Clinical Trials Register

Summary
EudraCT Number:	2015-004137-27
Sponsor's Protocol Code Number:	ScanCLAD_1.0(formerVersion_0.1)
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-06-10
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

Denmark - DHMA

A.2

EudraCT number

2015-004137-27

A.3

Full title of the trial

A Scandinavian controlled, randomized, open-label, and multi-centre study evaluating if once-daily tacrolimus or twice-daily cyclosporin, reduces the 3-year incidence of chronic lung allograft dysfunction after lung transplantation

A.3.1

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

A clinical study in Scandinavian wherein a once-daily immunosuppresive drug reduces the 3-year incidence of rejection after lung transplantationor, compared with twice-daily drug.

A.3.2

Name or abbreviated title of the trial where available

ScanCLAD

A.4.1

Sponsor's protocol code number

ScanCLAD_1.0(formerVersion_0.1)

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	Transplantationscntrum, Sahlgrenska Universitetssjukhuset
B.1.3.4	Country	Sweden
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	Astellas Pharma Europe LTD
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gothia Forum
B.5.2	Functional name of contact point	Dennis Lindholm
B.5.3	Address:
B.5.3.1	Street Address	Sahlgrenska Universitetssjukhuset, Gröna stråket 12
B.5.3.2	Town/ city	Göteborg
B.5.3.3	Post code	413 45
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46700823610
B.5.6	E-mail	dennis.lindholm@vgregion.se

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	Advagraf (tacrolimus)
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe L.V.
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	TACROLIMUS
D.3.9.1	CAS number	104987-11-3
D.3.9.4	EV Substance Code	SUB10797MIG
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	0.5 to 5
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	Sandimmun Neoral (cyklosporine A)
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Sverige AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	Ciclosporin
D.3.9.3	Other descriptive name	CICLOSPORIN A
D.3.9.4	EV Substance Code	SUB129839
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	10 to 100
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

Recipients of primary bilateral lung transplant allograft

E.1.1.1

Medical condition in easily understood language

Recipients of primary bilateral lung transplant allograft

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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	10050433
E.1.2	Term	Prophylaxis against lung transplant rejection
E.1.2	System Organ Class	100000004865

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 study the cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) (including both Bronchioloitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation (LTx).

E.2.2

Secondary objectives of the trial

To compare the efficacy between treatment regimes by assessing the difference in mGFR, at 3 months.
The cumulative incidence of PGD at 72 hours.
Patient survival at 1 and 3 year.
The cumulative incidence of AR and CLAD at 6 months, 1 and 3 year.
Number of rejections.
The cumulative incidence of BOS and RAS at 6 months, 1 and 3 year.
The composite measure of freedom from AR, CLAD, graft survival, and patient survival at 12, 24 and 36 months.
Development of donor specific antibodies (DSA) at 12, 24 and 36 months, according to specific protocol.
Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance, at 12, 24 and 36 months.
Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different formulas, at 3, 12, 24 and 36 months.

The cumulative incidence of PTDM at 6, 12, 24 and 36 months after transplantation as defined below;
Cumulative incidence of Post transplant Diabetes Mellitus at 12, 24 and 36 months.
Incidence of antihypertensive and lipid lowering drugs at 12, 24 and 36 months.
Development and magnitude of proteinuria at 12, 24 and 36 months.
Lipid profile at 12, 24 and 36 months.
Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
Cumulative incidence of malignancy stratified by PTLD at 36 months.
Safety and tolerability.
Quality of life, at 12, 24 and 36 months.
Define the pharmacokinetics of Tacrolimus in non-CF patients (n=12) and all included CF patients (n=15-20).
Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro.
Occurrence of treatment failures up to or at 36 months.
Recovery of right heart function irrespective of diagnosis in patients with PAH.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Substudy protocol date: 2016-02-15
1. Donor specific antibodies (DSA) and its relation to CLAD and clinical outcome.
2. PTDM – and oral glucose test.
3. Immunological Equipotency of tacrolimus QD and CyA A in vivo and in vitro.
4. Quality of life assessments.
5. CMV and its relation to CLAD
6. CLAD and imaging
7. Pharmacokinetics of Tacrolimus and Advagraf in non-CF and CF patients.
8. Recovery of RV failure in PAH
9. Donor risk factors and its corelation to CLAD and PGD
10. Molecular biomarkers as potential targets for therapeutic strategies after LTx
11. LSort – Lung score and gene activation as biomarker of rejection
12. Waist-to-height (WHtR) as a predictor for CLAD and survival after LTx
13. Cytokines and inflammatory variables in lung transplantation

E.3

Principal inclusion criteria

1. Male or female lung recipients 18-70 years of age undergoing primary double (including size reduction) lung Transplantation (LTx).
2. Patient willing and capable of giving written informed consent for study participation and anticipated to be able to participate in the study for 36 months.

