Basal Cell Carcinoma
Conditions
Keywords
Nodular Basal Cell Carcinoma, Basal Cell Carcinoma, Photodynamic therapy (PDT), Metvix, Histological verification, PDT with Metvix cream, PDT with Placebo cream
Brief summary
Photodynamic therapy (PDT) was the selective destruction of abnormal cells through light activation of a photosensitiser in the presence of oxygen. These cells accumulated more photosensitiser than normal cells. The photosensitiser generated reactive oxygen species upon illumination. For skin diseases, there had been an increasing interest in using precursors of the endogenous photosensitiser protoporphyrin IX (PpIX). The most commonly used precursors had been 5-aminolevulinic acid (ALA) and its derivatives. The present test drug, Metvix®, contained the methyl ester of ALA, which penetrated the lesions well and shows high lesion selectivity . In vitro studies of animal and human tissues had shown significant intracellular formation of photoactive porphyrins after addition of Metvix®. The increased levels of photoactive porphyrins induced cytotoxic effects in tumour cells after photoactivation. The primary objective was to compare PDT with Metvix® cream to PDT with placebo cream in terms of participant complete response rates based on histologically verified disappearance of the lesions at 6 months after last treatment cycle. Secondary objectives were to compare the two treatments in terms of histological and clinical mean participant response weighted by the number of lesions within a participant, lesion response rates across participants, clinical complete participant response, cosmetic outcome and adverse events.
Detailed description
A participant was randomised to PDT with Metvix® cream or PDT with placebo cream. All eligible Basal cell carcinoma (BCC) lesions within a participant had got the same treatment. All participants got two consecutive treatments one week apart. At the 3-months follow-up visit, lesions with no clinical response or progression had been surgically excised. Lesions with partial response (50% or greater reduction on lesion area) had been re-treated, if they do not show complete response three months later they would have been be surgically excised. Lesions with complete response had been surgically excised 6 months after the first or second PDT cycle. All excised tissue specimens had been histologically examined.
Interventions
DRUGPDT with Metvix 160 mg/g cream
DRUGPlacebo
Sponsors
Galderma R&D
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A participant with primary, nodular BCC lesion(s) suitable for entry is defined as a participant with * Clinically diagnosed primary nodular BCC lesion(s). * Histologically confirmed diagnosis of BCC. * BCC lesions suitable for simple excision surgery. * Males or females above 18 years of age. * Written informed consent.
Exclusion criteria
A participant that is ineligible for inclusion is a participant fulfilling any of the following criteria: * Participants with porphyria. * Participant with Gorlin's syndrome. * Participant with Xeroderma pigmentosum. * Participants concurrently receiving immunosuppressive medication. * Participants with a history of arsenic exposure. * Known allergy to Metvix®, a similar PDT compound or excipients of the cream. * Participation in other clinical studies either concurrently or within the last 30 days. * Pregnant or breast-feeding: All women of child-bearing potential must use adequate contraception (e.g. barrier methods, oral contraceptives or intrauterine device) during the treatment period and one month thereafter. In addition, they must have a negative pregnancy test prior to treatment. * Conditions associated with a risk of poor protocol compliance. Lesion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Histologically Confirmed Complete Response (CR) | up to 6 months | Complete Response (CR) was defined as 100 percentage of the lesions within the participant having negative findings for nodular basal cell carcinoma (BCC) in the histological examination. Histological examination included evaluation of all the microscopical slides from the excised tissue for presence of malignant basal cells. Complete response was defined as complete disappearance of lesion. Percentage of participants with histologically confirmed complete response were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Histological Lesion Response | Up to 3 months | Histological examination included from the excised tissue were examined for presence of malignant basal cells, where complete response (CR) was no signs of malignant basal cells and non-CR was evidence of malignant basal cells |
| Percentage of Participants With Clinically Confirmed Participant Complete Response (CR) | Up to 9 months | A CR to treatment was documented clinically by visual evaluation and palpation. The on-site investigator evaluated the lesion response by comparing with the lesion size before treatment using the following definitions: CR - complete disappearance of a lesion. Partial response (PR) -the longest diameter of the lesion is reduced by 50% or more. No response (NR) - the longest diameter of the lesion is less than 50% reduced. Progression - the longest diameter is increased by 20% or more. |
| Percentage of Lesions Per Participant: Histologically Confirmed Participant Weighted Response | Up to 3 months | Histological response weight means no signs of malignant basal cells in all microscopical slides containing excised tissue. The histologically confirmed participant weighted response, weighted by percentage of lesions per participant are reported in this outcome measure. Number of lesions per participant with-in treatment group were calculated in following way: ni = number of lesions within 1 participant, ci= number of lesions in complete response within 1 participant, xi= 100%. ci/ni= response rate within one participant, Nt= number of participant within one treatment, nt=number of lesions with-in one treatment, wi=ni/nt= weight for one participant with Nt Σ wi (i=1) = 1 for each treatment. |
