A Multicenter, Randomized, Placebo-Controlled, Double-Blind, Adaptive Phase 3 Study to Evaluate the Efficacy and Safety of Sinecatechins (Defined Extract of Green Tea Leaves) Ointment in Adult Patients with Actinic Keratosis of the Scalp and the Face.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aresus Pharma GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

4 Sep 2024 → ongoing

Decision date (initial)

2023-10-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of the study is to show superiority of Veregen® 10% ointment to Placebo measured by complete (100%) clearance of a pre-defined treatment area (TA) following a treatment period of 12 weeks and a 4-weeks post-treatment (PT) period (i.e., after 16 weeks at most in patients without complete clearance at the end of the treatment (EoT) period).

Secondary objectives 5

1. To evaluate the efficacy of treatment with Veregen® 10% ointment (treatment period 12 weeks) compared to Placebo measured by clinical clearance of a pre-defined TA, lesion count, AK severity grading of the TA and assessment of erythema and thickness of individual AK lesions in the TA.
2. To evaluate the recurrence of AK in the TA at any timepoint after complete clinical clearance until the end of the Post-treatment Follow-up (PTFU).
3. To evaluate the safety profile of the treatment with Veregen® 10% ointment (treatment period 12 weeks) compared to Placebo measured by AE/SAE recording, local skin reactions, investigator`s and patient`s tolerability assessment as well as physical examination and vital signs.
4. To evaluate the incidence of squamous cell carcinoma (SCC) in the TA and on the head during the course of the study
5. To evaluate patient satisfaction with Veregen® 10% ointment treatment compared to Placebo.

Conditions and MedDRA coding

Actinic Keratosis (AK) of the Scalp and/or the Face.

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patients willing to participate, obtained written informed consent.
2. Male or female patients ≥ 18 years.
3. Clinically confirmed diagnosis of mild to moderate Actinic keratosis (AK) of the face including the forehead (excluding eyelids, lips and mucosa) and/or the bald scalp.
4. Presence of at least 4 but not more than 8 isolated (i.e. discrete and quantifiable) AK lesions located in a contiguous treatment area (TA) on the face and/or bald scalp of 25 square-cm.
5. AK lesions of the TA must be clinically typical AK lesions of Olsen grade I and/or grade Olsen grade II.
6. Ability to follow study instructions and likely to complete all study requirements.