E.4

Principal exclusion criteria

1. Recipients of multiorgan transplant, and or previously transplanted with any organ, including previous lung transplantation.
2. Patients with hypersensitivity to, or other reasons to not be able to take the immunosuppressive drugs used in the study.
3. Donor lung cold ischemic time > 12 hours.
4. Patients who previously have been treated with anti-thymocyte globuline preparations (e.g. ATG-Fresenius®, Thymoglobulin®).
5. Patients who are recipients of ABO-incompatible transplants.
6. Patients with platelet count < 50,000/mm3 at the evaluation before transplantation.
7. Patients who are unlikely to comply with the study requirements.
8. Patients, and/or those receiving organs from donors, who are positive for HIV, Hepatitis B surface antigen or Hepatitis C virus.
9. Patients with donor greater than 75 years.
10. Patient who have received an unlicensed drug or therapy within one month prior to study entry or if such therapy is to be instituted post-transplantation.
11. Patient unable to participate in the study for the full 36-month period
12. Patients with any past (within the past 3-5 years) or present malignancy (other than excised basal cell carcinoma).
13. Females capable of becoming pregnant must have a negative pregnancy test prior to randomization.

E.5 End points

E.5.1

Primary end point(s)

Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) (including both Bronchioloitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation (LTx).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 3 years of treatment with study drug.

E.5.2

Secondary end point(s)

1. Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance at 3 months.
2. The cumulative incidence of primary graft dysfunction (PGD) at 72 hours.
3. Patient survival at 1 and 3 year.
4. The cumulative incidence of acute allograft rejection (AR) and CLAD at 6 months, 1 and 3 year.
5. Determined by clinical criteria, computed tomography (CT) and trans bronchial lung biopsy with broncho-alveolar lavage (BAL).
6. Number of rejections (cellular and antibody mediated), stratified by biopsy and non-biopsy verified rejections.
7. The cumulative incidence of BOS and RAS at 6 months, 1 and 3 year.
8. The composite measure of freedom from AR, CLAD, graft survival, and patient survival at 12, 24 and 36 months after transplantation. The diagnosis of AR will be based on either clinical signs or histological biopsy confirmation using the ISHLT Working Classification of Lung Transplant Pathology.
9. Development of donor specific antibodies (DSA) at 12, 24 and 36 months, according to specific protocol.
10. Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance, at 12, 24 and 36 months.
11. Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different formulas, at 3, 12, 24 and 36 months.
12. The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) at 6, 12, 24 and 36 months after transplantation as defined below;
o Cumulative incidence of:
 ≥2 Fasting Plasma Glucose (FPG) ≥7,0 mmol/L ≥ 30 consecutive days apart.
 Oral hypoglycaemic treatment ≥30 consecutive days.
 Insulin ≥30 consecutive days.
 HgbA1c ≥6.5% (according to American Diabetes Association – ADA)
 Symptoms of Diabetes and Random Plasma Glucose (RPG) ≥ 11.1 mmol/L.
 2-hour Plasma Glucose (2-hPG) ≥ 11.1 mmol/L during an oral glucose tolerance test (OGTT).
13. Use of antidiabetic medication at 6, 12, 24 and 36 months.
14. Incidence and number of antihypertensive and lipid lowering drugs at 12, 24 and 36 months.
15. Development and magnitude of proteinuria at 12, 24 and 36 months.
16. Lipid profile at 12, 24 and 36 months.
17. Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
18. Cumulative incidence of malignancy stratified by PTLD and all other at 36 months.
19. Safety and tolerability.
20. Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ), both self-administered, at 12, 24 and 36 months.
21. Define the pharmacokinetics of Tacrolimus in non-CF patients (n=12) and all included CF patients (n=15-20) undergoing primary lung transplantation (LTx) treated with an Advagraf® based-immunosuppression.
22. Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro, according to separate protocol.
23. Occurrence of treatment failures up to or at 36 months; defined as a composite endpoint of graft loss, death, loss to follow up or discontinuation due to lack of efficacy or toxicity (at least one condition must be present).
24. Recovery of right heart function irrespective of diagnosis in patients with pulmonary arterial hypertension (PAH, categories 1-5 according to WHO 1-5).

E.5.2.1

Timepoint(s) of evaluation of this end point

Se above (E.5.2)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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)

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

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

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:

222

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

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

242

F.4.2.2

In the whole clinical trial

242

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)

Since lifelong CNI treatment after lung transplantation is needed investigators will discuss following treatment with the patient in quesion.

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

2016-08-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-24

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

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