| Number of Participants With Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Up to 6 months | An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily had a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE was any untoward medical occurrence that at any dose: results in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect. |
| Cosmetic Outcomes for Lesions Assessed by Participants | Up to 3 months | Cosmetic outcome for those lesions with complete histological response was assessed by both the investigator and by the participant. Cosmetic outcome was assessed with regards to occurrence of the following signs or symptoms like scarring, atrophy, induration, redness, and change in pigmentation. The cosmetic outcome was graded as excellent: no scarring, atrophy or induration, and no or slight occurrence of redness or change in pigmentation compared to adjacent skin; good: no scarring, atrophy or induration but moderate redness or change in pigmentation compared to adjacent skin; fair: slight to moderate occurrence of scarring, atrophy or induration; poor: extensive occurrence of scarring, atrophy or induration. |
| Cosmetic Outcomes for Lesions Assessed by Investigator | Up to 3 months | Cosmetic outcome for those lesions with complete histological response was assessed by both the investigator and by the participant. Cosmetic outcome was assessed with regards to occurrence of the following signs or symptoms like scarring, atrophy, induration, redness, and change in pigmentation. The cosmetic outcome was graded as excellent: no scarring, atrophy or induration, and no or slight occurrence of redness or change in pigmentation compared to adjacent skin; good: no scarring, atrophy or induration but moderate redness or change in pigmentation compared to adjacent skin; fair: slight to moderate occurrence of scarring, atrophy or induration; poor: extensive occurrence of scarring, atrophy or induration. |
Countries
Australia
Participant flow
Recruitment details
This study was conducted in Australia between 1 October 2000 to 30 September 2002.
Pre-assignment details
A total of 66 participants were included in this study.
Participants by arm
| Arm | Count |
|---|---|
| Metvix® Cream 160 Milligram Per Gram Methyl aminolevulinate hydrochloride 160 milligram (mg)/gram (g) cream were received by participants with primary nodular basal cell carcinoma. A thick layer of study cream was applied directly on the lesion and on 5 mm of the surrounding tissue. An approximately 1 mm thick layer of cream was applied to cover the lesion completely. The study cream was applied for at least 3 hours followed by illumination using non-coherent red (570-670 nm) light at a fluence of 50- 75 J/cm\^2. | 33 |
| Placebo Participants with primary nodular basal cell carcinoma received Metvix® matching placebo cream. A thick layer of study cream was applied directly on the lesion and on 5 mm of the surrounding tissue. An approximately 1 mm thick layer of cream was applied to cover the lesion completely. The study cream was applied for at least 3 hours followed by illumination using non-coherent red (570-670 nm) light at a fluence of 50- 75 J/cm\^2. | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Metvix® Cream 160 Milligram Per Gram |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 11 | 68 years STANDARD_DEVIATION 11 | 70 years STANDARD_DEVIATION 10 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 33 Participants | 66 Participants | 33 Participants |
| Sex: Female, Male Female | 6 Participants | 17 Participants | 11 Participants |
| Sex: Female, Male Male | 27 Participants | 49 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 33 | 0 / 33 |
| other Total, other adverse events | 0 / 33 | 0 / 33 |
| serious Total, serious adverse events | 1 / 33 | 2 / 33 |
Outcome results
Primary
Percentage of Participants With Histologically Confirmed Complete Response (CR)
Complete Response (CR) was defined as 100 percentage of the lesions within the participant having negative findings for nodular basal cell carcinoma (BCC) in the histological examination. Histological examination included evaluation of all the microscopical slides from the excised tissue for presence of malignant basal cells. Complete response was defined as complete disappearance of lesion. Percentage of participants with histologically confirmed complete response were reported.
Time frame: up to 6 months
Population: Intent to treat (ITT) population that included all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Percentage of Participants With Histologically Confirmed Complete Response (CR) | 67 percentage of participants |
| Placebo | Percentage of Participants With Histologically Confirmed Complete Response (CR) | 18 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Cosmetic Outcomes for Lesions Assessed by Investigator
Cosmetic outcome for those lesions with complete histological response was assessed by both the investigator and by the participant. Cosmetic outcome was assessed with regards to occurrence of the following signs or symptoms like scarring, atrophy, induration, redness, and change in pigmentation. The cosmetic outcome was graded as excellent: no scarring, atrophy or induration, and no or slight occurrence of redness or change in pigmentation compared to adjacent skin; good: no scarring, atrophy or induration but moderate redness or change in pigmentation compared to adjacent skin; fair: slight to moderate occurrence of scarring, atrophy or induration; poor: extensive occurrence of scarring, atrophy or induration.
