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    Summary
    EudraCT Number:2013-000488-95
    Sponsor's Protocol Code Number:6520-9961-04
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-08-29
    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 ConcernedAustria - BASG
    A.2EudraCT number2013-000488-95
    A.3Full title of the trial
    Efficacy and tolerability of nicotinamide as add-on therapy compared to placebo in dialysis-dependent patients with hyperphosphatemia
    Wirksamkeit und Verträglichkeit von Nicotinamid als Add-on-Therapie im Vergleich zu Placebo bei Dialysepatienten mit Hyperphosphatämie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and tolerability of nicotinamide as add-on therapy compared to placebo in dialysis-dependent patients with elevated phosphat level
    Wirksamkeit und Verträglichkeit von Nicotinamid als Zusatztherapie im Vergleich zu Placebo bei Dialysepatienten mit erhöhtem Blutphosphatspiegel
    A.3.2Name or abbreviated title of the trial where available
    NOPHOS Trial
    NOPHOS Studie
    A.4.1Sponsor's protocol code number6520-9961-04
    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 SponsorMEDICE Arzneimittel Pütter GmbH & Co. KG
    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 supportMEDICE Arzneimittel Pütter GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMEDICE Arzneimittel Pütter GmbH & Co. KG
    B.5.2Functional name of contact pointMedizinische Abteilung
    B.5.3 Address:
    B.5.3.1Street AddressKuhloweg 37
    B.5.3.2Town/ cityIserlohn
    B.5.3.3Post code58638
    B.5.3.4CountryGermany
    B.5.4Telephone number492371937512
    B.5.5Fax number492371937360
    B.5.6E-maila.engels@medice.de
    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 nameNicotinamid 250 mg retard Kapseln
    D.3.4Pharmaceutical form Modified-release 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 INNNICOTINAMIDE
    D.3.9.1CAS number 98-92-0
    D.3.9.2Current sponsor codeM111, nicotinamide MR
    D.3.9.3Other descriptive nameniacinamide, pyridine 3-carboxamide, pyridine 3-carboxylic acid amid, nicotinic acid amide, nicotinamide, vitamin PP
    D.3.9.4EV Substance CodeSUB09246MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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, hard
    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
    Dialysis-dependent patients with hyperphosphatemia
    Dialysepflichtige Patienten mit Hyperphosphatämie
    E.1.1.1Medical condition in easily understood language
    Dialysis-dependent patients with elevated phosphat levels
    Dialysepflichtige Patienten mit erhöhtem Blutphosphatspiegel
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10020712
    E.1.2Term Hyperphosphatemia
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Nicotinamide MR compared to placebo as an add-on therapy to approved individual phosphate binders in the long term reduction of elevated phosphate levels in haemodialysis patients
    Nicotinamide MR im Vergleich zu Placebo als Add-on Therapie mit genehmigten individuellen Phosphatbindern in der Lanzeitsenkung von erhöhten Serumphosphatspiegel bei Hämodialysepatienten
    E.2.2Secondary objectives of the trial
    not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Males or females aged 18 years or older
     Patients with CKD stage 5 and on a stable haemodialysis regimen, 3 times a week for at
    least 6 months prior to screening
     Study visits must be conducted either on Sunday, Monday (morning, midday/afternoon,
    evening or overnight dialysis session) or on Tuesday (morning or midday/afternoon
    dialysis sessions)
     Dialysis regimen should remain constant at least until study visit W12
     Unmodified phosphate binding therapy with one or two phosphate binders for at least 1
    month prior to screening
     Serum phosphate concentration at screening < 2.80 mmol/l (8.7 mg/dl) and > 1.45
    mmol/l (4.5 mg/dl)
     If the patient is on vitamin D replacement and active vitamin D therapy, the dose must
    have remained stable for at least 1 month prior to screening
     If the patient takes calcimimetics, the dose must have remained stable for at least 1
    month prior to screening
     Patient is willing and able to regularly attend the examination and follow-up appointments
     Written informed consent
    • Männer oder Frauen im Alter von 18 Jahren oder älter
    • Patienten mit CKD Stadium 5 unter stabiler Hämodialysebehandlung (3 mal wöchentliche Dialyse seit mindestens 6 Monaten vor dem Screening)
    • Studienvisiten müssen entweder am Sonntag, Montag (Dialyse morgens, mittags / nachmittags, abends oder über Nacht) oder am Dienstag (Dialyse morgens, mittags oder nachmittags) durchgeführt werden
    • Dialyse-Regime muss bis zur W12-Untersuchung unverändert bleiben
    • Unveränderte Phosphatbinder-Therapie mit einem oder zwei Phosphatbindern für mindestens 1 Monat vor dem Screening
    • Serum-Phosphat-Konzentration bei Screening <2,80 mmol/l (8,7 mg/dl) und >1,45 mmol/l (4,5 mg/dl)
    • Bei Patienten mit Vitamin-D Supplementation oder aktiver Vitamin-D-Therapie muss die Dosis seit mindestens 1 Monat vor dem Screening konstant geblieben sein
    • Bei Patienten unter Calcimimetika-Behandlung muss die Dosis bei Screening seit mindestens 1 Monat konstant geblieben sein
    • Vorliegen einer schriftlichen Einwilligungserklärung
    E.4Principal exclusion criteria
     Chronic heart failure NYHA III or IV in adequate volume state.
