Clinical Trials Register

Summary
EudraCT Number:	2017-001790-16
Sponsor's Protocol Code Number:	LSC2-II-01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-05-14
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 - PEI

A.2

EudraCT number

2017-001790-16

A.3

Full title of the trial

AN INTERVENTIONAL, OPEN-LABEL, MULTICENTER PHASE I/IIA CLINICAL TRIAL TO INVESTIGATE THE SAFETY AND EFFICACY OF ASCENDING DOSES OF ALLOGENEIC ABCB5-POSITIVE LIMBAL STEM CELLS (LSC2) FOR THE TREATMENT OF LIMBAL STEM CELL DEFICIENCY (LSCD)

A.3.1

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

Clinical trial to investigate how efficacious and safe different doses of the allogeneic investigational medicinal product named LSC2 are for treatment of limbal stem cell deficiency (LSCD)

A.4.1

Sponsor's protocol code number

LSC2-II-01

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	RHEACELL GmbH & Co. KG
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	RHEACELL GmbH & Co. KG
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	RHEACELL GmbH & Co. KG
B.5.2	Functional name of contact point	Information Office
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 517
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	496221718330
B.5.5	Fax number	4962217183329
B.5.6	E-mail	office@rheacell.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2111
D.3 Description of the IMP
D.3.1	Product name	LSC2
D.3.2	Product code	LSC2
D.3.4	Pharmaceutical form	Eye drops, suspension in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T402-4
D.3.9.3	Other descriptive name	LSC1; Allogeneic ABCB5-positive limbal stem cells
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.3
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
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	Yes
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	No
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/3/18/2111
D.3 Description of the IMP
D.3.1	Product name	LSC2
D.3.2	Product code	LSC2
D.3.4	Pharmaceutical form	Eye drops, suspension in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T402-4
D.3.9.3	Other descriptive name	LSC1; Allogeneic ABCB5-positive limbal stem cells
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.0
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
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	Yes
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	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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2111
D.3 Description of the IMP
D.3.1	Product name	LSC2
D.3.2	Product code	LSC2
D.3.4	Pharmaceutical form	Eye drops, suspension in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T402-4
D.3.9.3	Other descriptive name	LSC1; Allogeneic ABCB5-positive limbal stem cells
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.7
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
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	Yes
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: 4
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2111
D.3 Description of the IMP
D.3.1	Product name	LSC2
D.3.2	Product code	LSC2
D.3.4	Pharmaceutical form	Eye drops, suspension in single-dose container
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T402-4
D.3.9.3	Other descriptive name	LSC1; Allogeneic ABCB5-positive limbal stem cells
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4.0
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
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	Yes
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

Limbal stem cell deficiency (LSCD)

E.1.1.1

Medical condition in easily understood language

Complete or partial loss of vision due to secondary injuries

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

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	10072138
E.1.2	Term	Limbal stem cell deficiency
E.1.2	System Organ Class	10015919 - Eye 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

The aim of this clinical trial is to investigate the efficacy (by monitoring neovascularization and epithelial defects) of up to four doses of the investigational medicinal product (IMP) LSC2 topically administered on the target eye of patients with LSCD and the safety (by monitoring adverse events [AEs]) of the IMP during and after application.

E.2.2

Secondary objectives of the trial

Not applicable.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female patients aged 18 to 85 years
2.Patients with secondary bilateral or unilateral LSCD (injury that caused LSCD at least 6 months prior to inclusion)
3.Neovascularization: Vessel penetration of at least 2 quadrants, with central cornea involved
4.Patients understand the nature of the procedure and are providing written informed consent prior to any clinical trial procedure
5.Women of childbearing potential must have a negative blood pregnancy test at Visit 1
6.Women of childbearing potential must be willing to use highly effective contraceptive methods during the course of the clinical trial

