Clinical Trials Register

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

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2013-000488-95

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

NOPHOS Trial

NOPHOS Studie

A.4.1

Sponsor's protocol code number

6520-9961-04

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	MEDICE Arzneimittel Pütter GmbH & Co. KG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MEDICE Arzneimittel Pütter GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MEDICE Arzneimittel Pütter GmbH & Co. KG
B.5.2	Functional name of contact point	Medizinische Abteilung
B.5.3	Address:
B.5.3.1	Street Address	Kuhloweg 37
B.5.3.2	Town/ city	Iserlohn
B.5.3.3	Post code	58638
B.5.3.4	Country	Germany
B.5.4	Telephone number	492371937512
B.5.5	Fax number	492371937360
B.5.6	E-mail	a.engels@medice.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Nicotinamid 250 mg retard Kapseln
D.3.4	Pharmaceutical form	Modified-release capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NICOTINAMIDE
D.3.9.1	CAS number	98-92-0
D.3.9.2	Current sponsor code	M111, nicotinamide MR
D.3.9.3	Other descriptive name	niacinamide, pyridine 3-carboxamide, pyridine 3-carboxylic acid amid, nicotinic acid amide, nicotinamide, vitamin PP
D.3.9.4	EV Substance Code	SUB09246MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Dialysis-dependent patients with hyperphosphatemia

Dialysepflichtige Patienten mit Hyperphosphatämie

E.1.1.1

Medical condition in easily understood language

Dialysis-dependent patients with elevated phosphat levels

Dialysepflichtige Patienten mit erhöhtem Blutphosphatspiegel

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10020712
E.1.2	Term	Hyperphosphatemia
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary objectives of the trial

not applicable

E.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary end point(s)

Serum phosphate concentration

Serum Phosphat-Konzentration

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks post baseline

E.5.2

Secondary 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.5.2.1

Timepoint(s) of evaluation of this end point

different time points (see secondary end points)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

315

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

385

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

700

F.4.2.2

In 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-10-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-03-14

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