     Cardiac decompensation requiring hospital admission in the last 6 months
     Myocardial infarction in the last 6 months
     Uncontrolled hypertension although receiving 3 or more antihypertensive medications
     Patient with planned parathyroidectomy in the next year
     High urgency transplant candidate as defined at Eurotransplant at screening
     Peptic ulcers in the last 6 months
     Gastro-intestinal haemorrhage –except anal skin tags- in the last 6 months
     Patients with dysphagia or swallowing difficulties in the last 6 months
     Intestinal obstructions / ileus in the last 6 months
     Patients with impaired intestinal absorption (e.g. impaired intestinal motility, pseudo-
    obstructions, megacolon, short bowel syndrome, Crohn's or coeliac disease)
     Active gastroparesis, identifiable from nausea and vomiting
     Rhabdomyolysis
     Severely impaired vision (e.g. macular edema, severe nonproliferative retinopathy or
    proliferative retinopathy)
     Severe liver disease (especially persistent Hepatitis B/C/D with viral load, cirrhosis or
    severe fibrosis according to IASL 4 (Numerous bridges or septa, liver cancer, liver transplantation planned or performed))
     Hypersensitivity to nicotinamide or one of the other ingredients
     Absolute or severe lactose intolerance
     Simultaneous participation in another clinical trial within the last 2 months
     Patients who are legally incapacitated or are institutionalized by court or official order
     Patient with an inadequate command, or no command of written and spoken national
    language
     Failure to use highly-effective contraceptive methods in women of child-bearing age. The
    following contraceptive methods with a Pearl Index lower than 1% are regarded as
    highly-effective:
     Tubal ligation (female sterilisation)
     Intrauterine devices that release hormones (hormone spiral)
     Vaginal hormonal contraception
     Dermal hormonal contraception
     Contraceptive plaster
     Long-acting injectable contraceptives
     Implants that release progesterone
     Double barrier methods
    o This means that the following are not regarded as safe: condom plus spermicide, simple barrier methods (vaginal pessaries, condom, female condoms), copper spirals, the rhythm method, basal temperature method, and the withdrawal method (coitus interruptus).
     sexual abstinence or vasectomised partner can also considered as adequate as investigators discretion (taking patient’s medical history and lifestyle into account)
     Alcohol, drug or pharmaceutical abuse within the last year prior to trial commencement
     Known persistent (> 1 month before inclusion) non compliance (< 70%) with prescribed
    medication regimes.
