| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Moderate to Severe Upper Facial Lines |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of Moderate to Severe Upper Facial Lines |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Physical Phenomena [G01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052610 |
| E.1.2 | Term | Frown lines |
| E.1.2 | System Organ Class | 100000004858 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052609 |
| E.1.2 | Term | Glabellar frown lines |
| E.1.2 | System Organ Class | 100000004858 |
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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 assess the safety and tolerability of increasing doses of a single treatment of IPN10200 compared with placebo in participants with moderate to severe GL.
To assess the safety and efficacy of IPN10200 compared with placebo in improving the appearance of moderate to severe lines (GL,FHL, LCL) as measured by the Investigator’s Live Assessment (ILA) and Subject’s Self-assessment (SSA) at maximum contraction at Day 29. |
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| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of IPN10200 compared with placebo in improving the appearance of moderate to severe upper facial lines (GL, FHL and LCL) measured by the ILA and SSA at maximum contraction at Day 29
To assess:
- the efficacy of increasing and parallel doses of a single treatment cycle of IPN10200 compared with placebo (and/or Dysport) in the improvement of the appearance of moderate to severe lines treated (GL/LCL/FHL) at each post treatment timepoint, assessed by the investigator as measured by the ILA at rest and maximum contraction, and by the participant as measured by the SSA at maximum contraction and Subject’s Level of Satisfaction.
- time to onset of treatment response
- safety
- the presence of IPN10200 antibodies and presence of BoNT-A antibodies.
- overall satisfaction with facial appearance
To determine the duration of treatment response based on ILA and SSA at maximum contraction
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Moderate or severe (Grade 2 or 3) GL at maximum contraction at Baseline, as assessed by the ILA using a validated 4-point photographic scale.
3. Moderate or severe (Grade 2 or 3) GL at maximum contraction at Baseline, as assessed by the SSA using a validated 4-point categorical scale.
4. Moderate or severe (Grade 2 or 3) FHL at maximum contraction and moderate to severe GL at maximum contraction at Baseline or moderate to severe (Grade 2 or 3) LCL at maximum contraction (Stage as assessed by the ILA using a validated
4-point photographic scale).
5. Moderate or severe (Grade 2 or 3) FHL at maximum contraction and moderate to severe GL at maximum contraction at Baseline and moderate to severe (Grade 2 or 3) LCL at maximum contraction (Stage as assessed by the ILA using a validated 4-point photographic scale).
6. Moderate or severe (Grade 2 or 3) FHL at maximum contraction and moderate to severe GL maximum contraction at Baseline or moderate to severe (Grade 2 or 3) LCL at maximum contraction as assessed by the SSA using a validated 4-point categorical scale.
7. Moderate or severe (Grade 2 or 3) FHL at maximum contraction and moderate to severe GL maximum contraction at Baseline and moderate to severe (Grade 2 or 3) LCL at maximum contraction, as assessed by the SSA using a validated 4-point categorical scale.
8. Dissatisfied or very dissatisfied (Grade 2 or 3) with their lines at Baseline, as assessed by the SLS.
Sex
9. Male and female participants (only female for dose escalation)
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male participants:
Male participants must agree that, if their partner is at risk of becoming pregnant, they will use an effective method of contraception. The participants must agree to use the contraception during the whole period of the study and for 12 weeks after the study intervention injection.
• Female participants:
o A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
-Is a woman of non-childbearing potential (WONCBP) as defined in Appendix 4 Contraception and Barrier Guidance.
OR
-Is a WOCBP and using an acceptable contraceptive method as described in Appendix 4: Contraceptive and Barrier Guidance during the study intervention period (at a minimum until after the last dose of study intervention). The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention
o A WOCBP must have a negative highly sensitive pregnancy test at Baseline ([urine or serum]) as required by local regulations). Non-childbearing potential is defined as postmenopausal for at least 1 year; surgical sterilisation at 3 months before entering the study; or hysterectomy.
-If a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
o Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5.
o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
Informed Consent
10. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Other Inclusions
11. Participant has both the time and the ability to complete the study and comply with study instructions.
12. Does not reside in an institution by administrative or court order.
13. Is not a sponsor employee or clinical research unit personnel directly affiliated with the study or is not an immediate family member. Immediate family is defined as a spouse, parent, child or sibling whether biological or legally adopted.
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| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. An active infection or other skin problems in the upper face including the GL, FHL, and LCL area (e.g. acute acne lesions or ulcers).
2. A history of eyelid blepharoplasty or brow lift within the past 5 years
3. A history of facial nerve palsy.
4. Marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, or thick sebaceous skin.
5. Any known medical condition that may put the participant at increased risk in regard to exposure to BoNT of any serotype (i.e. myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, etc.)
6.a Has COVID-19 illness or a positive SARS-CoV-2 test, or the presence of any other condition (e.g. neuromuscular disorder or other disorder that could interfere with neuromuscular function), laboratory finding or circumstance that, in the judgement of the investigator, might increase the risk to the participant or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
Prior/concomitant Therapy
7. Previous treatment with any BoNT serotype (for dose-escalation only) or any recent treatment (within the past 6 months prior to Baseline) with any BoNT serotype.
