Clinical Trials Register

Summary
EudraCT Number:	2019-002240-24
Sponsor's Protocol Code Number:	SIMASPK01b
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-06-27
Trial 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

Czechia - SUKL

A.2

EudraCT number

2019-002240-24

A.3

Full title of the trial

The evolution of advanced microangiopathic diabetic complications before and after simultaneous pancreas and kidney transplantation evaluated with progressive non-invasive methods

VÝVOJ ORGÁNOVÝCH KOMPLIKACÍ DIABETU PŘED A PO KOMBINOVANÉ TRANSPLANTACI LEDVINY A PANKREATU SLEDOVANÝ PROGRESIVNÍMI NEINVAZIVNÍMI METODAMI

A.3.1

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

Evolution of organ complications of diabetes mellitus after pancreas and kidney transplantation

Vývoj orgánových komplikací diabetu po transplantaci ledviny a pankreatu

A.3.2

Name or abbreviated title of the trial where available

SIMA-SPK 01b

A.4.1

Sponsor's protocol code number

SIMASPK01b

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	Institut klinické a experimentální medicíny
B.1.3.4	Country	Czechia
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Institut klinické a experimentální medicíny
B.4.2	Country	Czechia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut klinické a experimentální medicíny
B.5.2	Functional name of contact point	Klinika diabetologie
B.5.3	Address:
B.5.3.1	Street Address	Vídeňská 1958/9
B.5.3.2	Town/ city	Praha 4 - Krč
B.5.3.3	Post code	140 21
B.5.3.4	Country	Czechia
B.5.4	Telephone number	+420261364107
B.5.6	E-mail	frantisek.saudek@ikem.cz

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	Yes
D.2.1.1.1	Trade name	Rapamune
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Europe MA EEIG
D.2.1.2	Country which granted the Marketing Authorisation	Czechia
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	Tablet
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	SIROLIMUS
D.3.9.1	CAS number	53123-88-9
D.3.9.2	Current sponsor code	Rapamune
D.3.9.3	Other descriptive name	Rapamune
D.3.9.4	EV Substance Code	SUB10537MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 2
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.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	Cellcept
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Czechia
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
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	Cellcept
D.3.9.2	Current sponsor code	Cellcept
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	250 to 500
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.IMP: 3
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	Myfenax
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Czechia
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
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	Myfenax
D.3.9.2	Current sponsor code	Myfenax
D.3.9.3	Other descriptive name	MYCOPHENOLATE MOFETIL
D.3.9.4	EV Substance Code	SUB03360MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	250 to 500
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Surgical complications (hernia) after simultaneous pancreas and kidney transplantation

Chirurgické komplikace (zejména kýla) po kombinované transplantaci ledviny a slinivky

E.1.1.1

Medical condition in easily understood language

Risk of hernia in patients after pancreas and kidney transplantation

Riziko vzniku kýly po transplantaci ledviny a slinivky

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]

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

The incidence of incisional hernia in patients after simultaneous pancreas and kidney transplantation treated by sirolimus versus mycophenolate mofetil
- To compare the evolution of incisional hernia requiring surgery at 1, 2 and 3 years post-transplant

Incidence kýly v jizvě u pacientů po kombinované transplantaci ledviny a slinivky léčených sirolimem versus mykofenolátem mofetilem
Srovnání výskytu kýly v jizvě u obou léčebných skupin 1, 2 a 3 roky post-transplant

E.2.2

Secondary objectives of the trial

To compare other clinical parameters - graft survival, rejection rate, treatment tolerance, kidney and pancreas graft function and other parameters between the 2 groups

Porovnání ostatních klinických parametrů - funkce štěpů, rejekce, hospitalizace, komplikace mezi oběma skupinami

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 Male or female patients, of 18 to 65 years of age, with a pre- or an end-stage renal failure, Type 1-diabetic nephropathy, C¬-peptide-negative (defined as C-peptide upper limit 0.2 nmol/l . If C-peptide is > 0.1 nmol/l, mixed-meal test will be performed with C-peptide upper limit > 0.2 nmol/l).
2 Female patients of childbearing age must have a negative pregnancy test and must agree to maintain effective birth control practice throughout the study period (3 years).
3 Patient must have signed the Patient Informed Consent Form.
4 Patient is scheduled to be put on waiting-list for a primary simultaneous pancreas/kidney (SPK) cadaver transplant, with either intestinal or bladder and either portal or systemic venous drainages.

1 Muž nebo žena ve věku od 18 do 65 let, v pre-dialyzačním stádiu nebo v programu náhrady funkce ledvin (CKD 4-5) se selháním ledvin na podkladě diabet. nefropatie, C-peptid negativní, s diabetem 1.typu a diabetickou retinopatií.
2 Ženy ve fertilním věku musí mít negativní beta-HCG a musí souhlasit s používáním efektivní antikoncepční metody po dobu minimálně 2 let po dobu trvání studie.
3 Pacient podepsal formulář Informovaného souhlasu.
4 Pacient je indikován k zařazení do čekací listiny na kombinovanou transplantaci ledviny a slinivky.

