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    Summary
    EudraCT Number:2008-003535-20
    Sponsor's Protocol Code Number:CS8635-A-E303
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-06-03
    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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2008-003535-20
    A.3Full title of the trial
    A RANDOMISED, DOUBLE-BLIND, ADD-ON STUDY OF HYDROCHLOROTHIAZIDE IN SUBJECTS WITH MODERATE TO SEVERE HYPERTENSION NOT ACHIEVING TARGET BLOOD PRESSURE ON OLMESARTAN MEDOXOMIL/AMLODIPINE FIXED DOSE COMBINATION 40/10 MG ALONE
    A.4.1Sponsor's protocol code numberCS8635-A-E303
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDAIICHI SANKYO EUROPE GmbH
    B.1.3.4CountryGermany
    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 support
    B.4.2Country
    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 Sevikar 40 mg /10 mg
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameOM/AML 40/10 mg
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNolmesartan medoxomil
    D.3.9.1CAS number 144689-63-4
    D.3.9.3Other descriptive nameOM
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNamlodipine besylate
    D.3.9.1CAS number 88150-42-9
    D.3.9.3Other descriptive nameAML
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 HCT 12.5-1 A Pharma
    D.2.1.1.2Name of the Marketing Authorisation holder1A Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNhydrochlorothiazide
    D.3.9.1CAS number 58-93-5
    D.3.9.3Other descriptive nameHCTZ
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 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
    Essential hypertension
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10020772
    E.1.2Term Hypertension
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective (Period II, Week 8 to Week 16) is to demonstrate the additional antihypertensive efficacy for SeDBP gained by adding HCTZ 12.5 or 25 mg to the treatment regimen in subjects with moderate to severe HTN not adequately controlled on OM/AML 40/10 mg alone, at Week 16 (after 8 weeks of double-blind treatment) using conventional BP measurement.
    E.2.2Secondary objectives of the trial
    Period II: 1. Evaluate antihypertensive efficacy for SeDBP of triple combination OM/AML/HCTZ 40/10/12.5 & 40/10/25 mg vs OM/AML 40/10 mg at Wk(week)12. 2. Evaluate antihypertensive efficacy for SeSBP of OM/AML/HCTZ 40/10/12.5 & 40/10/25mg vs OM/AML 40/10mg at Wk12&16. 3. Evaluate antihypertensive efficacy from baseline to Wk16 (see protocol p36). 4. Evaluate % no. subjects achieving BP goal (SeBP, see protocol p36) and % no. subjects achieving SeBP thresholds (see protocol p.36) at Wk12&16. 5. Evaluate safety & tolerability of triple combination therapy at Wk8-16. Period III&IV: 1. Evaluate antihypertensive efficacy of up titration of dose to 40/10/25mg in subjects not reaching BP goal on dose 40/10/12.5mg based on changes from Wk24-32 (see protocol p36). 2. Evaluate % no. subjects achieving BP goal & BP thresholds (defined point 4 above) at Wk32. 3. Evaluate safety & tolerability of triple combination therapy during Wk16-32.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female aged 18 years or older.
    2. Mean trough SeBP of ≥ 160/100 mmHg (SeSBP of ≥ 160 mmHg and SeDBP ≥ 100 mmHg) at Screening if not currently on antihypertensive medication (e.g. newly diagnosed subjects) and a mean 24-hour DBP of at least 85 mmHg with at least 30% of daytime DBP readings over 90 mmHg.
    OR:
    For subjects on monotherapy: mean trough SeBP of ≥ 150/95 mmHg (SeSBP of ≥ 150 mmHg and SeDBP ≥ 95 mmHg) at Screening and mean 24-hour DBP of at least 80 mmHg and with at least 30% of daytime DBP readings over 85 mmHg.
    OR:
    For subjects on any combination of antihypertensive medications that includes either HCTZ, OM or AML for a duration of at least four weeks: mean trough SeBP of ≥ 140/90 mmHg (SeSBP of ≥ 140 mmHg and SeDBP ≥90 mmHg) at Screening and mean 24-hour DBP of at least 80 mmHg and with at least 30% of daytime DBP readings over 85 mmHg.
    OR:
    For subjects on any other combination of antihypertensive medications that includes neither HCTZ, OM nor AML: mean trough SeSBP ≥ 160 mmHg, mean trough SeDBP ≥ 100mmHg, at the end of the taper-off period and a mean 24-hour DBP of at least 85 mmHg, assessed by 24-hour ABPM, with at least 30% of daytime DBP readings above 90 mmHg.
