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Ingenol Mebutate (Picato): Topical Treatment of Non-hyperkeratotic, Non-hypertrophic Actinic Keratosis in Adults [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Feb.

Ingenol Mebutate (Picato): Topical Treatment of Non-hyperkeratotic, Non-hypertrophic Actinic Keratosis in Adults [Internet].

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3RESULTS

3.1. Findings From the Literature

A total of four studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 5 and described in Section 3.2. A list of excluded studies is presented in APPENDIX 3: EXCLUDED STUDIES.

Figure 1

QUOROM Flow Diagram for Inclusion and Exclusion pf Studies. QUOROM = Quality of Reporting of Meta-Analyses.

Table 5

Details of Included Studies.

3.2. Included Studies

3.2.1. Description of studies

Four multicentre, randomized, parallel-group, double-blind, vehicle-controlled trials met the inclusion criteria for this systematic review. PEP005-014 (N = 255) and PEP005-028 (N = 203) evaluated the efficacy and safety of ingenol mebutate gel, 0.05% for the treatment of AK on non-head locations (trunk and extremities; non-head studies).¹¹^,¹⁴ PEP005-016 (N = 269) and PEP005-025 (N = 278) evaluated the efficacy and safety of ingenol mebutate gel, 0.015% for the treatment of AK on the head (face and scalp; head studies).¹²^,¹³

All of the included trials were 57 days in duration and patients who achieved complete clearance of AK lesions were followed up for 12 months in study PEP005-032 (follow-up of PEP005-025) and study PEP005-030 (follow-up of PEP005-016 and PEP005-028). Results of these long-term follow-up trials are summarized in APPENDIX 6: LONG-TERM EFFICACY AND HARMS FROM EXTENSION STUDIES.

Patients were randomized in a 1:1 ratio with stratification by study site and anatomical location (arm, back of hand, chest, other locations; face or scalp) to ingenol mebutate gel or vehicle gel. In the non-head studies (PEP005-014 and PEP005-028), ingenol mebutate gel, 0.05% was applied topically once daily for two consecutive days to the selected treatment area by the patient at home. In the head studies (PEP005-016 and PEP005-025), ingenol mebutate gel, 0.015% was applied topically once daily for three consecutive days to the selected treatment area by the patient at home.

3.2.2. Populations

a. Inclusion and Exclusion Criteria

The main inclusion criterion was the presence of four to eight clinically typical, visible, and discrete AK lesions within a 25 cm² contiguous treatment area on the trunk and extremities (PEP005-014 and PEP005-028) or on the face and scalp (PEP005-016 and PEP005-025). The target treatment area was identified and documented using a three-point landmark technique study transparency, where three anatomical landmarks (e.g., scars, moles, birthmarks), the 25 cm² treatment area, and AK lesions were marked on a transparency using a marker.

Patients were excluded from the trial if the selected treatment area was within 5 cm of an incompletely healed wound or within 10 cm of a suspected basal cell or SCC, if they had been previously treated with ingenol mebutate, if the target treatment area contained hypertrophic or hyperkeratotic lesions, or if they had a history of other skin conditions or treatments that could interfere with the evaluation of study medication (e.g., topical medications, artificial tanners, immunosuppressive medications, immunomodulation agents, cytotoxic drugs, ultraviolet B phototherapy, other therapies for AK, or oral retinoids).

Patients who had received treatment with topical therapies such as 5-FU, imiquimod, and diclofenac within 2 cm of a selected treatment area within eight weeks before screening were excluded.

b. Baseline Characteristics

Baseline characteristics were generally well-balanced across treatment groups in the non-head studies (Table 6) and head studies (Table 7). In all studies, patients had a mean age of around 65 years and the majority of them were male (approximately 60% in non-head studies; approximately 80% in head studies).

Table 6

Summary of Baseline Characteristics of Non-Head Studies.

Table 7

Summary of Baseline Characteristics of Head Studies.

