Clinical Trials Register

Summary
EudraCT Number:	2012-002100-41
Sponsor's Protocol Code Number:	LL-37001B
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-05-22
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

Sweden - MPA

A.2

EudraCT number

2012-002100-41

A.3

Full title of the trial

A double-blind, randomized, placebo-controlled, safety and pilot dose-response study of LL-37 in hard-to-heal venous leg ulcers

A.3.1

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

A clinical trial with blinded patients and personnel investigating the safety and preliminary dose-finding effects of the medicinal product LL-37 in hard-to-heal leg ulcers in comparison with an inactive substance (placebo)

A.4.1

Sponsor's protocol code number

LL-37001B

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	Lipopeptide AB
B.1.3.4	Country	Sweden
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	Lipopeptide AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Lipopeptide AB
B.5.2	Functional name of contact point	Director Preclinical R&D
B.5.3	Address:
B.5.3.1	Street Address	Banvaktsvägen 12
B.5.3.2	Town/ city	Solna
B.5.3.3	Post code	SE-171 48
B.5.3.4	Country	Sweden
B.5.4	Telephone number	4684703746
B.5.5	Fax number	46851902548
B.5.6	E-mail	alvar@pergamum.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	No
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.3.2	Product code	LL-37
D.3.4	Pharmaceutical form	Concentrate for cutaneous solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	597562-32-8
D.3.9.2	Current sponsor code	LL-37
D.3.9.3	Other descriptive name	H-Leu-Leu-Gly-Asp-Phe5-Phe-Arg-Lys-Ser-Lys10-Glu-Lys-Ile-Gly-Lys15-Glu-Phe-Lys-Arg-Ile20- Val-Gln-Arg-Ile-Lys25-Asp-Phe-Leu-Arg-Asn30-Leu-Val-Pro-Arg-Thr35-Glu-Ser-OH
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
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	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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	LL-37
D.3.4	Pharmaceutical form	Concentrate for cutaneous solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	597562-32-8
D.3.9.2	Current sponsor code	LL-37
D.3.9.3	Other descriptive name	H-Leu-Leu-Gly-Asp-Phe5-Phe-Arg-Lys-Ser-Lys10-Glu-Lys-Ile-Gly-Lys15-Glu-Phe-Lys-Arg-Ile20- Val-Gln-Arg-Ile-Lys25-Asp-Phe-Leu-Arg-Asn30-Leu-Val-Pro-Arg-Thr35-Glu-Ser-OH
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8
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	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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	LL-37
D.3.4	Pharmaceutical form	Concentrate for cutaneous solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	597562-32-8
D.3.9.2	Current sponsor code	LL-37
D.3.9.3	Other descriptive name	H-Leu-Leu-Gly-Asp-Phe5-Phe-Arg-Lys-Ser-Lys10-Glu-Lys-Ile-Gly-Lys15-Glu-Phe-Lys-Arg-Ile20- Val-Gln-Arg-Ile-Lys25-Asp-Phe-Leu-Arg-Asn30-Leu-Val-Pro-Arg-Thr35-Glu-Ser-OH
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	16
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for cutaneous solution
D.8.4	Route of administration of the placebo	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hard-to-heal (HTH) venous leg ulcer

E.1.1.1

Medical condition in easily understood language

Hard-to-heal leg ulcer

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10066677
E.1.2	Term	Chronic leg ulcer
E.1.2	System Organ Class	100000004858

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 objectives of the study are to determine the safety and tolerability of LL 37.