Time frame: Up to 3 months
Population: ITT population that includes all treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Excellent | 13 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Good | 8 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Fair | 1 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Not Applicable | 1 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Not Applicable | 1 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Excellent | 2 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Fair | 1 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Investigator | Investigator: Good | 3 Lesions |
Secondary
Cosmetic Outcomes for Lesions Assessed by Participants
Cosmetic outcome for those lesions with complete histological response was assessed by both the investigator and by the participant. Cosmetic outcome was assessed with regards to occurrence of the following signs or symptoms like scarring, atrophy, induration, redness, and change in pigmentation. The cosmetic outcome was graded as excellent: no scarring, atrophy or induration, and no or slight occurrence of redness or change in pigmentation compared to adjacent skin; good: no scarring, atrophy or induration but moderate redness or change in pigmentation compared to adjacent skin; fair: slight to moderate occurrence of scarring, atrophy or induration; poor: extensive occurrence of scarring, atrophy or induration.
Time frame: Up to 3 months
Population: ITT population that includes all treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Excellent | 14 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Good | 8 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Fair | 0 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Not Applicable | 1 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Not Applicable | 1 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Excellent | 5 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Fair | 0 Lesions |
| Placebo | Cosmetic Outcomes for Lesions Assessed by Participants | Participants: Good | 1 Lesions |
Secondary
Histological Lesion Response
Histological examination included from the excised tissue were examined for presence of malignant basal cells, where complete response (CR) was no signs of malignant basal cells and non-CR was evidence of malignant basal cells
Time frame: Up to 3 months
Population: ITT population included all treated participants
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Histological Lesion Response | Lesions in CR | 23 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Histological Lesion Response | Lesions in non-CR | 8 Lesions |
| Metvix® Cream 160 Milligram Per Gram | Histological Lesion Response | Missing | 3 Lesions |
| Placebo | Histological Lesion Response | Lesions in CR | 7 Lesions |
| Placebo | Histological Lesion Response | Lesions in non-CR | 29 Lesions |
| Placebo | Histological Lesion Response | Missing | 0 Lesions |
Secondary
Number of Participants With Serious Adverse Events (SAEs) and AEs Leading to Discontinuation
An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily had a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE was any untoward medical occurrence that at any dose: results in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.
Time frame: Up to 6 months
Population: The analysis was performed on safety set population defined as all participants who received study drug and had at least one post-baseline safety assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Number of Participants With Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Serious adverse events | 1 Participants |
| Metvix® Cream 160 Milligram Per Gram | Number of Participants With Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Adverse events leading to discontinuation | 1 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Serious adverse events | 2 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Adverse events leading to discontinuation | 0 Participants |
Secondary
Percentage of Lesions Per Participant: Histologically Confirmed Participant Weighted Response
Histological response weight means no signs of malignant basal cells in all microscopical slides containing excised tissue. The histologically confirmed participant weighted response, weighted by percentage of lesions per participant are reported in this outcome measure. Number of lesions per participant with-in treatment group were calculated in following way: ni = number of lesions within 1 participant, ci= number of lesions in complete response within 1 participant, xi= 100%. ci/ni= response rate within one participant, Nt= number of participant within one treatment, nt=number of lesions with-in one treatment, wi=ni/nt= weight for one participant with Nt Σ wi (i=1) = 1 for each treatment.
Time frame: Up to 3 months
Population: ITT Population that included all treated participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Percentage of Lesions Per Participant: Histologically Confirmed Participant Weighted Response | 67.6 Percentage of lesions per participant | Standard Deviation 8.3 |
| Placebo | Percentage of Lesions Per Participant: Histologically Confirmed Participant Weighted Response | 19.4 Percentage of lesions per participant | Standard Deviation 6.7 |
Secondary
Percentage of Participants With Clinically Confirmed Participant Complete Response (CR)
A CR to treatment was documented clinically by visual evaluation and palpation. The on-site investigator evaluated the lesion response by comparing with the lesion size before treatment using the following definitions: CR - complete disappearance of a lesion. Partial response (PR) -the longest diameter of the lesion is reduced by 50% or more. No response (NR) - the longest diameter of the lesion is less than 50% reduced. Progression - the longest diameter is increased by 20% or more.
Time frame: Up to 9 months
Population: ITT population that includes all treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metvix® Cream 160 Milligram Per Gram | Percentage of Participants With Clinically Confirmed Participant Complete Response (CR) | 82 percentage of participants |
| Placebo | Percentage of Participants With Clinically Confirmed Participant Complete Response (CR) | 24 percentage of participants |