Clinical Trials Register

Summary
EudraCT Number:	2013-002819-10
Sponsor's Protocol Code Number:	M13-621
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-11-12
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

Spain - AEMPS

A.2

EudraCT number

2013-002819-10

A.3

Full title of the trial

A Double-blind, Randomized, Multicenter, Cross-over Study to Compare the Effect of Creon N and Creon® on Fat Digestion in Subjects ? 12 years of Age with Pancreatic Exocrine Insufficiency Due to Cystic Fibrosis

Estudio doble ciego, aleatorizado, multicéntrico y cruzado para comparar el efecto de Kreon N y Kreon® sobre la digestión de grasas en sujetos de 12 años o más edad con insuficiencia pancreática exocrina debida a fibrosis quística.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

M13-621

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	Abbott Laboratories GmbH
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	Abbott Laboratories GmbH
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	Abbott Laboratories GmbH
B.5.2	Functional name of contact point	Senior Clinical Trial Manager
B.5.3	Address:
B.5.3.1	Street Address	Freundallee 9A
B.5.3.2	Town/ city	Hannover
B.5.3.3	Post code	30173
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49511 6750 2733
B.5.5	Fax number	+49511 6750 2464
B.5.6	E-mail	gregor.eibes@abbott.com

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	KREON N 25000
D.3.4	Pharmaceutical form	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	Not applicable
D.3.9.1	CAS number	8049-47-6
D.3.9.2	Current sponsor code	KREON N
D.3.9.3	Other descriptive name	PANCREATIN
D.3.9.4	EV Substance Code	SUB12545MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/kg international unit(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Kreon 25000
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Laboratories GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	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	not assigned
D.3.9.1	CAS number	8049-47-6
D.3.9.3	Other descriptive name	PANCREATINA
D.3.9.4	EV Substance Code	SUB12545MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pancreatic exocrine Insufficiency due to Cystic Fibrosis

Insuficiencia pancreática exocrina debida a Fibrosis Quística

E.1.1.1

Medical condition in easily understood language

maldigestion of diatery macronutrients (pancreas not producing enough enzymes for digestion of fat, sugars and proteins) in Cystic Fibrosis

Mala digestión de macronutrientes de la dieta (el páncreas no produce suficientes encimas para la digestión de la grasa, azúcares y proteínas) in Fibrosis Quística

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the therapeutic equivalence of Creon N 25000 with Creon® 25000 on coefficient of fat absorption (CFA) in adolescent and adult subjects with pancreatic exocrine insufficiency (PEI) due to cystic fibrosis (CF).

Evaluar la equivalencia terapéutica de Kreon N 25000 con Kreon® 25000 sobre el coeficiente de absorción de grasas (CAG) en sujetos adolescentes y adultos con insuficiencia pancreática exocrina (IPE) debida a fibrosis quística (FQ).

E.2.2

Secondary objectives of the trial

To investigate the effect of Creon N 25000 and Creon® 25000 on coefficient of nitrogen absorption (CNA),on stool fat and clinical symptomatology (stool frequency, stool consistency, abdominal pain, flatulence).
Safety Objectives:
To evaluate the short-term safety of Creon N 25000 and Creon® 25000, including vital signs, body weight, physical examination, safety laboratory values, and adverse events (AEs).