E.4

Principal exclusion criteria

1. Patient is pregnant or breastfeeding.
2. Patient is allergic or intolerant to any drug comprising both immunosuppressive protocols
3. Patient has a positive T-cell cross-match on the most recent serum specimen.
4. Patient is known for active liver disease or has significant liver disease; defined by ASAT and ALAT serum levels greater than 3 times the upper limit of normal.
5. Patient has history of an established prothrombotic disorders.
6. Patient has malignancy or history of malignancy, with the exception of adequately treated localized squamous cell or basal cell carcinoma, without recurrence.
7. Patient has been included in another clinical trial protocol for any investigational drug within 4 weeks prior to randomization.
8. Patient has any form of substance abuse, psychiatric disorder or condition, which, in the opinion of the investigator, may invalidate communication.
9. Patient receives a kidney transplant from a living donor, or receives segmental pancreatic transplant, or a previous kidney transplant alone.
10. Donor is older than 65 years of age.
11. The use of any other commercial or investigational immunosuppressive drugs is prohibited if it is not clinically indicated.
12. Patient has a high immunological risk, defined as a PRA grade > 50%
13. Patient has a history of an extensive abdominal operation or a hernia in the abdominal wall

1. Pacientka je těhotná nebo kojící.
2. Pacient je alergický nebo u něj byla prokázána intolerance látek obsažených v imunosupresivních léčivech, která se budou v této studii podávat.
3. Pacient má pozitvní recentní T-cell cross-match.
4. Pacient má aktivní jaterní onemocnění definované jako elevace sérových transamináz (AST a ALT) nad trojnásobek normálních hodnot.
5. Pacient má prokázaný trombofilní stav a/nebo opakované trombózy v anamnéze.
6. Pacient má nebo v minulosti prodělal maligní onemocnění s výjimkou adekvátně léčeného lokalizovaného basocelulárního nebo spinocelulárního karcinomu bez rekurence.
7. Pacient byl ve 4 týdnech předcházejících randomizaci zařazen do jiné klinické studie zahrnující podávání studijního léčiva.
8. Pacient trpí formou abúzu, psychiatrickým či jiným onemocněním, ketré dle mínění investigátora může mít negativní dopad na komunikaci s pacientem.
9. Pacient podstoupil transplantaci ledviny od žijícího dárce, transplantaci segmentu slinivky a nebo transplantaci samotné slinivky po ledvině ze zemřelého dárce.
10. Dárce je starší než 65 let.
11. Použití jiných komerčně vyráběných nebo studijních imunosupresivních látek je zakázáno, pokud není klinická indikace.
12. Pacient má vysoké imunologické riziko definované jako PRA > 50%.
13. Pacient má v anamnéze rozsáhlou břišní operaci nebo kýlu v oblasti břišní stěny.

E.5 End points

E.5.1

Primary end point(s)

A new occurrence of an incisional hernia that is closely related to the transplantation procedure.
Hypothesis: There is no higher incidence of incisional hernia in sirolimus group compared to mycophenolate mofetil treated subjects

Nově vzniklá kýly v jizvě po transplantaci ledviny a slinivky
Hypotéza: není vyšší incidence kýly v jizvě po transplantaci ledviny a slinivky u subjektů léčených sirolimem ve srovnání s mykofenolát mofetilem

E.5.1.1

Timepoint(s) of evaluation of this end point

1, 2 and 3 years

1, 2 a 3 roky

E.5.2

Secondary end point(s)

Surgical complications
a) A new occurrence of hernia in other localizations without relation to SPK surgery
b) A new occurrence of a lymphocele or other surgical complications (ureteral leak, bleeding, infection) whenever after transplantation
General parameters
i. Patient and graft survival rates
ii. Rejection rate (kidney, pancreas or both). A kidney or pancreas biopsy will be taken as clinically indicated in case of suspected rejection of either kidney or pancreas. Biopsy analysis will be done according to latest BANFF 2017 criteria
iii. Treatment intolerance (permanent mycophenolate mofetil or sirolimus withdrawal for more than 40 days
iv. blood glucose and C-peptide levels (AUC) following a mixed meal test, average levels; blood glucose variability assessed a standard error of glucose levels registered using continuous glucose monitoring (CGM) with a subcutaneous glucose sensor
v. creatinine clearance rate calculated by the CKD-EPI formula and glycosylated hemoglobin values

Chirurg. komplikace:
nově vznilá kýly v jizvě jinde než v ráně
vznik lymfokély či jiné chirurg. komplikace
Obecné parametry:
přežití pacientů a štěpů
rejekce
Hospitalizace
NÚ léků a intolerance
Funkce štěpů:
kreatinin, clearance kreatinu
HbA1C, C peptid, meal-test, CGM (kontinuální motorace glykémie)

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2, 4, 12, 24 and 36 months after transplantation

1,2,4,12,24 a 36 měs. po Tx

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

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

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:

120

F.1.3

Elderly (>=65 years)

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

120

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

žádné

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

2019-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-12

P. End of Trial
P.	End of Trial Status	Ongoing

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