E.4

Principal exclusion criteria

1.Compromised eyelid mobility and/or symblepharon; patient can be re-screened after appropriate treatment
2.Presence of eyelid malposition; patient can be re-screened after appropriate treatment
3.Active local ocular or systemic infection and/or inflammation. Patient can be re-screened after infection and/or inflammation is resolved.
4.Tumor diseases or history of tumour disease
5.Active ocular neoplastic disease (exclusion will be based on investigator’s assessment)
6.Corneal erosion or ulcer is bigger than 4 mm2; corresponding to less than 95% of continuous corneal epithelium). Patient can be re-screened after erosion or ulcer is resolved (≤ 4 mm2).
7.Positive for human immunodeficiency virus (HIV) 1 and/or 2 (diagnosed by serologic testing)
8. Clinically significant or unstable concurrent disease or other clinical contraindications to stem cell transplantation
9. History of glaucoma
10. Contraindications to trial related procedures/substances including
a. The surgical procedure (e.g. removing of the conjunctival pannus)
b. Contact lens complications due to contact lens use in the proposed trial (based on the Efron Grading scale for standard clinical reference for contact lens complications)
c. Tear secretion deficiency determined by Schirmer’s test
d. Allergy, sensitivity or intolerance to components/excipients of the IMP/ per protocol pre-planned concomitant medications
e. Conjunctival scarring with fornix shortening
f. General anesthesia (in case general anesthesia is required) or local anesthesia
g. Immunosuppression (being mandatory concomitant therapy)
11. Intraocular pressure (IOP) of ≥30 mm Hg
12. History or clinical signs of stroke or transient ischemic attacks
13. Active or suspected ocular or periocular infections
14. Active or suspected intraocular inflammation
15. Further clinical contraindications to IMP application (exclusion will be based upon investigator's judgment)
16. Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial
17. Previous participation in this clinical trial (except screening failure due to inclusion criterion 2 and/or exclusion criterion 1 and/or 2 and/or 3 and/or 6)
18. Known abuse of alcohol, drugs, or medicinal products
19. Patients unwilling or unable to comply with the requirements of the protocol
20. Lactating women
21. Evidence of any other medical conditions (such as psychiatric illness, physical examination, or laboratory findings) that may interfere with the planned treatment, affect the patient’s compliance, or place the patient at high risk of complications related to the treatment
22. Employees of the sponsor, or employees or relatives of the investigator

E.5 End points

E.5.1

Primary end point(s)

1. Primary efficacy endpoint:
Response rate at 12 months after IMP application (V16), where response is defined as:
- no or mild corneal neovascularization (no vessel penetration or vessel penetration up to 1 quadrant, without central cornea) AND
- no or mild epithelial defects (no corneal erosion or ulcer are present [corneal wounds are closed] or minimal superficial staining)
2. Primary safety endpoint:
- adverse events

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Month 12 after IMP application
2. During all patient visits except screening

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
1. response rate at 3 months after IMP application
2. neovascularization measured at V1, V6, V7, V8, V9, V10, V11, V12, V13, V14, V16
3. epithelial defects measured at V1, V7, V9, V11, V13, V14, V16
4. ocular symptoms of pain, photophobia, burning measured at V1, V7, V9, V11, V13, V14, V16
5. ocular inflammation measured at V1, V7, V9, V11, V13, V14, V16
6. corneal opacity measured at V1, V7, V9, V11, V13, V14, V16
7. visual acuity measured at V1, V7, V9, V11, V13, V14, V16
8. quality of life (visual function questionnaire-25 [VFQ-25]) questionnaire (investigator’s version) at V1, V13, V16

Secondary safety endpoint:
9. physical examination performed at V1, V13, V16
10. vital signs measured at V1, V13, V16
11. tonometry measured at V1, V6, V8, V12, V13

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy:
1. 3 M after IMP application
2. 14 to 9 D before; 1, 2, 3, 4, 5, 6, 7, 12 W, 6, 12 M after IMP application
3. 14 to 9 D before; 2, 4, 6, 12 W, 6, 12 M after IMP application
4. 14 to 9 D before; 2, 4, 6, 12 W, 6, 12 M after IMP application
5. 14 to 9 D before; 2, 4, 6, 12 W, 6, 12 M after IMP application
6. 14 to 9 D before; 2, 4, 12 W, 6, 12 M after IMP application
7. 14 to 9 D before; 2, 4, 6, 12 W, 6, 12 M after IMP application
8. 14 to 9 D before; 12 W, 12 M after IMP application

Safety:
9. 14 to 9 D before IMP application; 12 W, 12 M after IMP application
10. 14 to 9 D before IMP application; 12 W, 12 M after IMP application
11. 14 to 9 D before IMP application; 1, 3, 7, 12 W after IMP application

D: Days
W: Weeks
M: Months

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

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)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety and efficacy in patients

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Staggered dosing; Up to four different doses of the IMP

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

Yes

E.8.2.3.1

Comparator description

No comparator is used in this study;

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

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

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

E.8.9.2

In all countries concerned by the trial 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.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)

After withdrawal patients will receive standard medical care according to individual needs.

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

2018-11-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-07

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-06-07

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