Clinical Trials Register

Summary
EudraCT Number:	2014-004806-14
Sponsor's Protocol Code Number:	TKS-2014-001
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:	2015-09-09
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

Germany - BfArM

A.2

EudraCT number

2014-004806-14

A.3

Full title of the trial

Single-Arm Study to Assess the Efficacy of UVADEX® (methoxsalen) Sterile Solution in Conjunction with the THERAKOS® CELLEX® Photopheresis System in Pediatric Patients with Steroid-Refractory Acute Graft vs Host Disease (aGvHD)

A.3.1

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

Single-Arm Study to see if UVADEX® together with the THERAKOS® CELLEX® Photopheresis System is effective in Pediatric Patients with Steroid-Refractory Acute Graft vs Host Disease (aGvHD)

A.4.1

Sponsor's protocol code number

TKS-2014-001

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	Therakos, Inc.
B.1.3.4	Country	United States
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	THERAKOS, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Therakos, Inc.
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	10 North High Street
B.5.3.2	Town/ city	West Chester
B.5.3.3	Post code	PA 19380
B.5.3.4	Country	United States
B.5.4	Telephone number	908.238.6461
B.5.6	E-mail	henri.boodee@mnk.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	Yes
D.2.1.1.1	Trade name	UVADEX™ 20 Mikrogramm/ml Lösung zur Modifikation einer Blutfraktion
D.2.1.1.2	Name of the Marketing Authorisation holder	Therakos UK Ltd.
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/06/374
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for blood fraction modification
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Extracorporeal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	methoxsalen
D.3.9.1	CAS number	298-81-7
D.3.9.3	Other descriptive name	METHOXSALEN
D.3.9.4	EV Substance Code	SUB14541MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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

Acute graft-versus-host disease (aGvHD)

E.1.1.1

Medical condition in easily understood language

Graft-versus-host disease is a complication of bone marrow
transplantation in which immune cells in the transplanted marrow
recognize the recipients as "foreign" and mount an immunological attack

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10018651
E.1.2	Term	Graft versus host disease
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of extracorporeal photopheresis (ECP) in pediatric patients with steroid-refractory aGvHD

E.2.2

Secondary objectives of the trial

• To assess the safety of ECP
• To assess the duration of response to ECP
• To assess the steroid-sparing effect of ECP
• To assess the organ-specific response to ECP

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet all of the following criteria:
1. Male or female 1 to 21 years of age at the time of consent.
2. Steroid-refractory grade B-D aGvHD
* Steroid-refractory is defined as a failure to respond to steroid treatment, with failure to respond defined as any grade B-D (IBMTR grading) aGvHD that shows progression ≥ 3 days, or no improvement by
5 days of treatment with 2 mg/kg/day of methylprednisolone or equivalent in patients with lower GI or liver disease, or skin disease associated with bullae. Grade D organ involvement will be limited to skin and liver.
* Steroid refractory may also be defined as a failure to respond to 1 mg/kg/day of methylprednisolone or equivalent in patients with disease confined to upper GI disease or lesser degrees of skin GvHD.
* Patients with lack of complete response after 2 weeks of steroid treatment.
3. A Lansky Scale Performance Status score ≥ 30.
4. Laboratory values are within the following limits, assessed within 3 days of the first study treatment:
* Absolute neutrophil count > 0.5 × 109/L
* Creatinine level < 2 times the upper limit of normal
5. For patients with isolated upper gastrointestinal (GI) symptoms, pre- Screening biopsy results to confirm diagnosis of aGvHD.
6. Female patients of childbearing potential and nonsterilized males who are sexually active with a female partner must be practicing highly effective, reliable, and medically approved contraceptive regimen throughout their participation in the study and for 3 months following the last ECP treatment. Or, for the US only, abstinence may be used in place of an approved contraceptive regimen. Females of childbearing potential are those who have reached the onset of menarche, or 8 years of age, whichever comes first. Approved contraceptive methods for female patients of childbearing potential or nonsterilized males who are sexually active with a female partner are as follows:
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* Established use of oral, injectable, or implanted hormonal methods of
contraception.
* Placement of an intrauterine device or intrauterine system.
7. Signed informed consent/assent is obtained before conducting any study procedures; the parent, legal guardian, or legally authorized representative of a minor must also provide written informed consent.

E.4

Principal exclusion criteria

Any of the following would exclude the patient from participation in the
study:
1. Currently enrolled in another clinical trial for the treatment of aGvHD.
2. Use of any experimental regimens or medication(s) for aGvHD treatment.
3. Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within 30 days prior to the first study treatment.
4. Overt signs of relapse of the underlying condition.
5. Uncontrolled viral, fungal, or bacterial infection.
6. Platelet count < 20.0 × 109/L, despite platelet transfusion.
7. Total bilirubin value ≥ 15 mg/dL.
8. Inability to tolerate the extracorporeal volume shifts associated with ECP treatment.
9. Uncontrolled GI bleeding.
10. Veno-occlusive liver disease.
11. Life expectancy < 4 weeks.
12. Patient requires invasive ventilation or vasopressor support.
13. Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection (proof of seronegativity within 6 months of screening is required).
14. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its excipients.
15. Known hypersensitivity or allergy to heparin and Anticoagulant Citrate Dextrose Formula-A (ACD-A).
16. Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus, albinism) or aphakia.
17. Coagulation disorders that cannot be corrected with simple transfusion.
18. Co-existing melanoma, basal cell, or squamous cell skin carcinoma.
19. Previous splenectomy.
20. White blood cell count greater than 25,000 mm3.
21. Currently being treated with any systemic immunosuppressive or biologic therapy for the treatment of a medical condition other than aGvHD.
22. Female patient is breastfeeding or pregnant.
23. Any medical concerns that may pose risk to the patient.
24. Any psychological, familial, sociological, and/or geographical condition that may potentially hamper compliance with the study protocol and the follow-up schedule.

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients reaching an overall response (CR+PR) after 4 weeks (Day 28) of ECP treatment, regardless of steroid tapering, or fewer treatments if they discontinued treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 4 weeks (Day 28) of ECP treatment, regardless of steroid tapering.

E.5.2

Secondary end point(s)

* Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and SAEs
* Proportion of patients who achieve an overall response 8 weeks (Day 56) and 12 weeks (Day 84) after initiation of ECP treatment
* Duration of response, defined as the length of time a patient maintains a response through Week 16 of the Follow-up Period on a perpatient basis
* Proportion of patients who achieve an overall response after 4 weeks (Day 28, 8 weeks (Day 56) and 12 weeks (Day 84) of ECP treatment according to the modified Glucksberg criteria (see Appendix B: Modified Glucksberg Criteria) Source
data will be collected for each patient and entered into the eCRF, and a scoring algorithm will be applied to calculate the grade of aGvHD using the Modified Glucksberg Criteria
* Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks (Day 84) after initiation of ECP treatment
* Organ-specific grade at 4 weeks (Day 28, 8 weeks (Day 56) and 12 weeks (Day 84) after initiation of ECP treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

see above

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

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.8.3

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

Austria

France

Germany

Hungary

Italy

Poland

Spain

Turkey

United Kingdom

United States

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

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

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)

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

children

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)

Once a subject completes the participation in the trial, the subject will be treated according to standard care of treatment or may continue ECP treatment on commercial product at the discretion of the Principal Investigator.

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

2016-03-31

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-16

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