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    Summary
    EudraCT Number:2018-000536-10
    Sponsor's Protocol Code Number:LL-37002
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-06-21
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-000536-10
    A.3Full title of the trial
    A Study in Patients with Hard-to-Heal Venous Leg Ulcers to Measure Efficacy and Safety of Locally Administered LL-37; A Phase IIb, Double-blind, Randomised, Placebo-controlled, Multi-centre Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NA
    A.3.2Name or abbreviated title of the trial where available
    HEAL LL-37
    A.4.1Sponsor's protocol code numberLL-37002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPromore Pharma AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPromore Pharma AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPromore Pharma AB
    B.5.2Functional name of contact pointChief Scientific Officer
    B.5.3 Address:
    B.5.3.1Street AddressFogdevreten 2
    B.5.3.2Town/ citySolna
    B.5.3.3Post codeSE-171 65
    B.5.3.4CountrySweden
    B.5.4Telephone number+46706310109
    B.5.6E-mailmargit.mahlapuu@promorepharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code LL-37
    D.3.4Pharmaceutical form Concentrate for cutaneous solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 597562-32-8
    D.3.9.2Current sponsor codeLL-37
    D.3.9.3Other descriptive nameH-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.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code LL-37
    D.3.4Pharmaceutical form Concentrate for cutaneous solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 597562-32-8
    D.3.9.2Current sponsor codeLL-37
    D.3.9.3Other descriptive nameH-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.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for cutaneous solution
    D.8.4Route of administration of the placeboCutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hard-to-Heal (HTH) venous leg ulcer
    E.1.1.1Medical condition in easily understood language
    Hard-to-Heal leg ulcer
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066677
    E.1.2Term Chronic leg ulcer
    E.1.2System Organ Class 100000004858
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to determine the efficacy of LL-37, at concentrations of 0.5 and 1.6 mg/mL, in increasing the incidence of complete wound closure compared with placebo in the treatment of hard-to-heal (HTH) venous leg ulcers (VLUs).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to determine the efficacy of LL-37, at concentrations of 0.5 and 1.6 mg/mL, in promoting wound healing in relation to secondary efficacy endpoints, as well as to evaluate local tolerability and safety of LL-37, compared with placebo in the treatment of HTH VLUs.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The levels of LL-37, which are detectable in the wound, will be assessed in wound exudate from a subset of study participants (approximately 20 patients at 2-3 pre-selected sites) to build further understanding about stability of LL-37 at the site of application, in an exploratory approach.
    E.3Principal inclusion criteria
    1. Capable and voluntarily giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Provision of signed and dated written ICF must be prior to any mandatory study specific procedures, sampling and analyses.
    2. Male or female ≥18 years of age at the time of signing the ICF
    3. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) until the last dose of LL-37/matching placebo to prevent pregnancy. In addition, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.
    4. Negative pregnancy test (women of child-bearing potential only)
    5. Lower leg ulcers presumed to be caused by venous insufficiency
    6. Target leg ulcer that has failed to heal within a minimum of 6 weeks of compression therapy
    7. Ankle-brachial pressure index (ABI) >0.70 at screening
    8. Ulcer localisation above the foot and below the knee (ankle and malleoli included)
    9. Surface area of target ulcer 2 to 40 cm2 at screening
    10. Ulcer essentially free of necrotic tissue
    11. Ability to tolerate compression bandaging
    12. Appropriate state of health to participate in the study, as determined by the investigator. This will be determined by medical history, physical examination and clinical laboratory evaluations
    13. Willing to attend study visits and judged able to comply with the protocol requirements
    E.4Principal exclusion criteria
    1. Other known predominant aetiology than VLU of the target ulcer, such as trauma
    2. Malignant disease (excluding basal cell carcinoma) unless in remission for 5 years
    3. P-albumin <25 g/L or HbA1c >10%
    4. Presence of active psoriasis skin lesions within 1.5 cm of the ulcer area
    5. Ulcer which by location or extension is either difficult to assess or treat according to the protocol
    6. Presence of a non-study ulcer within 2 cm of the target VLU
    7. Exposure of bone, tendon or fascia within the target ulcer
    8. Clinical signs or symptoms of an infection of the target ulcer, erysipelas, or osteomyelitis requiring systemic antibiotic treatment
    9. Systemic immunosuppressive drugs with the exception of low-dose oral steroids: glucocorticoids corresponding to oral prednisolone ≤10 mg/day are allowed provided that drug treatment has been initiated not earlier than 4 weeks prior to the screening visit and at that time point, is expected to be maintained at similar dose level throughout the study period. Also, mineral corticoids are permitted.
