| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Actinic keratosis (and cutaneous squamous cell carcinoma) |
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| E.1.1.1 | Medical condition in easily understood language |
| Red, scaly skin lesions that may develop into cancerous skin lesions |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000614 |
| E.1.2 | Term | Actinic keratosis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Cutaneous squamous cell carcinoma (cSCC) is economically a major burden to the NHS. The incidence is rising rapidly, with approximately 30,000 new cases per year in the UK. Immunosuppressed organ transplant recipients (OTR) have a more than 100-fold increased risk and an accelerated carcinogenic process, making them an ideal population in which to test interventions aimed at preventing cSCC. Premalignant lesions, termed actinic keratoses (AK), are present on sun-damaged skin and effective topical agents are available to treat them. The close relationship between AK and cSCC means that such topical treatment of a field bearing multiple AK should significantly reduce subsequent risk of developing cSCC, but this assumption has never been proven. The main objective of the study is thus to determine the feasibility of performing a larger phase III randomised controlled trial using topical treatment of AK as a strategy for prevention of invasive cSCC.
The decision to perform a phase III ra |
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| E.2.2 | Secondary objectives of the trial |
1. To assess the activity of the treatment cream, determined by the clearance of AK at the end of the treatment period, the persistence of that clearance at the end of month 12, and the development of cSCC at 12 months after treatment.
2. To develop and evaluate an objective clinical system for measuring AK, taking into account lesion size, erythema (redness), hyperkeratosis (dry and scaly texture) and whether the AK appear as a continuous field. In addition, AK diagnosis by clinicians using the system described above will be compared to an independent photographic assessment of AK to determine the level of agreement between the two methods and the utility of photographs as a means of measuring AK.
3. Patient centred secondary objectives include ascertaining patient treatment preference and testing the sensitivity of QoL instruments in advance of a larger trial.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The Decision Choice Experiment (DCE) and Quality of Life (QoL) Study is integral part of the SPOT trial protocol. This study was developed at University of Dundee by Prof Charlotte Proby and Dr Paul Allanson. It is designed to establish patient treatment preferences and to pilot QoL measures for the phase III trial. These are key secondary objectives of the trial. The DCE includes 10 demographic questions, about lifestyle factors that may affect skin health, such as occupation, and the history of any skin problems including AK, treatments received for AK, and general health related variables. Patients are then given a range of hypothetical scenarios with photos of varying AK skin disease. They will be asked to choose from different hypothetical treatment options that vary in frequency and length of application, local skin response, improvement in skin appearance and reduction in skin cancer risk. This data will be used to determine which treatment option patients prefer. The QoL measure comprises parts of two published and validated questionnaires (used with permission) and one exploratory measure.
The Long Questionnaire (Long Q) will comprise the DCE and QoL measures. Both organ transplant recipients and immunocompetent patients will complete the full version of this questionnaire at baseline (after being registered into the trial). A slightly abridged version of the Long Q will be completed by the organ transplant recipients on completion of treatment. Throughout the trial, the organ transplant recipients randomised into the trial will also be asked to complete the QoL questions only (formed into the Short Questionnaire, or Short Q) to gauge their health perceptions whilst on the medication.
The baseline questionnaire will be given to patients when they attend the dermatology clinic. All other questionnaires will be sent in the post by the SPOT Trial Office. The questionnaire will be accompanied by a standard cover letter providing written instructions on how to complete the questionnaire. Patients will be instructed to return the questionnaires directly to the SPOT Trial Office in pre-paid envelopes provided.
The SPOT Trials Office will securely forward the Long Q information to the Dundee Health Economics Group for analyses while the QoL questionnaire will be analysed by the CRCTU, University of Birmingham.
The DCE has been piloted by the Dundee Group under a separate ethical approval.
All versions of the questionnaire and the cover letter are included with the research ethics application. (Please note that the DCE questions are shuffled at random to avoid bias so are not sequentially numbered.)
