A prospective, randomized, evaluator- and subject blinded, multi-center investigation to assess efficacy and safety of three different dosages of the same injection pattern of LetibotulinumtoxinA in the treatment of moderate and severe horizontal forehead lines

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Croma-Pharma GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

6 Nov 2024 → 28 Jul 2025

Decision date (initial)

2024-10-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary efficacy objective of this trial is to assess the response rates at maximum eyebrow elevation of the three different dosages of the same injection pattern of LetibotulinumtoxinA in the treatment of horizontal forehead lines.

Secondary objectives 3

1. To assess the FHL and responder status at maximum eyebrow elevation at various time points after treatment with LetibotulinumtoxinA for each of the three different dosages of the same injection pattern, based on Blinded Evaluating Investigator assessments.
2. To assess the skin displacement at maximum eyebrow elevation at various time points after treatment with LetibotulinumtoxinA for each of the three different dosages of the same injection pattern, based on blinded 3D surface imaging assessment.
3. To assess subject perceptions of treatment effect and satisfaction with treatment at various time points after treatment with LetibotulinumtoxinA for each of the three different dosages of the same injection pattern, based on blinded subjects’ selfassessment by patient reported outcomes (PROs) specifically developed for forehead lines.

Conditions and MedDRA coding

Moderate and severe horizontal forehead lines.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Subjects who understand the purpose and conduct of the trial and have given written informed consent prior to any trial-related activity and are willing and able to attend the trial visits as judged by the Investigator.
2. Female subjects aged between 18 and 75 years (75 years inclusive) at Screening visit.
3. Subjects with moderate or severe dynamic horizontal forehead lines at maximum eyebrow elevation (severity score of 3 or 4 on CDFLAS) as determined by in-clinic assessments by the Blinded Evaluating Investigator (where: 1= 'none', 2= 'mild', 3= 'moderate', 4= 'severe', 5=’very severe’).
4. Subjects who wear glasses must be able to adequately self-assess the appearance of their forehead, without glasses obstructing the forehead area.
5. Subjects with stable medical condition with no uncontrolled systemic disease (at the Investigator’s discretion).
6. Women of childbearing potential (WOCBP) must test negative for pregnancy at Screening and Baseline visit and must agree to use highly effective methods of birth control during the trial. This applies for the time period between Screening visit (method used must be working from Screening visit onwards) and until the final trial visit has been completed.