E.2.2

Secondary objectives of the trial

The secondary objective is to achieve preliminary dose response data in wound healing as a prerequisite for planning a larger Phase II dose-ranging study.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male subjects >18 years of age and post-menopausal or clinically sterile women.
2. Subjects with VLU, or combined venous-arterial ulcers with predominant venous component.
3. Subjects whose leg ulcers have failed to heal within 6 weeks of compression therapy.
4. Ankle-Brachial Pressure Index (ABI) >0.70 at screening.
5. Ulcer localization above the foot and below the knee (wrist and malleoli included).
6. Surface area of target ulcer 1-40 cm2 at screening.
7. Ulcer essentially free of necrotic tissue.
8. Ability to tolerate compression bandaging.
9. Subjects should be in an appropriate state of health to participate in the study, as determined by the Investigator. This will be determined by a medical history, physical examination, and clinical laboratory evaluations.
10. Subjects willing to attend study site visits and able to communicate effectively.
11. Subjects who have voluntarily signed and dated a patient IRB/EC approved Informed Consent Form (ICF).

E.4

Principal exclusion criteria

1. Other known predominant etiology than VLU of the target ulcer.
2. Malignant disease (excluding basal cell carcinoma) unless in remission for 5 years.
3. Subjects who have a past or present disease that, which as judged by the Investigator, may affect the safety of the subject or the outcome of the study.
4. Hematology values deviating 25% or more from the upper or lower limits of the normal range, and judged by the Investigator to affect the safety of the subject or the study outcome.
5. Liver function tests (ALT, AST, ALK PHOS and bilirubin) deviating 50% or more from the upper normal limits, and judged by the Investigator to affect the safety of the subject or the study outcome..
6. P-albumin <25 g/L or HbA1C >10%.
7. Presence of active psoriasis skin lesions within 1.5 cm of the ulcer area.
8. Ulcer that by location or extension will either be difficult to assess or to treat according to the protocol.
9. Presence of a non-study ulcer within 1 cm of the target VLU.
10. Exposure of bone, tendon or fascia within the target wound.
11. Clinical signs or symptoms of a clinical wound infection, erysipelas, or osteomyelitis.
12. Systemic immunosuppressive drugs with the exception of low-dose oral steroids: glucocorticoids corresponding to oral Prednisolone ≤10 mg/day, which is allowed provided that drug treatment was initiated within 4 weeks prior to screening visit, and at that time point, expected to be maintained at similar dose level throughout the study period. Also, mineral corticoids may be permitted.
13. Known hypersensitivity to any component of the trial product or standard wound dressing allowed during study treatment period or follow-up period.
14. Systemic treatment with antibiotics for target ulcer infection within 7 days prior to screening visit.
15. Participation in another clinical trial within 7 days prior to screening visit
16. Treatment with any of the following medications: topical antibiotics, and potassium permanganate.
17. Reduction in wound area per week* during run-in period:
a. >7% for a an ulcer with an initial area of >10 cm2
b. >10% for an ulcer with an initial area of 2-10 cm2
c. >13% for an ulcer with an initial area of <2 cm2

E.5 End points

E.5.1

Primary end point(s)

The study is primarily designed to assess the safety of LL-37 based on the following primary endpoints:
• Incidence of severe local reactions in wound and adjacent skin as exemplified by clinical signs of inflammation (edema, redness, odor and raised temperature) or skin irritation (scaling, redness, papules, vesicles, pustules). Any local reaction will be recorded on a graded scale (0-3).
• Incidence of >30% increase in wound area of relative to baseline
• Change in laboratory values and vital signs from baseline
• Overall incidence of AEs

E.5.1.1

Timepoint(s) of evaluation of this end point

End of treatment

E.5.2

Secondary end point(s)

The secondary endpoints are chosen to assess the efficacy of LL-37. Data will be collected to address the following endpoints:
• Wound healing rate within the study period.
• Number of ulcers attaining >30% area reduction from baseline.
• Changes in local pain using the VAS score (0-10).
• Change in wound characteristics (scores of slough, exudation, granulation tissue, necrosis) from baseline (scale 0-3).

E.5.2.1

Timepoint(s) of evaluation of this end point

End of treatment

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

Yes

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

Last visit of the last subject

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

Not applicable

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

2012-07-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-04-18

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