Exclusion criteria 25

1. TA is within 5 cm of an incompletely healed wound or infected area of the skin.
2. AK lesions in the TA with atypical clinical appearance (e.g. TA contains massively hyperkeratotic and hypertrohic lesions (Olsen grade III AK), recalcitrant lesions, cutaneous horns, and/or lesions that had not responded to 2 previous cryotherapies).
3. Within the TA, any suspicion of other malignant or benign skin tumors.
4. History of a genetic skin-cancer disorder (e.g. xeroderma pigmentosum) and/or invasive tumor in the TA, such as a Merkel cell tumor, an invasive spinocellular carcinoma or a BCC (Basal Cell Carcinoma) and/or any skin cancer (suspected or diagnosed recently or within 5 years ago before screening).
5. History or evidence of skin conditions other than AK that would interfere with evaluation of the study medication (e.g. eczema, unstable psoriasis).
6. Patients having any significant physical abnormalities in the TA that may cause difficulty with examination or AK assessments (e.g. tattoes, scars, hyperpigmentation, etc.).
7. Evidence of clinically significant or unstable medical conditions such as: (a) metastatic tumor or tumor with high probability of metastatic spread, (b) heart failure (NYHA class III or higher), (c) immunosuppressive disorder (e.g. HIV, organ transplant patients), (d) hematologic, hepatic, renal, neurologic or endocrine disorder, (e) collagen-vascular disorder (e.g. cerebro-vascular or other bleeding disorder), (f) gastrointestinal disorder (e.g. active ulcera or history of recurrent peptic ulcera or hemorrhage).
8. Patients not willing to stop using skin care products (e.g. self-tanning products, sunscreens, make-ups/colored day care cremes, topical treatments with anti-aging products, vitamin A, vitamin C, and/or vitamin E containing ointments and gels) in the TA during the interventional period of the study (i.e., during the treatment and until 4 weeks post-treatment).
9. Patients not willing to stop any use of make-ups colored day care cremes, and sunscreens in the treatment area within 12 hours prior to an on-site visit during the PTFU period.
10. Patients not willing to abstain from sunbathing (including solarium) or any outdoor activities with intensive sun exposure without taking appropriate measures to protect the treatment areas during the study.
11. Patients with a tendency to manipulate skin parts e.g. scratching.
12. Pregnant or breast-feeding patients.
13. Patients currently or within the past 4 weeks participating in another clinical study.
14. Any previous randomization into this clinical study.
15. Any suspicion of current drug and/or alcohol abuse.
16. Patient is institutionalized because of legal or regulatory order.
17. Dependency (as an employee or relative) to the sponsor/responsible CRO or investigator.
18. Any condition that in the opinion of the investigator can influence the evaluation of the treatment, and other assessments.
19. Hypersensitivity, intolerance or allergies against ingredients of Veregen® 10% ointment and/or Placebo ointment.
20. Have received the following topical or physical treatments for any indication in the treatment area within the designated time period before treatment with study drug: a) Curettage, Photodynamic therapy, Topical inhibitors of Src tyrosine kinase signaling and tubulin polymerization (e.g.,Tirbanibulin) for/in a period of 12 weeks; b) Topical retinoids, Topical diclofenac preparations, Topical 5-fluorouracil preparations, Topical immunomodulators (e.g., Imiquimod) for/in a period of 6 weeks; c) Topical steroids, Cryo-, thermo- or chemodestruction, Surgical excision for/in a period of 4 weeks.
21. Initiation of treatment with the following systemic treatments for any indication within 2 weeks before Baseline: Immunomodulators or immunosuppressive therapies, Diclofenac, Corticosteroids (oral or injectable), Inhaled corticosteroids (>1200 µg/day for beclomethasone, or >600 µg/day for fluticasone)
22. Current or planned intake of high dosed oral green tea preparations for any reason
23. Current or planned application of dermal preparations with astringent effect on the TA, such as zinc paste or tannin-containing ointments/creams
24. Patients taking a drug with known potential for skin reactions must have taken it at a stable dose for at least 2 weeks prior to Baseline, except in cases where no previous skin reactions have occurred at any dose.
25. Women of childbearing potential (WOCBP) will not be considered unless they use a highly effective method of contraception (failure rate of less than 1% per year) during the interventional period until 4-weeks PT (EoI, V9).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy Endpoint: Complete clinical clearance of the TA following a treatment period of 12 weeks and a 4-weeks PT period. [Complete (100%) clinical clearance is defined as complete disappearance of all clinically visible and/or palpable AK lesions in the TA; Total number of AK lesions (TN) = 0]