    10. Known hypersensitivity to any component of the study drug or standard ulcer dressing allowed during study treatment period or follow-up period
    11. Systemic treatment with antibiotics within 7 days prior to screening visit
    12. Participation in another clinical study within 7 days prior to screening visit
    13. Treatment with any of the following medications on the target ulcer on the day of screening: topical antibiotics, potassium permanganate
    14. Presence of heavy ulcer exudation that requires more frequent dressing changes than are allowed in the study (i.e. twice weekly) as judged by the investigator
    15. For women only: currently pregnant (confirmed by positive pregnancy test) or breast-feeding
    16. Any clinically significant disease judged by the investigator to affect the patient’s capability to participate in the study or to possibly influence the evaluation of study data

    Additional criterion to be checked at randomisation visit:
    17. Reduction in the target ulcer area per week during run-in period:
    a. >7% for an ulcer with an initial area of >10 cm2
    b. >10% for an ulcer with an initial area of ≥2 to ≤10 cm2
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed complete wound closure of the target ulcer, defined as skin re-epithelialization without drainage or dressing requirements at any time up to the end-of-treatment visit at 13 weeks, which is sustained at the post-wound closure visit 2 weeks after the first reported closure. The wound closure should always be documented by photography, both when first reported and when confirmed 2 weeks later.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 weeks after the first reported closure
    E.5.2Secondary end point(s)
    Secondary efficacy variables:
    • Wound healing rate of the target ulcer within the treatment period/or until complete closure, as applicable, estimated from an exponential decay model for the wound area
    • Time to confirmed complete wound closure of the target ulcer as defined above
    • Attainment of target ulcer area reduction of ≥50% compared to baseline (randomisation) at the end-of-treatment visit (Yes/No)
    • Attainment of target ulcer area reduction of ≥70% compared to baseline (randomisation) at the end-of-treatment visit (Yes/No)
    Exploratory efficacy variables:
    • Linear wound margin advance, estimated from a segmented ("broken stick") regression analysis of wound area
    • Wound area reduction (%) at the end-of-treatment visit compared to baseline (randomisation)
    Safety variables:
    • Incidence of local reactions as exemplified by clinical signs of inflammation of the target ulcer and the wound margin (oedema, redness and raised temperature) and skin irritation of the adjacent skin (scaling, redness, papules, vesicles, pustules) Any local reaction will be recorded on a graded scale (0-3: none, mild, moderate, severe).
    • Incidence of infection of the target ulcer
    • Overall incidence of AEs (including serious AEs [SAEs])
    • Change in laboratory values from baseline (randomisation)
    • Change in vital signs from baseline (randomisation)
    • Incidence of >50% increase in target ulcer area compared to baseline (randomisation)
    • Physical examination assessments
    Other outcomes:
    • Change in wound characteristics of the target ulcer (scores of slough, granulation tissue, necrosis, odour and exudation level) compared to baseline (randomisation). Any wound characteristics will be recorded using percentages (slough, granulation tissue and necrosis) or using a graded scale (odour 0-2: none, some, offensive; and exudation 0-3: none, mild, moderate, severe)
    • Change in local pain in the target ulcer compared to baseline (randomisation) using a graded visual analogue scale (VAS) score (0-10)
    • Collection of exudate before application of study product at Visit 7, Visit 8, Visit 9 and Visit 10 for LL-37 stability measurements in a subset of patients (approximately 20 patients at 2 to 3 pre-selected sites)
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 79
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state119
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 159
    F.4.2.2In the whole clinical trial 159
    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)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-07-13
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