Clinical Trials Register

Summary
EudraCT Number:	2014-000924-11
Sponsor's Protocol Code Number:	CTCL
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-03-13
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

Germany - BfArM

A.2

EudraCT number

2014-000924-11

A.3

Full title of the trial

Phase IIA Study on therapy with the NF-kB inhibiting and apoptosis inducing drug dimethylfumarate (DMF) in Patients with Cutaneous T cell lymphoma.

A.3.1

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

Treatment of patients with cutaneous T-Zell Lymphom

Studie zur Behandlung von Patienten mit kutanem T-Zell Lymphom

A.4.1

Sponsor's protocol code number

CTCL

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	Ruprecht-Karls-University Heidelberg, Medical Faculty Mannheim represented by the chancellor
B.1.3.4	Country	Germany
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	Helmholtz-Allianz für Immuntherapie
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	University Medical Center Mannheim
B.5.2	Functional name of contact point	Dermatology
B.5.3	Address:
B.5.3.1	Street Address	Theodor-Kutzer-Ufer 1-3
B.5.3.2	Town/ city	Mannheim
B.5.3.3	Post code	68167
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496213832280
B.5.6	E-mail	jan.nicolay@umm.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	Yes
D.2.1.1.1	Trade name	Fumaderm initial
D.2.1.1.2	Name of the Marketing Authorisation holder	Biogen Idec GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Fumaderm initial
D.3.4	Pharmaceutical form	Gastro-resistant 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	Dimethyl fumarate
D.3.9.1	CAS number	624-49-7
D.3.9.3	Other descriptive name	DIMETHYL FUMARATE
D.3.9.4	EV Substance Code	SUB13608MIG
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	30
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ethyl fumarate Calcium
D.3.9.1	CAS number	62008-22-4
D.3.9.3	Other descriptive name	Ethyl hydrogen fumarate Calcium salt (2:1)
D.3.9.4	EV Substance Code	SUB13742MIG
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	67
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ETHYL FUMARATE MAGNESIUM
D.3.9.1	CAS number	83918-60-9
D.3.9.3	Other descriptive name	Ethyl hydrogen fumarate Magnesium salt (2:1)
D.3.9.4	EV Substance Code	SUB13743MIG
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	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ETHYL FUMARATE ZINC
D.3.9.1	CAS number	62008-21-3
D.3.9.3	Other descriptive name	Ethyl hydrogen fumarate Zinc salt (2:1)
D.3.9.4	EV Substance Code	SUB13744MIG
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	3
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	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	Fumaderm
D.2.1.1.2	Name of the Marketing Authorisation holder	Biogen Idec GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Fumaderm
D.3.4	Pharmaceutical form	Gastro-resistant 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	Dimethyl fumarate
D.3.9.1	CAS number	624-49-7
D.3.9.3	Other descriptive name	DIMETHYL FUMARATE
D.3.9.4	EV Substance Code	SUB13608MIG
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	120
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ethyl fumarate Calcium
D.3.9.1	CAS number	62008-22-4
D.3.9.3	Other descriptive name	Ethyl hydrogen fumarate Calcium salt (2:1)
D.3.9.4	EV Substance Code	SUB13742MIG
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	87
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ETHYL FUMARATE MAGNESIUM
D.3.9.1	CAS number	83918-60-9
D.3.9.3	Other descriptive name	Ethyl hydrogen fumarate Magnesium salt (2:1)
D.3.9.4	EV Substance Code	SUB13743MIG
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	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ETHYL FUMARATE ZINC
D.3.9.1	CAS number	62008-21-3
D.3.9.3	Other descriptive name	Ethyl hydrogen fumarate Zinc salt (2:1)
D.3.9.4	EV Substance Code	SUB13744MIG
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	3
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

Cutaneous T cell lymphoma

E.1.1.1

Medical condition in easily understood language

Cutaneous T cell lymphoma (CTCL) is a rare malignant tumor of T lymphocytes, a subgroup of white blood cells. It can involve blood, skin and lymph nodes. So far, the disease is not yet curable.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028508
E.1.2	Term	Mycosis fungoides/Sezary syndrome
E.1.2	System Organ Class	100000004864

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 primary objective of the trial is to evaluate safety and efficacy of DMF treatment in patients with CTCL stage ≥Ib according to EORTC-ISCL consensus classification.