Secondary endpoints 27

1. Efficacy Endpoints - Clinical Clearance, During the interventional study period: Complete (100%; TN = 0) clinical clearance of the TA at every on-site visit during the treatment period (i.e. at 2, 4, 8 and 12 weeks of treatment) and at 4-weeks PT (for patients without complete clearance at EoT).
2. Efficacy Endpoints - Clinical Clearance, During the interventional study period: Time to complete clinical clearance during the course of the study (defined as the on-site visit at which complete clinical clearance of the TA is seen for the first time)
3. Efficacy Endpoints - Clinical Clearance, During the interventional study period: At least 75% clinical clearance of the TA at every on-site visit during the treatment period (i.e. at 2, 4, 8 and 12 weeks of treatment) and at 4-weeks PT. [75% clinical clearance is achieved if the number of all clinically visible and/or palpable AK lesions is reduced by 75% compared to TN at Baseline]
4. Efficacy Endpoints - Lesion count, During the interventional study period: TN in the TA at every on-site visit during the treatment period and at 4-weeks PT and mean change in TN from Baseline.
5. Efficacy Endpoints - Lesion count, During the interventional study period: Number of new AK lesions (not present at baseline) in the TA at every on-site visit during the treatment period and at 4-weeks PT and mean change in number of new AK lesions from Baseline.
6. Efficacy Endpoints - Lesion count, During the interventional study period: Number of baseline AK lesions that remain present in the TA at every on-site visit during the treatment period and at 4-weeks PT and mean change in number of baseline AK lesions from Baseline.
7. Efficacy Endpoints - AK severity grading, During the interventional study period: AK severity of the head (acc. to Olsen, modified acc. to Stockfleth) at Baseline and End of Treatment and mean change in AK severity of the head from Baseline.
8. Efficacy Endpoints - AK severity grading, During the interventional study period: AK severity of the TA (acc. to Olsen, modified acc. to Stockfleth and acc. to local AKASI) at every on-site visit during the treatment period and at 4-weeks PT and mean change in AK severity of TA from Baseline.
9. Efficacy Endpoints - AK severity grading, During the interventional study period: Change in Erythema (E) intensity and degree of thickness (T) (acc. to corresponding AKASI subscores) of all individual AK lesions present at every on-site visit during the treatment period and at 4-weeks PT.
10. Efficacy Endpoints - Clinical Clearance, During the post-treatment FU: Complete clinical clearance of TA (i.e., TN = 0) at every on-site visit during a 1-year post-treatment follow-up period (PTFU) (i.e. at 8 weeks PT, 3, 6, 9 and 12 months PT).
11. Efficacy Endpoints - Clinical Clearance, During the post-treatment FU: At least 75% clinical clearance at every on-site visit during a 1-year PTFU.
12. Efficacy Endpoint - Lesion count, During the post-treatment FU: TN in the TA at every on-site visit during a 1-year PTFU and mean change in TN from the End of Treatment (EoT) visit.
13. Efficacy Endpoint - Lesion count, During the post-treatment FU: Number of new AK lesions (not present at baseline) in the TA at every on-site visit during a 1-year PTFU and mean change in number of new AK lesions from the EoT visit.
14. Efficacy Endpoint - Lesion count, During the post-treatment FU: Number of baseline AK lesions that remain present in the TA at every on-site visit during a 1-year PTFU and mean change in number of baseline AK lesions from the EoT visit.
15. Efficacy Endpoint - AK severity grading, During the post-treatment FU: AK severity of the head (acc. to Olsen, modified acc. to Stockfleth) at every on-site visit during a 1-year PTFU and mean change in AK severity of the head from the EoT visit.
16. Efficacy Endpoint - AK severity grading, During the post-treatment FU: AK severity of the TA (acc. to Olsen, modified acc. to Stockfleth and acc. to local AKASI) at every on-site visit during a 1-year PTFU and mean change in AK severity of the TA from the EoT visit.
17. Efficacy Endpoint - AK severity grading, During the post-treatment FU: Change in Erythema (E) intensity and degree of thickness (T) (acc. to corresponding AKASI subscores) of all individual AK lesions present at every on-site visit during a 1-year PTFU.
18. Efficacy Endpoint - Reoccurrence: Proportion of patients with recurrence of AK (i.e. TN > 0) in the TA at every on-site visit after complete clinical clearance.
19. Efficacy Endpoint - Reoccurrence: Extent of recurrence (defined as the mean number of clinically visible and/or palpable AK lesions in the TA at every on-site visit after complete clinical clearance).
20. Efficacy Endpoint - Reoccurrence: Time to recurrence (defined as on-site visit at which the first clinically visible and/or palpable AK lesion is detected in the TA after complete clinical clearance).
21. Safety Endpoint - During the interventional study: Adverse events/serious adverse events as assessed by the investigator as well as self-reported by the patient (during on-site visits or by phone calls) from signing the informed consent until the End of the Interventional period (EoI), i.e. until 4-weeks PT.
22. Safety Endpoint - During the interventional study: Investigator’s assessment of local skin reactions using the Local Skin Reaction Scale (LRS) at every on-site visit during the treatment period and at 4-weeks PT.
23. Safety Endpoint - During the interventional study: Investigator’s Global Tolerability Assessment (IGTA) at every on-site visit during the treatment period and at 4-weeks PT.
24. Safety Endpoint - During the interventional study: Patient’s Global Tolerability Assessment (PGTA) at every on-site visit during the treatment period and at 4-weeks PT.
25. Safety Endpoint - During the post-treatment FU: AEs (dermatological AEs on TA or outside TA [limited to the head] as well as any AEs with at least suspected relation to IP use, only) and all SAEs from 4-weeks PT until the end of the PTFU period.
26. Safety Endpoint - During the post-treatment FU: Total number of SCCs in the TA during the course of the study (detected by visual inspection and subsequent removal for histological confirmation of diagnosis, according to general practice and in accordance with current guidelines).
27. Safety Endpoint - During the entire study period: Total number of SCCs on the head during the course of the study.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aresus Pharma GmbH

Sponsor organisation

Aresus Pharma GmbH

Address

Kastanienallee 46

City

Strausberg

Postcode

15344

Country

Germany

Scientific contact point

Organisation

Aresus Pharma GmbH

Contact name

Schimansky-Wabra

Public contact point

Organisation

Aresus Pharma GmbH

Contact name

Schimansky-Wabra

Third parties 9

Locations

1 EU/EEA country · 11 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 17 files

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

Application history

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