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    Summary
    EudraCT Number:2015-002164-16
    Sponsor's Protocol Code Number:CPH-301-201030
    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:2015-11-20
    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 number2015-002164-16
    A.3Full title of the trial
    Randomized double blind Phase 3 study to assess the efficacy and safety of BoNT/A-DP in the treatment of glabellar lines in comparison with placebo followed by an open label extension study
    Randomisierte doppelblinde Phase-III-Studie zur Bewertung der Wirksamkeit und Sicherheit von BoNT/A-DP bei der Behandlung von Glabellafalten im Vergleich zu Placebo, gefolgt von einer offenen Verlängerungsstudie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized and blinded Phase 3 trial to compare the safety and treatment effect of the botulinum toxin A product BoNT/A-DP with placebo for improvement of glabellar lines, followed by an extension part of the study providing BoNT/A-DP to all participants to investigate long term safety and efficacy.
    Randomisierte doppel-verblindete Studie zur Untersuchung der Sicherheit
    und Wirksamhkeit von BoN/A-DP zur Behandlung von Glabella Falten im
    Vergleich zu Placebo, gefolgt von einem nicht verblindeten Teil der Studie.
    A.3.2Name or abbreviated title of the trial where available
    Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study I (BLESS I)
    A.4.1Sponsor's protocol code numberCPH-301-201030
    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 SponsorCROMA-PHARMA GmbH
    B.1.3.4CountryAustria
    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 supportCROMA-PHARMA GmbH
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCROMA-PHARMA GmbH
    B.5.2Functional name of contact pointSonja Hoeller
    B.5.3 Address:
    B.5.3.1Street AddressIndustriezeile 6
    B.5.3.2Town/ cityLeobendorf
    B.5.3.3Post code2100
    B.5.3.4CountryAustria
    B.5.4Telephone number+43676846868286
    B.5.5Fax number+43226268468165
    B.5.6E-mailsonja.hoeller@croma.at
    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 Botulax
    D.2.1.1.2Name of the Marketing Authorisation holderHugel
    D.2.1.2Country which granted the Marketing AuthorisationKorea, Republic of
    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 BoNT/A-DP
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBotulinum Neurotoxin Type A
    D.3.9.1CAS number 180016-51-6
    D.3.9.2Current sponsor codeBoNT/A-DS
    D.3.9.4EV Substance CodeSUB77183
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate to severe glabellar lines
    Mittelschwere oder schwere Glabella Falten
    E.1.1.1Medical condition in easily understood language
    Moderate to severe glabellar lines
    Mittelschwere oder schwere Glabella Falten
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10052609
    E.1.2Term Glabellar frown lines
    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
    To assess the efficacy of BoNT/A-DP in reducing the severity of glabellar frown lines following treatment (compared with placebo) based on investigator and subject assessment.
    Zur Untersuchung der Reduktion von Glabellar Falten nach Behandlung
    mit BoNT/A-DP oder Plazebo
    E.2.2Secondary objectives of the trial
    1. To assess the proportion of responders at maximum frown and at rest at various time points after each treatment, based on investigator and subject assessments.
    2. To assess onset of effect and the duration of effect (at maximum frown) after a single treatment with BoNT/A-DP compared with placebo (first treatment cycle), based on investigator and subject assessments.
    3. To provide long term safety data of BoNT/A-DP based on multiple treatment cycles and to establish a sufficient safety database to support regulatory approval.
    4. To assess the psychological impact of BoNT/A-DP treatment on subjects (in terms of emotional and social functioning and concerns relating to their glabellar lines) in comparison with placebo after a single treatment.
    5. To assess subject perceptions of effect of, and satisfaction with, treatment in comparison with placebo (first treatment cycle) and during the open-label extension phase.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
     Aged ≥ 18 years or older at time of screening (upper limit 75 years).
     Has moderate to severe glabellar frown lines at maximum frown (severity score of 2 or 3 on FWS) as determined by in-clinic assessments by both the investigator and the subject (where: 0= 'none', 1= 'mild', 2= 'moderate', 3= 'severe').
     Subject has a stable medical condition with no uncontrolled systemic systemic disease.
     Female subjects of childbearing potential must test negative for
    pregnancy and agree to use highly effective birth control during the course of the study. Such methods include for example: combined
    (estrogen and progestogen containing) hormonal contraception
    associated with inhibition of ovulation, progestogen-only hormonal
    contraception associated with inhibition of ovulation, intrauterine
    device, intrauterine hormone-releasing system, bilateral tubal occlusion
    or vasectomized partner.
     Subjects who wear glasses must be able to adequately self-assess the severity of their glabellar lines, without glasses obstructing the forehead area.
     The moderate to severe glabellar lines have an important psychological impact on the subject as indicated by scores > 0 on either the Emotional or Functioning subscales of the modified Skindex-16 (GL-QoL).
    E.4Principal exclusion criteria
     Previous treatment with any serotype of botulinum toxin for any indication within the 12 months prior to screening, or any planned treatment with botulinum toxin of any serotype for any reason during the trial (other than the investigational treatment).
     Known hypersensitivity to the study medication or its excipients.
     Any medical condition that may place the subject at increased risk due to exposure to botulinum toxin, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, profound atrophy or weakness in the target muscles, or any other condition that might interfere with neuromuscular function or contraindicate botulinum toxin therapy.