E.2.2

Secondary objectives of the trial

Secondary objectives of the study will be:
• To determine effects of DMF on the systemic CTCL involvement using the established CTCL severity index/modified severity assessment tool (mSWAT)19,20
• Effects of DMF on life quality of CTCL patients using the well-established dermatologic life quality index (DLQI)21
• Effects of DMF on pruritus and sensations of “burning pain” measured by a visual analog scales (VAS)
• DMF effect on immunologic and morphologic blood involvement if applicable using FACS
• changes in immunologic and cell death markers in skin samples of the patients using histologic, immune histologic and molecular biological methods

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histopathologically confirmed Mycosis fungoides or Sézary syndrome (CTCL stage ≥ Ib according to EORTC-ISCL consensus classification2) at study entry with progressive, persistant or recurrent disease
• Pretreatment with topical steroid and/or local PUVA, if the prior therapy is not possible anymore or if there is unsatisfactory response to PUVA or local steroid respectively. Patients with history of first line systemic treatment (interferone or bexarotene) may be included in the study too
• Karnofsky index ≥70 % (according to Karnofsky DA, Burchenal JH. (1949). "The Clinical Evaluation of Chemotherapeutic Agents in Cancer." In: MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. Page 196)
• Life expectancy > 3 months
• Age ≥ 18 years
• Adequate organ function:
• differential blood count: hemoglobin ≥ 10 g/dl without transfusions, leukocyte count > 3000/µl, lymphocyte count > 700/µl
• liver enzymes ≤ 2 x upper limit of normal (ULN)
• serum creatinine ≤ 1.5 mg/dl or calculate creatinine clearance ≥ 50 ml/min,
• Negative Pregnancy test from blood, agreement for efficient contraception in male and female patients unless infertility is documented (DMF is not approved during pregnancy)
• Ability to understand character and individual consequences of the clinical trial and to provide written informed consent to participate in the study
• written informed consent must be given according to ICH/GCP, and national/local regulations, before patient registration and prior to any study specific procedures.

E.4

Principal exclusion criteria

• Another active malignant disease with the following exceptions:
• Basal or squamous cell carcinoma of the skin
• In situ carcinoma of the cervix or the skin
• Topical chemotherapy, superficial radiotherapy, photopheresis or systemic CTCL treatment within 28 days before study therapy initiation
• Severe systemic disease or infection at study therapy initiation
• Prior treatment with DMF or simultaneous topical DMF treatment
• Contraindications for treatment with DMF (known hypersensibility to the drug, severe gastrointestinal disease (like ulcerations), Alcohol abuse, other obligately liver- or nephrotoxic medication, known clinically apparent renal or hepatic insufficiency)
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Participation in other clinical studies within 14 days before study therapy initiation
• Pregnant or lactating patients

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint of the study will be the response rate of patients to DMF treatment. Practically this will be assessed by evaluating the eventual change in modified Severity Weighted Assessment (mSWAT) after an oral DMF treatment period of 24 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

after 24 weeks

E.5.2

Secondary end point(s)

Secondary endpoints will be changes in CTCL severity index, influence of DMF therapy on DLQI, pruritus and pain as well as effects of DMF treatment on blood involvement if applicable. (In patients with stage IV disease the CD4/CD8 ratio and the number of circulating Sézary cells will be monitored.) In addition changes in immunologic and cell death markers in the skin of treated patients will be a secondary endpoint

E.5.2.1

Timepoint(s) of evaluation of this end point

End of Trial

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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)

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

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:

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.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)

Patients who needed further Treatment after study end will be treated according to current Standard care. Patients who discontinued because of pogression will be followed up according to Standard care.

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

2015-06-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-10-20

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