All patients were white and their skin type was categorized according to the Fitzpatrick Scale, which is a numerical classification schema for the colour of skin with the following definitions: type I = burns easily, rarely tans; type II = burns easily, tans minimally; type III = burns moderately, tans gradually; type IV = burns minimally, tans well; type V = rarely burns, tans profusely; type VI = never burns, deeply pigmented.¹⁸ In the non-head studies, the majority of patients had Fitzpatrick skin type II, followed by types I and III. In the head studies, the majority of patients had Fitzpatrick skin type II, followed by type III and then type I.

In the non-head studies, the location of AK treatment area was evenly distributed between ingenol mebutate and vehicle groups, with the majority of patients having lesions on the arm (approximately 60%) and back of the hand (20% to 30%). In the head studies, approximately 80% of patients had lesions on the face and 20% had lesions on the scalp.

More than 75% of patients in all of the studies had received previous treatment for AK with cryotherapy on any previous AK lesion, and a smaller percentage had received treatment with topical therapies. Approximately 20% of patients had previously received treatment with topical 5-FU. Subsequent to a request from the CDR, the manufacturer confirmed that the prior AK treatments and procedures were not specific to the lesions studied in the reviewed trials.

3.2.3. Outcomes

The primary efficacy outcome was the proportion of patients achieving complete clearance of all clinically visible AK lesions in the target treatment area at day 57. Clinical AK lesion assessment was performed by a board certified dermatologist. The same dermatologist performing screening assessments was to perform all subsequent study assessments for each individual patient and across enrolled patients.

Secondary outcomes of interest included the following:

Proportion of patients achieving partial clearance of AK lesions at day 57, defined as a reduction of 75% or more in the number of clinically visible AK lesions in the target treatment area.
Percentage change from baseline in the total number of AK lesions (not pre-specified in the trial protocol). Change in Skindex-16 Dermatological Survey score from baseline at day 8, day 29, and day 57.
The Treatment Satisfaction Questionnaire for Medication (TSQM) scores at day 57.

The Skindex-16 Dermatological Survey is a validated, 16-item, self-administered instrument that measures the effect of skin disease on patient quality of life. There are three domains: Symptoms (four items), Emotions (seven items), and Functioning (five items), and items are rated on a seven-point Likert-type scale, with higher scores indicating increased “bothersomeness.” Each of the items was transformed to a 0 to 100-point scale, and the mean of the transformed scores was calculated for each domain.

TSQM is a validated, 14-item, self-administered instrument with four domains: Effectiveness (three items), Side Effects (five items), Convenience (three items), and Global Satisfaction (three items). Items were rated on a five or seven-point Likert-type scale, and the sum of the individual items comprising each of the four domains was transformed to a 0 to 100-point scale (least favourable to most favourable).

Adverse events were defined as any unfavourable and unintended sign, symptom, or disease temporarily associated with the use of a study medication, whether or not related to the investigational product. Pre-existing conditions that worsened during the treatment period were reported as adverse events. The relationship of an adverse event to the study medication was assessed by the investigator (treatment-related adverse events). An adverse event was considered a serious adverse event if it was fatal, life-threatening, required participant hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or a medically significant event.

Local skin responses (LSRs), including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, or erosion/ulceration, were assigned a grade of 0 to 4 according to the LSR Grading Scale, with higher numbers indicating greater severity. A composite LSR score was calculated based on the sum of the six individual LSR scores and ranged from 0 to 24. A summary of the LSR grading criteria is presented in Table 8.

Table 8

Local Skin Response Grading Criteria.

Pigmentation and scarring were assessed by presence and then graded. Hypopigmentation and hyperpigmentation were assigned a grade of 0 (not present) to 3 (darker pigment or depigmented); scarring was assigned a grade of 0 (not present) to 2 (entire treatment area).

For a more detailed description of study outcomes, see APPENDIX 5: VALIDITY OF OUTCOME MEASURES.

3.2.4. Statistical analysis

a. Efficacy Criteria

A sample size of approximately 250 patients (PEP005-014, PEP005-016, PEP005-025) was determined to be sufficient to provide at least 90% power to detect at least a 20% difference in complete clearance rate of AK lesions at day 57 between-treatment groups (alpha = 0.05), assuming a 5% attrition rate. In PEP005-028, a sample size of approximately 200 patients was calculated to provide at least 90% power to detect this difference (alpha = 0.05), assuming a 10% complete clearance rate for the vehicle group as observed from PEP005-014.
The primary analysis for the primary end point (complete clearance of AK) and key secondary end points (partial clearance of AK lesions, percentage change from baseline in number of AK lesions) was performed using the intention-to-treat (ITT) population.
The per-protocol (PP) population was used for supportive efficacy analyses.
Missing clinical AK lesion assessments at day 57 were imputed using the last observation carried forward (LOCF) method for complete and partial clearance analyses. An additional sensitivity analysis was performed for complete clearance rate, in which all missing or out-of-window observations were considered treatment failures.
The Cochran-Mantel-Haenszel (CMH) test controlling for anatomical location was used to compare complete and partial clearance rates between-treatment groups. A logistic analysis of variance (ANOVA) model was used with treatment, anatomical location, and geographic location (Australia versus US) as factors to test for treatment effect in addition to the CMH test.
For the per cent reduction from baseline in the number of AK lesions at day 57, mean percentage reduction with a 95% CI was summarized by treatment group. No imputation of missing data was performed.
The Skindex-16 Dermatological Survey scores were transformed from the original scale of 0 to 6 to a linear scale of 0 to 100, with the mean of the transformed subscores computed for the domains (emotions, functioning, symptoms). If two or more responses were missing within a domain, that domain was considered missing. There was no imputation for missing data. The transformed scores at each scheduled visit (baseline, day 8, day 29, day 57) were treated as continuous variables and analyzed using ANOVA with treatment and analysis site as factors to test for treatment effect.
The TSQM scores were transformed to a scale from 0 to 100 and summarized by treatment group for each domain (effectiveness, side effects, convenience, global satisfaction). If more than one item within a domain was missing, that domain was considered missing. There was no imputation for missing data. The transformed scores for each domain at day 57 were treated as continuous variables and analyzed using ANOVA with treatment and analysis site as factors to test for treatment effect.
All hypotheses were tested for statistical significance using two-tailed P values. Results of all tests were considered statistically significant if their P value was less than or equal to 0.05. No adjustments for multiple testing were made.

b. Analysis Populations

In all four trials, the following data sets were defined:

ITT population: All patients randomized to receive study medication.

PP population: A subset of the ITT population that included all randomized patients considered to be sufficiently compliant with the protocol.

Safety data set: Patients who received at least one dose of study medication and had at least one post-baseline safety evaluation. Patients were counted in the group in which they were actually treated.

3.3. Patient Disposition

The disposition of patients in the non-head studies is presented in Table 9 and that of the head studies is presented in Table 10. The percentage of patients who withdrew from the trials was low (< 5%), and there were no notable between-treatment differences.

Table 9

Patient Disposition in Non-Head Studies.

Table 10

Patient Disposition in Head Studies.

3.4. Exposure to Study Treatments

In all four included trials, all patients randomized to vehicle applied the gel for the required duration; whereas, a number of patients randomized to ingenol mebutate failed to apply the gel for the required duration (Table 11 and Table 12). In study PEP005-014, one patient did not apply the second dose of ingenol mebutate due to an AE, and another patient did not apply the second dose due to a LSR. In study PEP005-028, one patient missed the second dose of ingenol mebutate due to losing the study medication tube. In study PEP005-016, two patients applied one dose of ingenol mebutate and one patient applied two doses. In study PEP005-025, one patient applied one dose and another patient applied two doses of ingenol mebutate. Reasons for the lack of adherence to the prescribed administration in studies PEP005-016 and PEP005-025 were not reported.

Table 11

Extent of Exposure in Non-Head Studies.

Table 12

Extent of Exposure in Head Studies.

3.5. Critical Appraisal

3.5.1. Internal validity

The PEP005 trials employed appropriate methods of randomization and allocation concealment (randomized centrally with the manufacturer), and baseline characteristics were well-balanced across treatment groups. Patients, investigators, and study site personnel were blinded to treatment assignment. However, during the trials, the increased incidence of LSRs in patients receiving ingenol mebutate gel may have resulted in unblinding of patients and assessors, potentially influencing patient-reported outcomes (Skindex-16 Dermatology Survey and TSQM) and lesion assessments by assessors.
Patients self-applied study medication, which may have resulted in varying practices and a lack of consistency. Treatment adherence was assessed simply by having the patients return the study medication kit with the tubes, which may not be sound evidence of adherence to treatment protocol.
The frequency of study withdrawal was low (< 5%), and similar across treatment groups, in all trials, supportive of internal validity.
Assessment of AK lesions at study entry and subsequent study visits were assessed by the same dermatologists across patients.
No minimum clinically important difference (MCID) values were identified for Skindex-16 Dermatological Survey and TSQM scores for patients with AK.

3.5.2. External validity

Ingenol mebutate gel was compared with vehicle gel and not with any other topical treatments for AK lesions.
Inclusion criteria required patients to have four to eight lesions within a contiguous 25 cm² area, which may not be representative of what is seen in clinical practice. The clinical expert consulted for this review mentioned that patients with AK frequently have scattered lesions, rather than lesions localized within a small area.
There was limited evidence for patients who had failed treatment with 5-FU, given that patients previously treated with 5-FU accounted for approximately 20% of trial participants and the response to prior treatment was not reported. In addition, prior 5-FU treatment was not necessarily specific to the lesions treated in the PEP005 trials.
Partial clearance of AK lesions was not considered to be a relevant outcome by the clinical expert consulted for this review, as the treatment area would require retreatment if there were any remaining lesions. The FDA medical review of ingenol mebutate also questioned the clinical meaningfulness of this outcome, stating, “However, it is not clear that partial clearing (e.g., 75%) is clinically meaningful. For example, a 75% or greater reduction in the number of AK lesions could still leave the largest AK lesion in the treatment area unaffected, and the lesion could progress into a squamous cell carcinoma.”¹⁵
The duration of the trials is insufficient to provide long-term efficacy and safety specific to ingenol mebutate gel, particularly with regard to progression of AK lesions to SCC or BCC.

3.6. Efficacy

Only those efficacy outcomes identified in the review protocol are reported below (Section 2.2, Table 4). See APPENDIX 4: DETAILED OUTCOME DATA for detailed efficacy data.

3.6.1. Complete clearance of AK lesions

The proportion of patients achieving complete clearance of all clinically visible AK lesions in the target treatment area at day 57 was statistically significantly higher in the ingenol mebutate group than the vehicle group in all studies. In the included trials, the proportion of patients achieving complete clearance of AK lesions at day 57 ranged from 27.8% to 47.2% with ingenol mebutate gel, and 2.2% to 5.1% with vehicle gel (Table 19 and Table 20). The risk difference of achieving complete clearance of AK lesions at day 57 with ingenol mebutate versus vehicle is presented in Table 13 along with numbers needed to treat. In all studies, the point estimates for risk difference favoured ingenol mebutate gel over vehicle gel.

Table 13

Ingenol Mebutate Versus Vehicle — Complete Clearance of Ak Lesions at Day 57.

3.6.2. Partial clearance of AK lesions

The proportion of patients achieving partial clearance of AK lesions (reduction of 75% or more in the number of clinically visible AK lesions in the target treatment area) was statistically significantly higher in the ingenol mebutate group than the vehicle group in all studies. In the included trials, the proportion of patients achieving partial clearance of AK lesions at day 57 ranged from 44.4% to 67.6% with ingenol mebutate gel, and 6.7% to 8.1% with vehicle gel. The risk difference of achieving complete clearance of AK lesions at day 57 with ingenol mebutate versus vehicle is presented in Table 14 along with NNTs. In all studies, the point estimates for risk difference favoured ingenol mebutate gel over vehicle gel. Additional details regarding partial clearance rates are presented in Table 21 and Table 22.

Table 14

Ingenol Mebutate Versus Vehicle — Partial Clearance of Ak Lesions at Day 57.

3.6.3. Per cent reduction from baseline in AK lesion count

The median reduction in the number of AK lesions compared with baseline at day 57 was 0% in the vehicle groups in all studies (Table 23 and Table 24). In the non-head studies, the median reduction in the number of AK lesions from baseline was 69% in study PEP005-014 and 75% in study PEP005-028 (Table 23). In the head studies, the median reduction in the number of AK lesions from baseline was 83% in study PEP005-016 and 87% in study PEP005-025 (Table 24). No analyses to determine the statistical significance of these findings were reported by the manufacturer.

3.6.4. Health-related quality of life

A summary of the Skindex-16 Dermatological Survey change in scores from baseline at days 8, 29, and 57 for the three domains (emotions, functioning, symptoms) is presented in Table 15 for the non-head studies and Table 16 for the head studies. Higher scores indicate greater patient concern, or “bothersomeness.” Change from baseline was calculated by subtracting the baseline score from the post-baseline score, thereby making a negative change an improvement in(health-related quality-ofe-life (HRQoL), and a positive change a decline or deterioration in HRQoL.

Table 15

Skindex-16 Dermatological Survey Change from Baseline; Mean (Sd) at Days 8, 29, and 57 in Non-Head Studies.

Table 16

Skindex-16 Dermatological Survey Change from Baseline; Mean (Sd) at Days 8, 29, and 57 in Head Studies.

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Skindex-16 Dermatology Survey scores at baseline and day 57 are summarized in Table 25, Table 26, Table 27, and Table 28.

3.6.5. Treatment Satisfaction Questionnaire for Medication

TSQM domain scores were transformed to a 0 to 100-point scale with higher scores indicating greater satisfaction. TSQM scores at day 57 for the non-head and head studies are presented in Table 29 and Table 30.

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3.6.6. Subgroup analyses

A post-hoc subgroup analysis of complete clearance in patients who had received previous treatment with cryotherapy, imiquimod, and 5-FU was conducted by the manufacturer using the pooled RCTs for the non-head studies (PEP005-014 and PEP005-028) and the head studies (PEP005-016 and PEP005-025). Results of this analysis are presented in Table 31 and Table 32.

Prior AK topical treatments were not specific to the target treatment area or lesions of interest in the included studies. Data on prior AK topical treatments specific to the target treatment area were requested from the manufacturer, but this information was not collected in the included studies.

Among ingenol mebutate-treated patients in the pooled non-head studies, there were no statistical differences in the proportion of patients achieving complete clearance based on prior treatment with cryotherapy, imiquimod, or 5-FU.

Among ingenol mebutate-treated patients in the pooled head studies, patients previously treated with 5-FU were less likely to achieve complete clearance than patients not previously treated with 5-FU: 27.3% versus 45.9% (P = 0.014). There was no statistical difference in the proportion of patients achieving complete clearance based on prior treatment with cryotherapy or imiquimod.

3.6.7. Progression to SCC

In study PEP005-014, one patient in the vehicle group developed a SCC in the target treatment area. In study PEP005-028, one patient in the ingenol mebutate group and two patients in the vehicle group developed a SCC, but it was unclear whether these were in the target treatment area. No cases of progression to SCC were reported in the head studies.

3.6.8. Recurrence of AK lesions

In study PEP005-014, one patient in the vehicle group experienced proliferation of AK lesions in the target treatment area. Recurrence of AK lesions was assessed in the follow-up studies of patients who achieved complete clearance in the included studies (APPENDIX 6: LONG-TERM EFFICACY AND HARMS FROM EXTENSION STUDIES).

3.7. Harms

Only those harms identified in the review protocol are reported below (see 2.2, Protocol).

3.7.1. Adverse events

Across all studies, the proportion of patients that reported at least one adverse event was greater in the ingenol mebutate group compared with the vehicle group: PEP005-014, 32.0% versus 28.7%; PEP005-028, 35.0% versus 25.2%; PEP005-016, 47.0% versus 23.0%; PEP005-025, 28.2% versus 21.3% (Table 33 and Table 34). In the non-head and head studies, the most commonly reported adverse events fell in the categories of infections and infestations, and general disorder and administration site conditions for patients treated with ingenol mebutate gel. The proportion of patients that reported at least one adverse event that fell into the category of general disorder and administration site conditions was greater in the ingenol mebutate group compared with the vehicle group: PEP005-014, 4.0% versus 0%; PEP005-028, 24.0% versus 5.8%; PEP005-016, 24.2% versus 3.0%; PEP005-025, 14.1% versus 2.2%. In the head studies, the proportion of patients who experienced any ocular AEs was higher in the ingenol mebutate group compared with the vehicle group (PEP005-016, 3.8% versus 0.7%; PEP005-025, 3.5% versus 0.7%).

A greater number of patients who received ingenol mebutate gel experienced at least one AE considered by the investigator to be related to treatment compared with patients who received vehicle gel. The most frequently reported treatment-related adverse events included general disorder and administration site conditions such as application site pruritus, application site pain, and application site irritation. Patients treated on the face or scalp had eye-associated disorders such as eyelid edema and periorbital edema.

3.7.2. Serious adverse events (SAEs)

The percentage of patients who experienced at least one serious adverse event was < 3% in all treatment groups in all trials, and did not differ noticeably between treatments.

3.7.3. Withdrawals due to adverse events (WDAEs)

The percentage of patients who discontinued due to adverse events was < 2% across all studies and treatment groups.

3.7.4. Mortality

No deaths were reported in any of the included trials.

3.7.5. Notable harms

3.7.6. Local skin responses

The mean composite LSR scores for patients treated with ingenol mebutate gel and vehicle gel at baseline and days 3, 8, 15, 29 and 57 are presented in Table 35 and Table 36). In all trials baseline mean LSR scores in both treatment groups were greater than zero, indicating a localized irritation at the lesion sites which was predominantly attributed to erythema and flaking/scaling. In the ingenol mebutate groups across all studies, the composite mean LSR scores peaked at the first or second assessment post-baseline: day 3 or day 8 for non-head studies; day 4 for head studies, before returning to approximately baseline values at day 29. In all trials, mean LSR scores in the vehicle groups were relatively stable at all time points.

A graphed time-course of the mean composite LSR scores for the pooled non-head and pooled head studies depicts this increase and decrease in patients treated with ingenol mebutate gel (Figure 2).

Figure 2

Time Course of Mean Composite LSR Scores. Source: Health Canada Module 2.7.4.

3.7.7. Pigmentation and scarring

In all studies, the majority of patients showed no hypopigmentation, hyperpigmentation, or scarring at baseline or at day 57 in all treatment groups (Table 17 and Table 18). Generally, hypopigmentation, hyperpigmentation, or scarring that was present at baseline remained unchanged at the end of the study. A greater proportion of patients who had hypo or hyperpigmentation at baseline was absent at the end of the study in ingenol mebutate-treated patients than with vehicle-treated patients. A small proportion of patients that had no pigmentation or scarring at baseline showed pigmentation or scarring at the end of the study.

Table 17

Incidence of Patients with Pigmentation and Scarring Change from Baseline at Day 57 for Non-Head Studies.

Table 18

Incidence of Patients with Pigmentation and Scarring Change from Baseline at Day 57 for Head Studies.

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