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    Summary
    EudraCT Number:2021-004349-18
    Sponsor's Protocol Code Number:M-14789-41
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-05-11
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2021-004349-18
    A.3Full title of the trial
    A Phase 4, Multi-centre, Randomized, Evaluatorblinded, Active-controlled Study to Determine the Incidence of Squamous Cell Carcinoma and Evaluate the Long-term Safety of Tirbanibulin 10 mg/g Ointment and Diclofenac Sodium 3% Gel for the Treatment of Adult Patients with Actinic Keratosis on the Face or Scalp
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-term clinical safety study to evaluate the risk of actinic keratosis progressing to skin cancer following treatment of the face or scalp with tirbanibulin 10 mg/g ointment and in comparison to diclofenac 3% gel in adult patients. Tirbanibulin and diclofenac are used to treat adults with actinic keratosis on the face and scalp. Actinic keratosis is a precancerous, abnormal skin growth that develops after too much exposure to sunlight.
    A.4.1Sponsor's protocol code numberM-14789-41
    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 SponsorAlmirall, S.A.
    B.1.3.4CountrySpain
    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 supportAlmirall, S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlmirall, S.A.
    B.5.2Functional name of contact pointInternat. Clinical Trial Manager
    B.5.3 Address:
    B.5.3.1Street AddressRonda General Mitre 151
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08022
    B.5.3.4CountrySpain
    B.5.6E-mailgco@almirall.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 Yes
    D.2.1.1.1Trade name Klisyri 10 mg/g ointment
    D.2.1.1.2Name of the Marketing Authorisation holderAlmirall, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Ointment
    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.3.8INN - Proposed INNTirbanibulin
    D.3.9.2Current sponsor codeKX2-391
    D.3.9.4EV Substance CodeSUB198081
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 RoleComparator
    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 Yes
    D.2.1.1.1Trade name Solaraze 3%, gel
    D.2.1.1.2Name of the Marketing Authorisation holderAlmirall S.A.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Gel
    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.3.8INN - Proposed INNn/a
    D.3.9.2Current sponsor coden/a
    D.3.9.3Other descriptive nameDICLOFENAC SODIUM
    D.3.9.4EV Substance CodeSUB01674MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Actinic Keratosis on the Face or Scalp
    E.1.1.1Medical condition in easily understood language
    Actinic keratosis is a precancerous, abnormal skin growth that develops after too much exposure to sunlight.
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10000614
    E.1.2Term Actinic keratosis
    E.1.2System Organ Class 10040785 - Skin and subcutaneous tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the incidence of biopsyconfirmed invasive SCC in the selected TF after administration of topical tirbanibulin 10 mg/g ointment or diclofenac sodium 3% gel over the 3-year study period.
    E.2.2Secondary objectives of the trial
    To evaluate the safety of topical tirbanibulin 10 mg/g ointment and diclofenac sodium 3% gel over the 3-year study period
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female and ≥18 years old.
    2. A TF on the face or scalp (excluding lips, eyelids, ears, and inside the nostrils), that:
    • Is a contiguous area measuring 25 cm2,
    • Contains 2 to 8 clinically typical, visible, and discrete AK lesions, and
    • Has an overall clinical picture that is consistent with Olsen grade 1.
    3. If a WOCBP, ie, fertile, defined as a female in the life period from menarche and until becoming post-menopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (with hysterectomy, bilateral salpingectomy or bilateral oophorectomy at least 3 months prior to Screening), she must:
    • Have a negative urine pregnancy test using a highly sensitive method at screening and on Day 1 prior to treatment administration.
    • Be using effective methods of birth control.
    • Agree to have pregnancy tests while in the study and at the end of the study (according to the Schedule of Assessments in Table 1).
    4. Patients should be willing to avoid sunlight or UV light exposure, including the use of tanning beds, to the face or scalp during the study.
    5. Patients should have the ability to understand the purpose and risks of the study, willingness and ability to comply with the protocol, and provide written informed consent in accordance with institutional and regulatory guidelines.
    E.4Principal exclusion criteria
    1. The location of the TF is:
    a) On any location other than the face or scalp.
    b) Within 5 cm of an incompletely healed wound.
    c) Within 10 cm of a suspected basal cell carcinoma (BCC) or other neoplasm.
    d) On the lips, eyelids, ears, or inside the nostrils, periorbital, perioral, or the skin surrounding the nostrils.
