E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of lateral canthal rhytides in the periorbital region (Crow's Feet Lines) |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of facial wrinkles (Crow's Feet Lines) |
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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 | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040954 |
E.1.2 | Term | Skin wrinkling |
E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and efficacy of BOTOX compared to placebo in subjects with
lateral canthal rhytides in the periorbital region (Crow's Feet Lines). |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female 18 years of age or older
2. Presence of bilaterally symmetrical CFL of moderate to severe rating at maximum smile, as measured using the FWS by both the investigator and subject at day 1(prior to study treatment) (investigator and subject rating at maximum smile must be the same)
3. Subjects must have sufficient visual acuity without the use of eyeglasses (contact lens use acceptable), to accurately assess their facial wrinkles
4. Female subjects of childbearing potential must have a negative urine pregnancy test at day 1 prior to study treatment. A woman is considered NOT to be of childbearing potential if she either is postmenopausal with at least 12 consecutive months of amenorrhea or has no uterus.
5. Written informed consent has been obtained
6. Written Authorization for Use and Release of Health and Research Study Information (US sites only) and Data Protection Consent (European sites only) and/or other documentation in accordance with the relevant country and local privacy requirements has been obtained
7. Ability to follow study instructions and likely to complete all required visits. |
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E.4 | Principal exclusion criteria |
1. Any condition which precludes a subject’s ability to comply with study requirements, including completion of the study visits or inability to read, understand, and/or self-assess CFL severity using the FWS
2. Concurrent or previous botulinum toxin treatment of any serotype
3. Known immunization or hypersensitivity to any botulinum toxin serotype
4. Anticipated need for treatment with botulinum toxin of any serotype for any reason during the study (other than study treatment)
5. Any medical condition that may put the subject at increased risk with exposure to BOTOX including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other condition that might interfere with neuromuscular function
6. Known allergy or sensitivity to any of the components of the study treatments, or any materials used in the study procedures
7. Any of the following procedures or treatments occurring in the specified period prior to enrollment (day 1)
a. 3 months: Non-ablative resurfacing laser or light treatment, microdermabrasion or superficial peels
b. 6 months: Any facial cosmetic procedure with medium depth to deep facial chemical peels (eg, trichloroacetic acid [TCA] and phenol), or mid facial or periorbital laser skin resurfacing
c. 12 months: Mid facial or periorbital treatment with non-permanent soft tissue fillers
8. Subjects on topical retinoid therapy and/or topical hormone cream applied to the face, who have not been on a consistent dose regimen for at least 6 months prior to enrollment and who are unable to maintain the same regimen for the study
9. Subjects on oral retinoid therapy within 1 year prior to study enrollment
10. Prior periorbital surgery, facial lift (full face or mid face), brow lift, or related procedures (eg, eyelid (blepharoplasty) and/or eyebrow surgery)
11. Prior mid face or periorbital treatment with permanent soft tissue fillers, synthetic implantation (eg, Gore-Tex®), and/or autologous fat transplantation
12. Marked facial asymmetry, dermatochalasis, deep dermal scarring, excessively thick sebaceous skin, or the inability to substantially lessen facial rhytides even by physically spreading them apart, as determined by the investigator
13. Presence of any clinically relevant abnormal finding as observed from the neurologic assessment (See Protocol)
14. Any eyebrow or eyelid ptosis at baseline as determined by the investigator
15. Infection or skin disorder at the injection sites
16. History of facial nerve palsy
17. Females who are pregnant, nursing, or planning a pregnancy
18. Females of childbearing potential, not using a reliable means of contraception
19. Any uncontrolled systemic disease
20. Recent history of alcohol or drug abuse based on the investigator’s judgment
21. Anticipated need for surgery or overnight hospitalization during the study
22. Subjects who plan for an extended absence away from the immediate area of the study center that would preclude them from returning for all protocol specified study visits
23. Subjects who, in the investigator’s opinion, are unable or unwilling to maintain their standardized skin care regimen throughout the study period
24. Current enrollment in an investigational drug or device study or participation in such a study within 30 days of entry into this study
25. Permanent make-up which would interfere with the assessment of facial wrinkles
26. Subject has a condition or is in a situation which in the investigator's opinion may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The co-primary efficacy endpoints are the proportion of subjects achieving a grade of none or mild on the investigator’s and on the subject’s assessment of the severity of CFL at maximum smile, based on the FWS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
day 30 of the first treatment cycle |
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E.5.2 | Secondary end point(s) |
The Secondary efficacy endpoints are:
1. The proportion of responders of the investigator’s FWS in CFL at rest at day 30, among subjects who were rated as at least mild at baseline, where a responder is defined as achieving a 1-grade improvement on the investigator-rated FWS at rest in CFL.
2. The proportion of responders of the investigator’s FWS in CFL at maximum smile at day 30, where a responder is defined as achieving a 1-grade improvement on the investigator-rated FWS at maximum smile in CFL.
3. The proportion of responders of the investigator’s FWS in CFL at maximum smile at day 30, where a responder is defined as achieving a rating of none or mild on the investigator-rated FWS at maximum smile in CFL (for US FDA only).
4. Values at day 30 for the subject’s Global Assessment of Change in CFL (using a 7-point scale) will be analyzed using analysis of variance (ANOVA) with treatment, as the main effect.
5. The proportion of subjects with a ≥ 2 point improvement over baseline for FLO item #2 at day 30: When I look in the mirror, my facial lines make me look older than I want to look.
6. The proportion of subjects with a ≥ 2 point improvement over baseline for FLO item #5 at day 30: My facial lines make me look less attractive.
7. The proportion of subjects with a ≥ 3 point improvement over baseline for FLO item #8 at day 30: My facial lines make me look tired.
8. Analysis will be performed on the proportion of subjects at day 30, who rate themselves in a younger SPA category than at baseline (ie, from “look my current age” at baseline to “look younger” or from “look older” at baseline to “look my current age/younger”). Only subjects who rated themselves as looking their current age or older at baseline will be included in the denominator of this analysis. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 | No |
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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |