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To identify the Maximum Tolerated Dose levels of ingenol mebutate gel after once daily treatment for 2 or 3 consecutive days and to evaluate efficacy of ingenol mebutate gel in different doses after once daily treatment for 2 or 3 consecutive days compared to vehicle gel
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1A: Ingenol mebutate gel 0.005% | Experimental | Open-label, dose escalation, 3 days treatment |
|
| Part 2: Ingenol mebutate gel 0.018% for 3 days treatment | Active Comparator | Randomized, 3 days treatment |
|
| Part 2: Ingenol mebutate gel 0.018% for 2 days treatment | Active Comparator | Randomized 2 days treatment |
|
| Part 2: Ingenol mebutate gel 0.027% for 3 days treatment | Active Comparator | Randomized 3 days treatment |
|
| Part 2: Ingenol mebutate gel 0.027% for 2 days treatment | Active Comparator | Randomized 2 days treatment |
|
| Part 2: Placebo for 3 days treatment | Placebo Comparator |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ingenol mebutate gel | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | Dose tolerability was measures looking at the composite score of Local Skin Responses (LSR). The MTD was defined as the highest dose level with less than 4 subjects out of 12 experiencing dose limiting toxicity (DLT). DLT was defined as one or more of the following three local skin LSRs:
The grading is a scale of 1 to 4 (highest grade). | 8 days after initial treatment |
| Part 2: Number of Subjects With Complete Clearance of AKs | Number of subjects with complete clearance of Actinic Keratosis lesions (AKs) at week 8 after 2 or 3 consecutive days of treatment with ingenol mebutate gel on the full face, full balding scalp or approximately 250 cm² on the chest | 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Part 2: Reduction in AK Count | Reduction in actinic keratosis lesion count from baseline to week 8 (percentage, adjusted for anatomical location and pooled site) | From baseline to Week 8 |
| Part 2: Number of Subjects With Partial Clearance of AKs |
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Inclusion Criteria:
Subjects must be competent to understand the nature of the trial and provide informed consent
Part 1: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the face Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on either the face, the balding scalp (the balding part of the scalp should be at least 25 cm2) or a contiguous area of approximately 250 cm2 on the chest
Subject at least 18 years of age
Female subjects must be of either:
Female subjects of childbearing potential1 must be willing to use effective contraception at trial entry and until completion
Exclusion Criteria:
Location of the treatment area (full face, full balding scalp or chest)
Prior treatment with ingenol mebutate gel within the treatment area
Lesions in the treatment areas that have:
History or evidence of skin conditions other than the trial indication that would interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis, xeroderma pigmentosum)
Use of cosmetic or therapeutic products and procedures which could interfere with the assessments of the treatment areas.
Clinical diagnosis/history or evidence of any medical condition that would expose a subject to an undue risk of a significant AE or interfere with assessments of safety and efficacy during the course of the trial, as determined by the investigator's clinical judgment
Any abnormal laboratory tests that are medically significant and would impact the safety of the subjects or the interpretation of the trial results, as determined by the investigator's judgment
Anticipated need for hospitalisation or out-patient surgery during the first 15 days after the first trial medication application. Note that cosmetic/therapeutic procedures are not excluded if they fall outside of the criteria detailed in Prohibited Therapies or Medications
Known sensitivity or allergy to any of the ingredients in ingenol mebutate gel
Presence of acute sunburn within the treatment areas
Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial.
Subjects previously assigned to treatment in Part 1 or rand
Female subjects who are breastfeeding.
In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state)
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| Name | Affiliation | Role |
|---|---|---|
| C. William Hanke, MD | Laser & Skin Surgery Center of Indiana | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Laser & Skin Surgery Center of Inidana | Carmel | Indiana | 46032 | United States |
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Part 1: There was 1 of the 82 subjects who withdrew before receiving any treatment but after collection of baseline characteristics. 81 subjects received treatment and all completed the trial.
Part 2: There were 2 of the 315 randomized subjects who withdrew consent prior to any baseline characteristics being recorded (therefore they received no treatment) and are excluded from the total number of participants, full analysis set and safety analysis.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1A: Ingenol Mebutate Gel 0.005% | Administration on full face, once daily for 3 consecutive days |
| FG001 | Part 1A: Ingenol Mebutate Gel 0.008% | Administration on full face, once daily for 3 consecutive days |
| FG002 | Part 1A: Ingenol Mebutate Gel 0.012% | Administration on full face, once daily for 3 consecutive days |
| FG003 | Part 1A: Ingenol Mebutate Gel 0.018% | Administration on full face, once daily for 3 consecutive days |
| FG004 | Part 1A: Ingenol Mebutate Gel 0.027% | Administration on full face, once daily for 3 consecutive days |
| FG005 | Part 1A: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily for 3 consecutive days |
| FG006 | Part 1B: Ingenol Mebutate Gel 0.06% | Administration on full face, once daily for 2 consecutive days |
| FG007 | Part 1B: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily for 2 consecutive days |
| FG008 | Part 2: Ingenol Mebutate Gel 0.018% for 2 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days |
| FG009 | Part 2: Ingenol Mebutate Gel 0.018% for 3 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days |
| FG010 | Part 2: Ingenol Mebutate Gel 0.027% for 2 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days |
| FG011 | Part 2: Ingenol Mebutate Gel 0.027% for 3 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days |
| FG012 | Part 2: Vehicle Gel (Placebo) for 2 Days | Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days |
| FG013 | Part 2: Vehicle Gel (Placebo) for 3 Days | Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 (Part 1) |
|
| ||||||||||||||||||
| Phase 2 (Part 2) |
|
For the Safety Analysis set for Part 1 the was 1 subject out of 12 not included in the Part 1B Ingenol Mebute Gel 0.06%. This subject discontinued before receiving any trial medication. Therefore, there are only 11 subjects.
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| ID | Title | Description |
|---|---|---|
| BG000 | Part 1A: Ingenol Mebutate Gel 0.005% | Administration on full face, once daily for 3 days |
| BG001 | Part 1A: Ingenol Mebutate Gel 0.008% | Administration on full face, once daily for 3 days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | Dose tolerability was measures looking at the composite score of Local Skin Responses (LSR). The MTD was defined as the highest dose level with less than 4 subjects out of 12 experiencing dose limiting toxicity (DLT). DLT was defined as one or more of the following three local skin LSRs:
The grading is a scale of 1 to 4 (highest grade). | The composite (sum) score was obtained by summing the 6 individual LSRs | Posted | Count of Participants | Participants | 8 days after initial treatment |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part 1A: Ingenol Mebutate Gel 0.005% | Administration on full face, once daily 3 days |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Application site pain | General disorders | MedDRA 16.0 | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Disclosure Manager | LEO Pharma A/S | +45 4494 5888 | ctr.disclosure@leo-pharma.com |
Not provided
| ID | Term |
|---|---|
| D055623 | Keratosis, Actinic |
| ID | Term |
|---|---|
| D011230 | Precancerous Conditions |
| D009369 | Neoplasms |
| D007642 | Keratosis |
| D012871 | Skin Diseases |
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Part 1 was an open-label, dose escalation. Part 2 was a randomised, double-blind, parallel group
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Masking only for Part 2
Randomized 3 days treatment
|
| Part 2: Placebo for 2 days treatment | Placebo Comparator | Randomized 2 days treatment |
|
| Part 1A: Ingenol mebutate gel 0.008% | Experimental | Open-label, dose escalation, 3 days treatment |
|
| Part 1A: Ingenol mebutate gel 0.012% | Experimental | Open-label, dose escalation, 3 days treatment |
|
| Part 1A: Ingenol mebutate gel 0.027% | Experimental | Open-label, dose escalation, 3 days treatment |
|
| Part 1A: Ingenol mebutate gel 0.04% | Experimental | Open-label, dose escalation, 3 days treatment |
|
| Part 1B: Ingenol mebutate gel 0.06% | Experimental | Open-label, dose escalation, 2 days treatment |
|
| Part 1A: Ingenol mebutate gel 0.018% | Experimental | Open-label, dose escalation, 3 days treatment |
|
| Part 1B: Ingenol mebutate gel 0.04% | Experimental | Open-label, dose escalation, 2 days treatment |
|
| placebo | Drug |
|
Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in the number of clinically visible AKs
| Week 8 |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| BG002 | Part 1A: Ingenol Mebutate Gel 0.012% | Administration on full face, once daily for 3 days |
| BG003 | Part 1A: Ingenol Mebutate Gel 0.018% | Administration on full face, once daily for 3 days |
| BG004 | Part 1A: Ingenol Mebutate Gel 0.027% | Administration on full face, once daily for 3 days |
| BG005 | Part 1A: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily for 3 days |
| BG006 | Part 1B: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily for 2 days |
| BG007 | Part 1B: Ingenol Mebutate Gel 0.06% | Administration on full face, once daily for 2 days |
| BG008 | Part 2: Ingenol Mebutate Gel 0.018% for 3 Days Treatment | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days Ingenol mebutate gel 0.018% |
| BG009 | Part 2: Ingenol Mebutate Gel 0.027% for 3 Days Treatment | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days Ingenol mebutate gel 0.027% |
| BG010 | Part 2: Ingenol Mebutate Gel 0.018% for 2 Days Treatment | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days Ingenol mebutate gel 0.018% |
| BG011 | Part 2: Ingenol Mebutate Gel 0.027% for 2 Days Treatment | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days Ingenol mebutate gel 0.027% |
| BG012 | Part 2: Vehicle Gel (Placebo)for 2 Days Treatment | Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days Vehicle gel (placebo) |
| BG013 | Part 2: Vehicle Gel (Placebo) for 3 Days Treatment | Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days Vehicle gel (placebo) |
| BG014 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Administration on full face, once daily for 3 consecutive days
| OG001 | Part 1A: Ingenol Mebutate Gel 0.008% | Administration on full face, once daily for 3 consecutive days |
| OG002 | Part 1A: Ingenol Mebutate Gel 0.012% | Administration on full face, once daily for 3 consecutive days |
| OG003 | Part 1A: Ingenol Mebutate Gel 0.018% | Administration on full face, once daily for 3 consecutive days |
| OG004 | Part 1A: Ingenol Mebutate Gel 0.027% | Administration on full face, once daily for 3 consecutive days |
| OG005 | Part 1A: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily for 3 consecutive days |
| OG006 | Part 1B: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily for 2 consecutive days |
| OG007 | Part 1B: Ingenol Mebutate Gel 0.06% | Administration on full face, once daily for 2 consecutive days |
|
|
| Primary | Part 2: Number of Subjects With Complete Clearance of AKs | Number of subjects with complete clearance of Actinic Keratosis lesions (AKs) at week 8 after 2 or 3 consecutive days of treatment with ingenol mebutate gel on the full face, full balding scalp or approximately 250 cm² on the chest | Posted | Number | participants | 8 weeks |
|
|
|
|
| Secondary | Part 2: Reduction in AK Count | Reduction in actinic keratosis lesion count from baseline to week 8 (percentage, adjusted for anatomical location and pooled site) | Posted | Number | 95% Confidence Interval | Percentage reduction | From baseline to Week 8 |
|
|
|
|
| Secondary | Part 2: Number of Subjects With Partial Clearance of AKs | Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in the number of clinically visible AKs | Posted | Number | percentage of participants | Week 8 |
|
|
|
|
| 0 |
| 3 |
| 0 |
| 3 |
| 1 |
| 3 |
| EG001 | Part 1A: Ingenol Mebutate Gel 0.008% | Administration on full face, once daily 3 days | 0 | 12 | 0 | 12 | 7 | 12 |
| EG002 | Part 1A: Ingenol Mebutate Gel 0.012% | Administration on full face, once daily 3 days | 0 | 10 | 0 | 10 | 9 | 10 |
| EG003 | Part 1A: Ingenol Mebutate Gel 0.018% | Administration on full face, once daily 3 days | 0 | 12 | 0 | 12 | 10 | 12 |
| EG004 | Part 1A: Ingenol Mebutate Gel 0.027% | Administration on full face, once daily 3 days | 0 | 12 | 0 | 12 | 12 | 12 |
| EG005 | Part 1A: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily 3 days | 0 | 10 | 0 | 10 | 10 | 10 |
| EG006 | Part 1B: Ingenol Mebutate Gel 0.04% | Administration on full face, once daily 2 days | 0 | 11 | 0 | 11 | 11 | 11 |
| EG007 | Part 1B: Ingenol Mebutate Gel 0.06% | Administration on full face, once daily 3 days | 0 | 11 | 0 | 11 | 10 | 11 |
| EG008 | Part 2: Ingenol Mebutate Gel 0.018% for 3 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days | 0 | 62 | 0 | 62 | 58 | 62 |
| EG009 | Part 2: Ingenol Mebutate Gel 0.018% for 2 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days | 0 | 64 | 0 | 64 | 59 | 64 |
| EG010 | Part 2: Ingenol Mebutate Gel 0.027% for 3 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days | 0 | 64 | 0 | 64 | 60 | 64 |
| EG011 | Part 2: Ingenol Mebutate Gel 0.027% for 2 Days | Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days | 0 | 61 | 0 | 61 | 58 | 61 |
| EG012 | Part 2: Vehicle Gel (Placebo) for 3 Days | Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days | 0 | 31 | 0 | 31 | 8 | 31 |
| EG013 | Part 2: Vehicle Gel (Placebo) for 2 Days | Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days | 0 | 31 | 0 | 31 | 8 | 31 |
| Application site pruritus | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Application site discomfort | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Application site paraesthesia | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Appilcation site dryness | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Cyst rupture | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Nasopharyngititis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Folliculitis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Eye irritation | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Eye swelling | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Lacrimation increased | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | MedDRA 16.0 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 16.0 | Non-systematic Assessment |
|
| Joint stiffness | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Pulmonary congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Eyelid oedema | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Chills | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Transient ischaemic attack | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Application site reaction | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Application site oedema | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Tenderness | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Periorbital oedema | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Skin burning sensation | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Salivary gland neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.0 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Conjunctival hyperaemia | Eye disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| oral herpes | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Lung infection | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
|
| Parosmia | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Systematic Assessment |
|
| Scoliosis | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Nasal septum deviation | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| upper airway cough syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Non-systematic Assessment |
|
| Ear pain | Ear and labyrinth disorders | MedDRA 16.0 | Non-systematic Assessment |
|
Not provided
Not provided
| D017437 |
| Skin and Connective Tissue Diseases |
| Superiority or Other (legacy) |
| See comment in analysis 1 | Fisher Exact | 0.0037 | see comments in analysis 1 | 2-Sided | Superiority or Other (legacy) |
| See comments in analysis 1 | Fisher Exact | 0.0171 | See comments in analysis 1 | 2-Sided | Superiority or Other (legacy) |
| Fisher Exact | 0.0001 | 2-Sided | Superiority or Other (legacy) |
| See comment in analysis 1 | z-test | < 0.001 | 2-Sided | Superiority or Other (legacy) |
| See comment analysis 1 | z-test | < 0.001 | 2-Sided | Superiority or Other (legacy) |
| See comment in analysis 1 | z-test | < 0.001 | Superiority or Other (legacy) |
| < 0.001 |
| 2-Sided |
| Superiority or Other (legacy) |
| Fisher Exact | < 0.001 | 2-Sided | Superiority or Other (legacy) |
| Fisher Exact | < 0.001 | 2-Sided | Superiority or Other (legacy) |