Estudiar el efecto de Kreon N 25000 y Kreon® 25000 sobre el coeficiente de absorción de nitrógeno (CAN), sobre la grasa fecal y la sintomatología clínica (frecuencia de las deposiciones, consistencia de las heces, dolor abdominal, flatulencia).
Objetivos de seguridad
Evaluar la seguridad a corto plazo de Kreon N 25000 y Kreon® 25000, incluyendo constantes vitales, peso corporal, exploración física, valores analíticos de seguridad y acontecimientos adversos (AA).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent given by the subject, or the parents, or a legally acceptable representative. If required by the Institutional Review Board/Ethics Committee (IRB/IEC), assent will be given by the subject
2. Age ? 12 years
3. Subjects who are able to swallow capsules with each meal and snacks
4. Diagnosis of CF confirmed by two positive chloride sweat tests or gene analysis
5. Diagnosis of pancreatic exocrine insufficiency proven by:
a. CFA < 70% without supplementation
b. or
Human fecal elastase < 50 µg/g stool
6. Currently receiving treatment with a commercially available pancreatic enzyme product and on a continuous dose of this product for more than 3 months
7. Clinically stable condition without evidence of acute respiratory disease within 1 month of enrollment
8. Stable body weight defined as no more than a 5% decline within 3 months of enrolment
9. Females of child-bearing potential should agree to continue using a medically acceptable method of birth control throughout the study and for 30 days immediately after the last dose of study drug. Medically acceptable methods of birth control include bilateral tubal ligation or the use of either a contraceptive implant, a contraceptive injection (Depo-Provera?), an intrauterine device, or an oral contraceptive taken within the past 3 months where the subject agrees to continue using during the study or to adopt another birth control method, or a double-barrier method which consists of a combination of any two of the following: diaphragm, cervical cap, condom, or spermicide.

1. Consentimiento informado firmado por el sujeto, los progenitores o un representante legal. Si el Comité Ético de Investigación Clínica/Comité de Revisión Institucional (CEIC/IRB) lo requiere, se obtendrá el asentimiento del sujeto.
2. Edad ? 12 años.
3. Sujetos que sean capaces de tragar las cápsulas con cada comida o tentempié.
4. Diagnóstico de FQ confirmado por dos pruebas positivas de cloruro en sudor o análisis génico.
5. Diagnóstico de insuficiencia pancreática exocrina demostrado por:
a. CAG < 70% sin suplementación
b. o
Elastasa fecal humana < 50 µg/g de heces.
6. Estar recibiendo actualmente tratamiento con un producto de enzimas pancreáticas disponible en el mercado y a una dosis continua de este producto durante más de 3 meses.
7. Enfermedad clínicamente estable sin indicios de enfermedad respiratoria aguda en el mes previo a la inclusión en el estudio.
8. Peso corporal estable definido como una reducción no superior al 5% en los 3 meses previos a la inclusión en el estudio.
9. Las mujeres en edad fértil deben estar de acuerdo en continuar usando un método anticonceptivo médicamente aceptable durante todo el estudio y durante los 30 días inmediatamente posteriores a la última dosis del fármaco del estudio. Los métodos anticonceptivos médicamente aceptables son: ligadura de trompas bilateral o el uso de un implante anticonceptivo, inyección anticonceptiva (Depo-Provera?), dispositivo intrauterino o anticonceptivo oral tomado durante los últimos 3 meses y que la paciente acepte continuar tomando durante el estudio o adoptar otro método anticonceptivo, o un método de doble barrera que consista en una combinación de cualquiera de los siguientes métodos: diafragma, capuchón cervical, preservativo o espermicida.

E.4

Principal exclusion criteria

1. Evidence of cardiovascular, respiratory, urogenital, gastrointestinal/hepatic (except underlying disease), hematologic/immunologic, head, ears, eyes, nose, throat, dermatologic/connective tissue, musculoskeletal, metabolic/nutritional (except underlying disease), endocrine (except diabetes mellitus), neurologic/psychiatric, allergy, recent major surgery, or other relevant diseases as revealed by history, physical examination and/or laboratory assessments, which could limit participation in or completion of the study
2. History of acute abdomen
3. History of fibrosing colonopathy
4. History of distal intestinal obstruction syndrome (DIOS) within 6 months prior to enrollment
5. Solid organ transplant or surgery affecting the large bowel other than appendectomy
6. Small bowel surgery that significantly affected absorptive capacity (e.g. gastrectomy or pancreatectomy)
7. Pregnancy or lactation
8. Any type of malignancy involving the digestive tract in the last 5 years
9. Celiac disease or Crohn?s disease
10. Known allergy to pancreatin or inactive ingredients (excipients) of pancreatin capsules
11. Suspected non-compliance or non-cooperation
12. Intake of experimental drugs within 30 days prior to study start
13. Mental disability or any other lack of fitness, in the Investigator's opinion, to preclude subject?s participation in or ability to complete the study
14. Diagnosis of human immunodeficiency virus in medical history.

