and the QTcs averaged; if the average QTc is > 470 msec then the subject is excluded)
    15. Known history of Gilbert’s syndrome
    16. HIV, hepatitis B, or hepatitis C positivity at screening
    17. Any malignancy within the previous 5 years, other than curatively treated basal or squamous cell skin cancer or cervical carcinoma in situ
    18. Previous exposure to any amount of ATR-101
    19. Participation in any study of an investigational drug within 30 days prior to screening
    20. Significant psychiatric disease, recent severe physical stress, malnutrition, chronic excessive exercise, or
    any other medical or psychiatric condition that, in the opinion of the Investigator, is likely to confound the
    interpretation of the study results or prevent the subject from understanding the requirements of or
    successfully completing the study
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of subjects with either a normal 24-hr UFC or a reduction in 24-hr UFC of ≥ 50% relative to their baseline value at the end of the double-blind randomized withdrawal period
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to End of Treatment
    E.5.2Secondary end point(s)
    • The proportion of subjects with a normal 24-hr UFC at the end of the double-blind randomized withdrawal period
    • The proportion of subjects with a reduction in 24-hr UFC of ≥ 50% relative to their baseline value at the end of the double-blind randomized withdrawal period
    • The proportion of subjects with a normal 24-hr UFC at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period
    • The proportion of subjects with a reduction in 24-hr UFC of ≥ 50% relative to their baseline value at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period
    • The change and percentage change in the 24-hr UFC from randomization at the end of the double-blind randomized withdrawal period
    • The change and percentage change in the 24-hr UFC from baseline at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period
    • The proportion of subjects with a normal late night salivary cortisol at the end of the double-blind randomized withdrawal period
    • The proportion of subjects with a normal late night salivary cortisol at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period
    • The change and percentage change in the late night salivary cortisol from randomization at the end of the double-blind randomized withdrawal period
    • The change and percentage change in the late night salivary cortisol from baseline at the end of the open-label dose-escalation period and at the end of the additional open-label dosing period
    • The change and percentage change from baseline in blood hormone levels, including 11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T
    • The change from baseline in fasting glucose, insulin, lipid panel, systolic blood pressure, diastolic blood pressure and BMI
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to End of Treatment
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.5Parallel group No
    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 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.8.5.1Number of sites anticipated in the EEA4
    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 Kingdom
    United States
    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
    Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    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: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 16
    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)
    Subject is to begin treatment with another agent at the discretion of his/her physician
    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 Decision2017-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-08-12
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