    2. Presence in the TF of:
    a) Clinically atypical and/or rapidly changing AK lesions
    b) Hyperkeratotic or hypertrophic lesions, recalcitrant disease (had cryosurgery onc2 previous occasions), and/or cutaneous horn.
    c) Confluent AK lesions (ie, non-discrete lesions, as per inclusion criterion 2).
    d) Persisting AK lesions at the screening visit following topical treatment with diclofenac sodium 3% gel.
    3. History of any malignant skin tumour in the TF or history of skin tumour in any region of the body which has metastasized or in which metastasis within the study period is likely.
    4. History of any malignant tumour with systemic antitumor treatment (including radiotherapy) within 12 weeks prior to the Screening Visit or systemic antitumor treatment is expected while on the study.
    5. Immunocompromised patients, including patients with a history of chronic systemic lymphoma or chronic myeloid leukaemia, or organ transplant recipients.
    6. Any other dermatological disease that causes difficulty with examination within the treatment area.
    7. Anticipated need for inpatient hospitalization or inpatient surgery during the study.
    8. Previous treatment with tirbanibulin 10 mg/g ointment in the selected TF.
    9. Treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, photodynamic therapy, or other topical treatments for AK within the TF or within 2 cm of the TF, within 8 weeks prior to the Screening Visit.
    10. Use of the following therapies and/or medications within 4 weeks prior to the Screening Visit:
    a) Treatment with cytotoxic drugs (eg, cyclophosphamide, vinblastine, chlorambucil, methotrexate)
    b) Treatment with systemic medications that modulate and/or suppress the immune system (eg, cyclosporine, prednisone, methotrexate, alefacept, infliximab, interferons or interferon inducers)
    c) Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene)
    11. Use of the following therapies and/or medications within 2 weeks prior to the Screening
    Visit:
    a) Cosmetic or therapeutic procedures (eg, use of liquid nitrogen, surgical excision, curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing) within the TF or within a 2 cm margin of the selected TF.
    b) Acid-containing therapeutic products (eg, salicylic acid or fruit acids, such as alpha and beta-hydroxyl acids and glycolic acids), topical retinoids, or light chemical peels within the TF or within a 2 cm margin of the selected TF.
    c) Topical steroids within the TF or within a 2 cm margin of the selected TF.
    d) Artificial tanners within the TF or within a 5 cm margin of the selected TF.
    12. History of sensitivity and/or allergy to any of the ingredients in the study medications to tirbanibulin, diclofenac, or nonsteroidal anti-inflammatory drugs (ie, NSAIDs).
    13. A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open wounds) that, in the opinion of the Investigator, might interfere with the study conduct or evaluations, or which exposes the patient to unacceptable risk by study participation.
    14. Significant uncontrolled or unstable medical diseases or conditions that, in the opinion of the Investigator, would expose the patient to unacceptable risk by study participation.
    15. Females who are pregnant or nursing or who are intending to become pregnant
    16. Participated in an investigational drug study during which an investigational study medication was administered within 30 days or 5 half-lives of the investigational product, whichever is longer, prior to screening
    17. Patient who is an employee or a relative to an employee at the research site or Almirall
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients with histologically confirmed invasive SCC in the TF over the 3-year study period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please refer to E.5.1
    E.5.2Secondary end point(s)
    • AEs and SAEs over 3 years
    • Proportion of patients with any other skin cancer (other than SCC) in the TF over the 3-year study period.
    • Time to occurrence of invasive SCC from baseline in the TF.
    • Proportion of patients requiring rescue treatment after 1 treatment course.
    • Proportion of patients requiring rescue treatment at any time during the study.
    • Proportion of patients with no lesions after treatment of the first recurrence with tirbanibulin during the first 52 weeks.
    • Other safety assessments (vital signs, PE) over 3 years
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to E.5.2
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    incidence
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    reference IMP Diclofenac sodium 3% gel
    E.8.2.4Number of treatment arms in the trial2
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA52
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United Kingdom
    France
    Germany
    Italy
    Poland
    Spain
    E.8.7Trial has a data monitoring committee No
    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 patient (LVLP)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days7
    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: 158
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 292
    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 Yes
    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 state127
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 450
    F.4.2.2In the whole clinical trial 450
    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 Decision2022-07-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-07-19
    P. End of Trial
    P.End of Trial StatusOngoing
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