1. Indicios de enfermedad cardiovascular, respiratoria, urogenital, gastrointestinal/hepática (a excepción de la enfermedad subyacente), hematológica/inmunológica, de cabeza, oídos, ojos, nariz y garganta, dermatológica/del tejido conjuntivo, osteomuscular, metabólica/nutricional (a excepción de la enfermedad subyacente), endocrina (a excepción de la diabetes mellitus), neurológica/psiquiátrica, alérgica, cirugía mayor reciente u otras enfermedades relevantes que revele la anamnesis, la exploración física y/o las evaluaciones de laboratorio, que pudieran limitar la participación o la realización del estudio.
2. Antecedentes de abdomen agudo.
3. Antecedentes de colonopatía fibrosante.
4. Antecedentes de síndrome de obstrucción intestinal distal (SOID) en los 6 meses previos a la inclusión en el estudio.
5. Trasplante de órgano sólido o cirugía que afecte al intestino grueso, aparte de apendectomía.
6. Cirugía del intestino delgado que afecte significativamente a la capacidad de absorción (p. ej., gastrectomía o pancreatectomía).
7. Embarazo o lactancia.
8. Un tipo de neoplasia maligna que afecte al tubo digestivo en los últimos 5 años.
9. Enfermedad celíaca o enfermedad de Crohn.
10. Alergia conocida a la pancreatina o a los componentes inactivos (excipientes) de las cápsulas de pancreatina.
11. Sospecha de falta de cumplimiento o falta de cooperación.
12. Uso de fármacos experimentales en los 30 días previos al inicio del estudio.
13. Discapacidad mental o cualquier otra falta de aptitud, en opinión del investigador, que imposibilite la participación o la capacidad para completar el estudio.
14. Diagnóstico de infección por el virus de inmunodeficiencia humana en los antecedentes patológicos.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy criterion is the CFA. CFA will be calculated from fat intake and fat excretion, according to the formula:
CFA (%) = 100 [fat intake ? fat excretion] / fat intake

El criterio principal de valoración de la eficacia es el CAG. El CAG se calculará a partir del aporte y la excreción de grasas, según la fórmula:
CAG (%) = 100 [aporte de grasas ? excreción de grasas] / aporte de grasas

E.5.1.1

Timepoint(s) of evaluation of this end point

The CFA values will be compared between the Creon N 25000 and Creon® 25000 treatment periods.

Los valores de CAG se comprarán entre los periodos de tratamiento con Kreon N 25000 y Kreon® 25000.

E.5.2

Secondary end point(s)

The Secondary efficacy criteria are the coefficient of nitrogen absorption (CNA), stool fat and clinical symptomatology (stool frequency, stool consistency, abdominal pain, flatulence).
The safety data collected during the study are vital signs, physical examination, safety laboratory values and adverses events.

Los criterios secundarios de valoración de la eficacia son el coeficiente de absorción de nitrógeno (CAN), la grasa fecal y la sintomatología clínica (frecuencia de las deposiciones, consistencia de las heces, dolor abdominal y flatulencia).
Los datos de seguridad que se recogerán durante el estudio incluyen: constantes vitales, exploración física, valores analíticos de la seguridad y acontecimientos adversos.

E.5.2.1

Timepoint(s) of evaluation of this end point

The values will be compared between the Creon N 25000 and Creon® 25000 treatment periods.
Safety parameters are assessed throughout the study.

Los valores se comprarán entre los periodos de tratamiento con Kreon N 25000 y Kreon® 25000.
Los parámetros de seguridad serán controlados a lo largo del estudio

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Russian Federation

E.8.7

Trial has a data monitoring committee

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

LVLP

LVLP última visita último paciente

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 months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

For minor childs, the parents will have to give their consent.

Para los menores de edad, los padres tendrán que otorgar su consentimiento

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

none

ninguno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-12-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-18

P. End of Trial
P.	End of Trial Status	Completed

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