     Facial laser or light treatment, microdermabrasion, superficial peels or retinoid therapy within the 3 months prior to screening or planned during the study.
     Apart from the procedures specified above, previous treatment with any facial aesthetic procedure in the glabellar area (including chemical peeling, injection with biodegradable fillers) within 12 months prior to screening or planned during the study.
     Previous insertion of permanent material in the glabellar area or planned during the study.
     Any surgery, or history of surgery, in the glabellar area including surgical removal of the corrugator, procerus or depressor supercili muscles or a combination of these, or scars in the glabellar area, or such surgery planned during the study.
     Active skin disease/infection or irritation at the treatment area.
     Inability to substantially lessen glabellar frown lines even by physically spreading them apart.
     Use of a muscle relaxant, within 2 weeks prior to screening or planned during the study.
     Marked facial asymmetry or ptosis of eyelid and/or eyebrow, or current facial palsy or neuromuscular junction disorders as judged by the investigator.
     Pregnant, breastfeeding or planning to become pregnant during the trial.
     Use of prohibited medication including anticholinergic drugs, or drugs which could interfere with neuromuscular function, including aminoglycoside antibiotics and curare-like compounds within 2 weeks prior to screening or planned during the study.
     Planned surgery with general anaesthetic (use of local anaesthetic outside the glabellar area is permitted).
     Participation in another clinical study within one month of screening and throughout the trial.
     Previous participation in another botulinum toxin aesthetic study which involved the treatment of glabellar lines in combination with canthal lines and/or forehead lines in the previous 18 months.
     Chronic drug or alcohol abuse (as per investigator discretion).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the proportion of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 4 visit (of the first treatment cycle) relative to baseline(responders), based on both the investigators’and the subjects’in-clinic assessments. Thus, the primary endpoint is a composite endpoint comprising investigator and subject assessments of treatment effectiveness.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At week 4 after each treatment
    E.5.2Secondary end point(s)
    1. The percentage of responders at maximum frown (as defined above) at week 12 (after the first treatment with BoNT/A-DP or placebo).
    2. The percentage of responders at week 16 (after the first treatment).
    3. The proportion of subjects with a ≥ 1 point reduction in FWS score at rest at week 4 in the first treatment cycle, based separately on the investigators’and the subjects’in-clinic assessments (applicable only for subjects who have a FWS score at rest ≥ 1 at baseline).
    4. The percentage of responders at week 20 or later (after the first treatment).
    5. The extent of change in psychological impact (emotional and social functioning and concerns relating to their glabellar lines) at week 4 after the first treatment, in the BoNT/A-DP group in comparison with placebo, relative to baseline, as assessed by the modified Skindex-16 (Glabellar Line Quality of Life Scale, [GL-QoL]) and the FACE-Q(Appraisal of Lines Between Eyebrows and Age Appraisal visual analog [VAS] scales).
    Additional Secondary Endpoints
    6. The proportion of responders among BoNT/A-DP and placebo groups with a FWS score at maximum frown of 0 or 1 and an improvement ≥ 2 points in FWS score (at maximum frown) during the first treatment cycle visit relative to baseline, based on both the investigators’ and the subjects’in-clinic assessments (composite endpoint, at weeks 1, 2 and 8).
    7. The proportion of subjects with ≥ 2-point reduction in FWS score (at maximum frown) in the BoNT/A-DP and placebo groups during the first treatment cycle visit relative to baseline, based on the independent rater’s assessment of photographs (at baseline and visits 2, 4, 12, 16 and 20 weeks after treatment, within the first treatment cycle).
    8. Time to onset of effect in the BoNT/A-DP and placebo groups in the first treatment cycle, as measured at weeks 1, 2 and 4 based separately on subject and investigator assessment. Onset of effect defined as at least a 1 point improvement in FWS score from baseline(at maximum frown). In addition, onset of effect will be assessed by subjects daily in the first 2 weeks after treatment, by recordings in the subject diary.
    9. The extent of subject perceptions of effect of, and satisfaction with, treatment in the BoNT/A-DP and placebo groups, during each treatment cycle, as assessed by the FACE-Q Satisfaction with Outcome Scale.
    10. The proportion of subjects with a > 1 point reduction in FWS score at rest in the BoNT/A-DP and placebo groups, relative to baseline, during the first treatment cycle, based on the independent rater’s assessment of photos.
    11. The percentage of subjects with a FWS score of 0 or 1 and an improvement ≥ 2 points in FWS score at maximum frown (investigator and subject assessment) at 4 weeks after re-treatment relative to the rating at the preceding end of cycle visit.

    Secondary Safety Endpoints
    1. Frequency, severity and causal relationship of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) during the entire study period.
    2. Antibody formation, evaluation pre-dose before each treatment, at 4 weeks after each treatment and at the final study visit.
    3. Safety assessments by evaluating hematology, clinical chemistry, vital signs and electrocardiogram (ECG) as per study schedule (Section 2.1).
    E.5.2.1Timepoint(s) of evaluation of this end point
    At week 4 and at further timepoints over the overall study duration.
    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 Yes
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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 States
    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
    LVLS
    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 months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days0
    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: 650
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state195
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 700
    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 Decision2016-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-16
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