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| E.3 | Principal inclusion criteria |
1. Organ Transplant Recipient (OTR) Patient Group:
•OTRs aged >18 years
•A minimum of 10 AK (with at least 5 AK occurring within the same skin zone)
•Demonstrably stable renal function on the basis of serum creatinine and estimated Glomerular Filtration Rate (eGFR)
•No recent change in immunosuppressive medication and predicted to remain stable over course of the study
•Able to apply topical cream as directed to the required area or having a carer who agrees to do this at the required frequency and times
•Women of child-bearing potential, or men in a relationship with a woman of child-bearing potential, prepared to adopt adequate contraceptive measures if sexually active
•Able to give written informed consent
•Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
2. Immunocompetent Patient Group (participating in the DCE substudy only):
•ICP patients aged >18 years
•Present or previous AK (any site, any number)
•Able to give written informed consent
•Willing to spend up at least 20 minutes completing the Long Q
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| E.4 | Principal exclusion criteria |
Organ Transplant Recipients (OTR) only:
•Pregnant (female patients of child bearing potential should have a urine or blood Human Chorionic Gonadotropin (hCG) test performed to rule out pregnancy prior to trial entry)
•Lactating females. Patients who agree to discontinue nursing 14 days prior to commencing treatment and do not nurse throughout all the treatment period are eligible
•Life expectancy less than 12 months
•Known hypersensitivity to 5-fluorouracil, imiquimod, sunscreen, or to any of the excipients (including but not limited to: methylhydroxybenzoate, propylhydroxybenzoate, cetyl alcohol, stearyl alcohol, polysorbate 60, propylene glycol, methyl parahydroxybenzoate and white soft paraffin)
•The use of brivudine, sorivudine and analogues is prohibited
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The main objective of this phase II trial is to determine the feasibility of performing a phase III randomised controlled trial using topical treatment of AK as a strategy for prevention of invasive cSCC.
The decision to perform a phase III randomised controlled trial will be based on a number of factors including:
•the proportion of eligible patients willing to be randomised;
•the proportion of patients who complete Treatment Cycle 1, for each active treatment arm;
•the proportion of patients who require Treatment Cycle 2 completed for each active treatment arm;
•the proportion of patients who would be willing to use the treatment again,
in addition to the activity of the interventions.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first main analysis will be performed once all patients have been followed up for a minimum of 16 weeks post-treatment, i.e, once the last patient to enter has completed month 7. Final analysis will be carried out after all patients have been followed up for a minimum of 12 months. |
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| E.5.2 | Secondary end point(s) |
1. The activity outcome measures will be determined by the following criteria:
•Clearance of AK trial treatment field(s): defined as the proportion of AKs identified at baseline that are no longer detectable at 4 and 8 weeks post treatment
•Persistence of AK clearance trial treatment field(s): defined as the proportion of AKs which were cleared at 4 and 8 weeks post treatment which remain undetectable at the completion of the 12 month follow-up period
•Development of cSCC: defined as the time from entry into the trial until development of cSCC. Patients will be censored at the date last seen alive without development of cSCC.
2. The evaluation outcome measures will be determined by the following criteria:
•Evaluation of the proposed overall AK quantification scoring criteria: defined as scores designated for lesion size (including area of contiguous field change), erythema and hyperkeratosis
•Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments.
3. The patient-centred outcome measures will be determined by:
•Patient treatment preferences: defined as the preference weights or relative values put on the various treatment attributes (duration of treatment, frequency of application, severity of reaction; improvement in appearance, reduction in skin cancer risk)
•Assessment of QoL measure: defined as differences between patient QoL scores before, during and after treatment and between alternative treatments.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As above, for evaluation of primary endpoint. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard care, i.e., discretionary use of sunscreen alone; also used discretionarily in other arms |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of trial will be 6 months after the last patient last visit. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The SPOT Trial Office will notify the Sponsor, the MHRA and REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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