8. Any prior treatment with permanent fillers in the upper face including the GL, FHL and LCL area.
9. Any prior treatment with long lasting dermal fillers in the upper face including the GL area within the past 3 years and/or skin abrasions/resurfacing (whatever the interventional technic used) within the past 5 years, or photo rejuvenation or skin/vascular laser intervention within the 12 months prior to Baseline.
10. Any planned facial cosmetic surgery during the study.
11. Use of concomitant therapy which, in the investigator’s opinion, would interfere with the evaluation of the safety or efficacy of the study intervention, including medications affecting bleeding disorders (e.g. antiplatelet agents and/or anticoagulants given for treatment or prevention of cardiovascular/cerebrovascular diseases).
12. Use of medications that affect neuromuscular transmission, such as curare-like non depolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics, within the past 30 days prior to Baseline.
Prior/concurrent Clinical Study Experience
13. Use of any experimental device within 30 days or use of any treatment with an experimental drug within five times the documented terminal half-life of the respective drug or its metabolites or if the half-life is unknown within 30 days prior to the start of the study (prior to Baseline) and during the conduct of the study.
Diagnostic Assessments
14. Known positive for hepatitis B antigen, or hepatitis C virus antibody, or for human immunodeficiency virus (HIV) or a diagnosis of acquired immunodeficiency syndrome.
15. Clinically diagnosed significant anxiety disorder, or any other significant psychiatric disorder (e.g. depression) that might interfere with the participant’s participation in the study
Other Exclusions
16. An inability to substantially lessen GL and/or horizontal forehead rhytids even by physically spreading them apart as determined by the investigator.
17. Known allergy or hypersensitivity to BoNT, or any excipients of IPN10200 or Dysport/Azzalure, or allergy to cow’s milk protein.
18. A history of drug or alcohol abuse.
19. Pregnant women, nursing women, premenopausal women or women of childbearing potential (i.e. not surgically sterile or 1 year postmenopausal) not willing to practice a highly effective form of contraception method at the beginning of the study, for the duration of the study and for a minimum of 12 weeks following last administration of study intervention. Highly effective methods of contraception are defined as methods of birth control which result in a low failure rate (less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, intrauterine devices, or vasectomised partner.
20. Male participants who are not vasectomised and who have female partners of childbearing potential and are not willing to use condoms with spermicide throughout study participation for a minimum of 12 weeks following initial double-blind administration of the treatment.
21a. Any uncontrolled systemic disease or other significant medical condition which would be harmful for the participant to be entered into the study or continue participation. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Incidence, severity, and nature, at each dose, of the TEAEs, SAEs, AEs (or SAEs) leading to discontinuations and AESIs.
• Vital signs
• Facial and physical examination.
• ECG
• Response to treatment as measured by the composite response of 2-grade improvement on both ILA and SSA at maximum contraction on the studied area at Day 29 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Follow up visits on Days 2, 3, 8, 15, 22 (telephone call), week 4 and then every 4 weeks (Week 8, 12, 16, 20, 24, 28, 32) until the end of the study (Week 36).
or
Follow up visits on Days 8, 15, 22 (telephone call), Week 4 and then every 4 weeks up to Week 36 (end of study visit). |
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| E.5.2 | Secondary end point(s) |
• Response to treatment as measured by the reduction of ≥2 grades on the ILA at maximum contraction at each post treatment visit for each concerned facial area.
• Response to treatment as achieved by a score of "none" or "mild" as measured by the ILA at maximum contraction at each post treatment visit for each concerned facial area.
• Response to treatment as achieved by a score of "none" or "mild" simultaneously for all three facial areas as measured by the ILA at
maximum contraction at Day 29.
• Response to treatment as achieved by a score of "none" or "mild" as measured by the ILA at rest at each post-treatment visit for each
concerned facial area.
• Response to treatment as measured by the reduction of ≥2 grades on the SSA at maximum contraction at each post-treatment visit for each concerned facial area.
• Response to treatment as achieved by a score of "none" or "mild" as measured by the SSA at maximum contraction at each post treatment visit for each concerned facial area.
• Response to treatment as achieved by a score of "very satisfied" or "satisfied" on the SLS at each post treatment visit.
• Time to onset of treatment response based on participant diary cards.
• The duration of treatment response based on the ILA and SSA at maximum contraction at each post treatment visits.
• Satisfaction with facial appearance scale score at post‑treatment visits V6, V8, V10, V13, V16 based on Face-Q satisfaction scale.
At each post treatment visits:
• Incidence, severity, and nature of the TEAEs, SAEs, AEs (or SAEs) leading to withdrawals and AESIs.
• Physical and facial examination
• Vital signs
At post treatment visits V8, V13, V16:
• Presence of IPN10200 antibodies and titres (binding and neutralising)
• Presence of BoNT-A antibodies and titres (binding and neutralising)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For timepoint details, refer to section E.5.2.
Follow-up visits on Days 2, 3, 8, 15, 22 (telephone call), Week 4 and then every 4 weeks (Week 8, 12, 16, 20, 24, 28, 32) until the end of the study (Week 36).
or
Follow up visits on Days 8, 15, 22 (telephone call), Week 4 and then every 4 weeks up to Week 36 (end of study visit). |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 | 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
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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 | 45 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 45 |
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