    3. Subject freely signs ICF after the nature of the study and the disclosure of his/her data has been explained.
    4. Female subjects of childbearing potential must be using adequate contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study [Visit 1]). Females taking oral contraceptives should have been on therapy for at least three months. Adequate contraceptives include hormonal intra-uterine devices, hormonal contraceptives (oral, depot, patch or injectable), and double barrier methods such as condoms or diaphragms with spermicidal gel or foam. If a female becomes pregnant during the study, she has to be withdrawn immediately.
    E.4Principal exclusion criteria
    1. Female subjects of childbearing potential who are pregnant or lactating.
    2. Subjects with serious disorders which may limit the ability to evaluate the efficacy or safety of the investigational products, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, haematological or oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic subjects.
    3. Subjects having a history of the following within the last six months: MI, unstable angina pectoris, percutaneous coronary intervention, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischaemic attack.
    4. Subjects with clinically significant abnormal laboratory values at Screening, including subjects with one or more of the following:
    • Aspartate aminotransferase (AST) > 3 times upper limit of normal (ULN)
    • ALT > 3 times ULN
    • Gamma-glutamyltransferase (GGT) > 3 times ULN
    • Potassium above ULN (unless high value is due to haemolytic blood sample)
    5. Subjects with secondary HTN of any aetiology such as renal disease, phaechromocytoma, or Cushing’s syndrome.
    6. Subjects with contraindication to OM, AML, HCTZ, or any of the excipients.
    7. Subjects with a mean SeSBP > 200 mmHg or SeDBP > 115 mmHg or bradycardia (heart rate < 50 beats/min at rest documented by mean radial PR or ECG at Screening (Visit 1) or immediately before taking Period I study medication (Visit 2).
    8. Subjects already taking four or more antihypertensive medications.
    9. Subjects with ECG evidence of 2nd or 3rd degree atrio-ventricular (AV) block, atrial fibrillation, or other cardiac arrhythmia (requiring treatment).
    10. Subjects with severe heart failure (New York Heart Association stage III IV), clinically significant aortic or mitral valve stenosis, uncorrected coarctation of the aorta, obstruction of cardiac outflow (obstructive, hypertrophic cardiomyopathy) or symptomatic coronary disease.
    11. Subjects with clinical evidence of renal disease including renovascular occlusive disease, nephrectomy and/or renal transplant, bilateral renal artery stenosis, unilateral renal artery stenosis in a solitary kidney, or severe renal impairment as evidenced by CrCl of < 30 mL/min calculated using the Cockcroft and Gault formula.
    12. Subjects with clinically relevant hepatic impairment.
    13. Subjects with biliary obstruction.
    14. Subjects with a history of a wasting disease (e.g. cancer), autoimmune diseases, connective tissue diseases, major allergies or angioneurotic oedema.
    15. Subjects who require or are taking any concomitant medication which may interfere with the objectives of the study.
    16. Subjects with known malabsorption syndromes.
    17. Subjects with psychiatric or emotional problems, which would invalidate the giving of Informed Consent or limit the ability of the subject to comply with study requirements.
    18. Subjects with a current history of alcohol and/or drug abuse.
    19. Subjects who have received any investigational drug within 30 days prior to Screening.
    20. Subjects who are unwilling or unable to provide informed consent or to participate satisfactorily for the entire study.
    21. Signs or symptoms which could exacerbate the occurrence of hypotension such as volume and salt depletion.
    22. Uncontrolled Type 1 or Type 2 diabetes defined as an HbA1c > 9.0%. Diabetics must have documentation of an HbA1c level within 6 months of the Screening Visit, or must have their HbA1c level documented prior to randomisation. Note: subjects with Type 1 or Type 2 diabetes controlled with insulin, diet or oral hypoglycaemic agents on a stable dose for at least 30 days may be included.
    23. Subjects with malignancy during the past 2 years excluding squamous cell or basal cell carcinoma of the skin.
    24. A subject with any medical condition, which in the judgment of the Investigator would jeopardise the evaluation of efficacy or safety and/or constitute a significant safety risk to the subject.
    25. Subjects on beta blockers or calcium channel blockers (CCBs) for both HTN and either ischemia, post-MI prophylaxis or tachyarrhythmias.
    E.5 End points
    E.5.1Primary end point(s)
    The mean change in trough SeDBP from the randomisation visit (end of the OM/AML run-in period [Week 8]) to the end of the double-blind Period II (Week 16).
    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 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.8.3 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA143
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months17
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months19
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-06-03. Yes
    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 state111
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1466
    F.4.2.2In the whole clinical trial 1965
    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 Decision2009-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-09-07
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