     Nursing mother
    • Chronische Herzinsuffizienz NYHA III oder IV bei adäquatem Status des Flüssigkeitsvolumens
    • Krankenhausaufenthalt aufgrund kardialer Dekompensation innerhalb der letzten 6 Monate
    • Herzinfarkt innerhalb der letzten 6 Monate
    • Nicht kontrollierte Hypertonie trotz Verschreibung von 3 oder mehr Antihypertensiva
    • Patienten mit geplanter Parathyreoidektomie im nächsten Jahr
    • Transplantationskandidaten mit hoher Dringlichkeit entsprechend Eurotransplant-Klassifikation
    • Magengeschwüre in den letzten 6 Monaten
    • Magen-Darm-Blutungen (ohne Hämorriden) in den letzten 6 Monaten
    • Patienten mit Dysphagie oder Schluckbeschwerden in den letzten 6 Monaten
    • Darmverschluss / Ileus in den letzten 6 Monaten
    • Patienten mit eingeschränkter intestinaler Resorption (z.B. beeinträchtigte Darmmotilität, Pseudoobstruktionen, Megakolon, Kurzdarmsyndrom, Morbus Crohn oder Zöliakie)
    • Aktive Gastroparese gekennzeichnet durch Übelkeit und Erbrechen
    • Rhabdomyolyse
    • Starke Sehbehinderung (z.B. Makulaödem, schwere nicht-proliferative oder proliferative Retinopathie)
    • Schwere Lebererkrankungen (speziell fortbestehende Hepatitis B/C/D mit Viruslast, Zirrhose oder schwere Zirrhose entsprechend IASL (zahlreiche Brücken oder Septen, Leberkarzinom, geplante oder stattgehabte Lebertransplantation))
    • Überempfindlichkeit gegen Nicotinamid oder einen der sonstigen Inhaltsstoffe der Prüfmedikation
    • Absolute oder schwerwiegende Laktoseintoleranz
    • Innerhalb der letzten 2 Monate oder gleichzeitige Teilnahme an einer weiteren klinischen Prüfung
    • In der Geschäftsfähigkeit eingeschränkte Personen
    • Personen, die auf gerichtliche oder behördliche Anordnung in einer Anstalt untergebracht sind
    • Patienten, die der nationalen Sprache und Schrift nicht oder nur unzureichend mächtig sind
    • Frauen im gebärfähigen Alter ohne ausreichenden Konzeptionsschutz
    • Schlecht eingestellter Diabetes (HbA1c > 9%) bei Screening
    • Thrombozytenzahl < 120/nl bei Screening
    • BMI < 19 bei Screening
    • Serum-Calcium > 2.65 mmol/l (10.6 mg/dl) bei Screening
    • Kreatinkinase-Wert ≥ 2-fach des Normbereichs (Männer > 380 U/l, Frauen > 334 U/l) bei Studienbeginn
    • Transaminasen (AST oder ALT) mehr als 3-fach erhöht gegenüber Norm bei Screening
    • Hämoglobinspiegel < 8 g/dl bei Screening
    • Mittlerer Blutdruck aus den letzten 6 Messungen in den letzten beiden Wochen vor Screening > 160 mmHg systolisch oder > 100 mmHg diastolisch
    • Geplante Änderung des Dialyseregimes innerhalb des nächsten Jahres
    • Schwangerschaft oder positiver Schwangerschaftstest bei Screening
    E.5 End points
    E.5.1Primary end point(s)
    Serum phosphate concentration
    Serum Phosphat-Konzentration
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks post baseline
    E.5.2Secondary end point(s)
     Serum phosphate concentration: end value 24 and 52 weeks post baseline
     Change from screening serum phosphate levels, end value 12, 24 and 52 weeks post
    baseline
     Number of responders/non-responder of all randomized patients belonging to the ITT-
    population. Patients will be considered as non-responders, if the phosphate value is
    missing at the specific measurement time point (week 12, 24, and 52) or if the study
    medication was discontinued before the time point. For the remaining cases, a response
    is defined according to the following 4 definitions separately for each of the 3
    measurement time points at week 12, 24 and 52:
    1. serum phosphate concentration ≤ 1.78 mmol/l (5,5 mg/dl)
    2. serum phosphate concentration ≤ 1.45 mmol/l (4.5 mg/dl)
    3. Individual serum phosphate target range achieved
     (1.0 mmol/l (3.1 mg/dl) to 1.45 mmol/l (4.5 mg/dl) in patients with screening
    phosphate levels < 2.0 mmol/l (6.25 mg/dl)
     1.0 mmol/l (3.1 mg/dl) to 1.78 mmol/l (5.5 mg/dl) in patients with screening
    phosphate levels ≥ 2.0 mmol/l (6.25 mg/dl
    4. Individual serum phosphate concentration improved ≥ 0.2 mmol/l (0.6 mg/dl)
    compared to screening
     Number of responders applying the definition of responders above but limiting the
    analyses to patients under study medication at the end of the trial with no missing data at
    the concerning measurement time point.

     Serum calcium concentration 12, 24 and 52 weeks post baseline
     iPTH 12, 24 and 52 weeks post baseline
     HDL, LDL and triglycerides 12, 24 and 52 weeks post baseline
     Number of patients receiving rescue therapy due to elevated serum phosphate
    E.5.2.1Timepoint(s) of evaluation of this end point
    different time points (see secondary end points)
    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 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.8.2.4Number 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA85
    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 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 years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    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: 315
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 385
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 700
    F.4.2.2In the whole clinical trial 700
    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)
    normal treatment of that condition
    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 Decision2014-10-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-09-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-14
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