Exclusion criteria 34

1. Females who are breastfeeding.
2. A positive pregnancy test indicating pregnancy in a WOCBP at Screening or Baseline or WOCBP planning to become pregnant during the trial.
3. Previous treatment with any serotype of botulinum toxin in the upper face (forehead, glabella region, or lateral canthal lines) within 6 months prior to Screening, or any planned treatment with botulinum toxin of any serotype for any reason in the upper face during the trial (other than the investigational treatment).
4. Clinical history suggestive of intolerance, hypersensitivity, allergies or idiosyncrasies to the IMP(s) or any ingredient or excipient of the IMP.
5. 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 (at the Investigator's discretion) that might interfere with neuromuscular function or contraindicate botulinum toxin therapy.
6. Subjects with solar elastosis on the forehead.
7. Any other (medical) condition or disease or circumstances that, at the Investigator’s discretion, would put the subject at any undue risk, prevent completion of the trial, or interfere with the analysis of the trial results.
8. Subjects with static forehead lines considered ‘severe’ or ‘very severe’ at Screening by inclinic assessments by the Blinded Evaluating Investigator using the Croma Static Forehead Lines Assessment Scale (CSFLAS).
9. Facial laser or light treatment, microdermabrasion, superficial peels, or retinoid therapy within the 3 months prior to Screening or planned during the trial in the forehead area (other parts of the body will be allowed).
10. Apart from the procedures specified above (ExC #9), previous treatment with any facial aesthetic procedure (including chemical peeling, injection with biodegradable fillers, microneedling, Radiofrequency [RF], High-Intensity Focused Ultrasound [HIFU], and High-Intensity Focused Electromagnetic [HIFEM] therapy) in the forehead area (other parts of the face will be allowed) within 12 months prior to Screening or planned during the trial.
11. Previous insertion of permanent material in the forehead area (other parts of the face will be allowed) or planned during the trial.
12. Any tattooing (except permanent make-up) in the forehead area or periorbital region (other parts of the body will be allowed) or such procedure planned during the trial. Permanent make-up in the forehead area or periorbital region will be excluded within 4 weeks before treatment (Visit 1), or such procedure planned during the trial including refreshment of permanent make-up.
13. Any piercing in the forehead area or periorbital region (other parts of the body will be allowed) or such a procedure planned during the trial.
14. Subjects with voluminous eyelashes extensions or such procedure planned during the trial.
15. Subjects not willing to keep the shape and color of their eyebrows the same during the entire trial.
16. Any surgery, or history of surgery, in the forehead area or periorbital region (other parts of the body will be allowed) including surgical removal of the frontalis, corrugator, procerus or depressor supercili muscles or a combination of these, or scars in the forehead area, or such surgery planned during the trial.
17. Active or recurrent skin disease/infection, inflammation, or irritation in the forehead area or periorbital region (other parts of the body will be allowed).
18. Subjects with active systemic or local infections (e.g., COVID-19, influenza, sinusitis, etc.), that could cause symptoms similar to those potentially provoked by IMP treatment (such as headache, pain behind the eyes, swelling around the eyes, eyelid ptosis, etc.; at the Investigator’s discretion).
19. Inability to substantially lessen horizontal forehead lines even by physically spreading them apart (at the Investigator's discretion).
20. Use of a central or peripherally acting muscle relaxants (e.g., dantrolene, tubocurarine, baclofen), within 2 weeks prior to Screening or planned during the trial.
21. Marked facial asymmetry or ptosis of eyelid and/or eyebrow at Screening/Baseline, or current facial palsy or neuromuscular junction disorders at Screening/Baseline (at the Investigator’s discretion).
22. Use of prohibited medication including anticholinergic drugs, or drugs which could interfere with neuromuscular function, such as aminoglycoside antibiotics (e.g., gentamicin), polypeptide antibiotics, lincosamides (e.g. clindamycin), tetracyclines, benzodiazepines and analogues (e.g. lorazepam, etizolam), and benzamides (e.g. sulpirid) within 2 weeks prior to Screening or planned during the trial. Inhalative anticholinergic drugs (tiotropium, ipratropium) are allowed.
23. History of or known bleeding tendencies or use of any drugs known to prolong bleeding or bruising within 10 days prior to treatment, such as antithrombotic and anti-inflammatory drugs including heparins, vitamin k antagonists (e.g., warfarin), oral anticoagulants (e.g. apixaban, dabigatran), and antiplatelets (e.g., aspirin, clopidogrel).
24. Planned surgery with systemic anesthetic or use of local anesthetic in the forehead area or periorbital region (use of local anesthetic at other parts of the body is allowed) during the trial.
25. History of anaphylaxis, dysphagia or aspiration.
26. Current participation in any other clinical trial or use of any other IMP within the last 30 days prior to Screening visit or within five half-lives of the IMP (whichever is longer) and throughout the trial.
27. Earlier participation in the treatment phase of the trial.
28. Any suspicion of current drug and/or alcohol abuse (at the Investigator’s discretion).
29. Subjects known to be positive for human immune deficiency (HIV), hepatitis B or hepatitis C virus.
30. Psychiatric condition that might limit the participation in the trial and/or that lead to the assumption that the ability to completely understand the consequences of consent is missing (such as legal custodian appointed due to mental disability).
31. Any dependent relationship of the subject with the Investigator, trial site or Sponsor/Sponsor’s delegates (e.g., employees or relatives)
32. Subjects who are institutionalized because of legal or regulatory order.
33. Subjects who are soldiers or other members of the armed forces, civil servants, etc.
34. At the Investigator’s discretion, the subject is unlikely to comply with the trial procedures as defined in the trial protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Response - defined as an improvement of ≥ 1 point in CDFLAS score compared to baseline, measured at maximum eyebrow elevation, based on Blinded Evaluating Investigator’s in-clinic assessment - at 4 weeks post treatment (Visit 2).

Secondary endpoints 8

1. CDFLAS scores at maximum eyebrow elevation, based on Blinded Evaluating Investigator’s in-clinic assessment at Baseline (Screening - Visit 0) and 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6).
2. Response – defined as an improvement of ≥ 1 point in CDFLAS score compared to baseline, measured at maximum eyebrow elevation, based on Blinded Evaluating Investigator’s in-clinic assessment at 12, 16, 20 and 24 weeks post treatment (Visit 3 to Visit 6).
3. Pronounced Response – defined as an improvement of ≥ 2 points in CDFLAS score compared to baseline, measured at maximum eyebrow elevation, based on Blinded Evaluating Investigator’s in-clinic assessment at 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6).
4. Score Response – defined as CDFLAS score 1 or 2, measured at maximum eyebrow elevation, based on Blinded Evaluating Investigator’s in-clinic assessment at 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6).
5. Skin displacement (ability to elevate the eyebrow in mm) at maximum eyebrow elevation, compared to Baseline (Visit 0 or Visit 1), based on blinded 3D surface imaging measurements at 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6).
6. The extent of subject’s satisfaction with the overall outcome of the treatment as selfassessed by the blinded subject using the Face-Q (TM) Questionnaire “Satisfaction with Outcome” at 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6).
7. The extent of subject’s appearance appraisal of the forehead and eyebrows compared to Baseline (Screening – Visit 0) as self-assessed by the blinded subject using the Face-Q (TM) Questionnaire “Appearance Forehead and Eyebrows” at 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6)
8. The extent of subject’s appearance appraisal of forehead lines compared to Baseline (Screening – Visit 0) as self-assessed by the blinded subject using the Face-Q (TM) Questionnaire “Appearance: Lines Forehead” at 4, 12, 16, 20 and 24 weeks post treatment (Visit 2 to Visit 6).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Croma-Pharma GmbH

Sponsor organisation

Croma-Pharma GmbH

Address

Cromazeile 2

City

Leobendorf

Postcode

2100

Country

Austria

Scientific contact point

Organisation

Croma-Pharma GmbH

Contact name

Croma-Pharma GmbH

Public contact point

Organisation

Croma-Pharma GmbH

Contact name

Croma-Pharma GmbH

Third parties 6

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications