A Randomized, Open-label, Comparative Study to Evaluate an Intermittent Dosing Regimen of Fluticasone Propionate 0.05% Cream (Twice Per Week) in Reducing the Risk of Relapse When Added to Regular Daily Moisturization Using PHYSIOGEL Lotion in Paediatric Subjects With Stabilized Atopic Dermatitis

This is an open-label, randomized, comparative study, including 4 phases: SCREENING, ACUTE, MAINTENANCE and FOLLOW-UP.

Subjects will complete the SCREENING phase to check the eligibility within 7 days after they sign the written informed consent form. All eligible subjects will be enrolled in ACUTE phase to receive twice daily Fluticasone propionate (FP) 0.05% cream up to 4 weeks. The efficacy and safety in ACUTE phase will be assessed every 2 weeks up to 4 weeks or until Treatment Success which depends on which time point comes first. Then subject can get into the MAINTENANCE phase receiving either emollient twice daily plus FP 0.05% cream once daily twice a week (Group A), or emollient twice daily (Group B), by 1:1 randomization. The treatment duration in MAINTENANCE phase will be up to 20 weeks. The efficacy and safety in MAINTENANCE phase will be assessed every 4 weeks up to 20 weeks or until AD relapse that depends on which time point comes first. If subjects don't experience relapse during MAINTENANCE phase, subsequent FOLLOW-UP phase applying emollient twice daily won't be longer than another 12 weeks.

Total study duration is up to 37 weeks. All subjects receive FP 0.05% cream twice daily up to 4 weeks to all affected sites and any newly occurring sites in ACUTE phase. After randomization in MAINTENANCE phase, subjects either receive emollient twice daily extendedly plus FP 0.05% cream once daily twice a week to all healed sites and any newly occurring sites (Group A), or emollient twice daily extendedly (Group B), up to 20 weeks. In FOLLOW-UP phase, all subjects apply emollient twice daily up to 12 weeks.

This study will enrol 120 subjects, and propose at least 80 subjects to be randomized.

Study Endpoints/Assessments:

Primary endpoint is to observe the median time to the first relapse of AD during MAINTENANCE phase.

Secondary endpoints are:

1. Median time to the first relapse of AD during the whole study (including maintenance phase and follow-up phase.
2. Numbers of recurrent patients at the end of MAINTENANCE phase;
3. Numbers of recurrent patients at the end of FOLLOW-UP phase;
4. The effective rates (proportion of "treatment success" patients) during ACUTE phase (V3, W-2±2days;V4, W0±2days )
5. Evaluate the safety during the whole study duration (ACUTE phase, MAINTENANCE phase, FOLLOW-UP phase respectively);
6. Evaluate visual skin assessment for signs of cutaneous atrophy, epidermal thickening / lichenification and abnormal pigmentation changes during the whole study duration (ACUTE phase, MAINTENANCE phase, FOLLOW-UP phase respectively);
7. The change of Quality of Life (QoL) from baseline at the end of MAINTENANCE phase;
8. The change of Quality of Life (QoL) from baseline at the end of FOLLOW-UP phase;
9. Subjects' post-study evaluation to drugs.

Background Atopic dermatitis (AD) is a chronic relapsing skin disease caused by the intervention of plural unspecific stimulation or specific allergens accompanied with cutaneous physiologic dysfunction. AD is one of the most common skin diseases which effects up to 20% of Children and 1-3% of adults in most of countries of the world. The data from a Chinese epidemiologic research shows the prevalence rate of AD is 10.9%in school-age adolescent and 15.3% in preschool children in 2010.

Around 65% patients with AD develop the symptoms in the first year of life; and 90% patients develop the symptoms before 5 years of age. Onset of atopic dermatitis in adolescence or later is uncommon.

The objective of treatment in AD is to relief symptoms and reduces the cutaneous inflammation. Emollients as the mainstay of maintenance therapy are able to restore skin barrier function. Topical glucocorticoids recommended as first line treatment are important anti-inflammatory drugs to be used in AD, especially in the acute phase.

One of the most troublesome features of AD is its chronic relapsing nature suggesting the need for a long-term therapy of this disease. The common long-term treatment of AD is a reactive treatment approach based on the daily application of emollients accompanied by the application of topical glucocorticoids (TCS) or calcineurin inhibitors (TCI) 'as needed'. However, a new alternative treatment 'proactive therapy' has been proven its effective and well-tolerated to reduce AD relapse in clinical trials and recommended by guidelines.

This proactive therapy starts with an intensive topical anti-inflammatory therapy until all lesions have virtually cleared, followed by long-term, low-dose intermittent application of anti-inflammatory drugs to previous affected and now clinically healthy-looking skin combined with daily application of emollients to always unaffected areas.

Latest Chinese guideline of AD recommends the application of emollients or moisturizers in both the acute and maintenance phase, and intermittent application of topical corticosteroids with daily use of emollients and moisturizers as the first-line option of AD therapy.

However, the concept of 'proactive therapy' of AD has not been well accepted by Chinese dermatologists. In context, the studies demonstrated 'proactive therapy' efficacy has been done mainly in Caucasian subjects instead of in Chinese population. For this reason, there still exist unmet medical needs to generate data on combination use of fluticasone propionate with moisturizer in AD maintenance therapy in China.

Rationale Fluticasone propionate (FP) is a synthetic fluorinated corticosteroid of medium strength for the topical treatment of skin disease. The established glucocorticoids showed anti-inflammatory, anti-proliferative and immunosuppressive effects. FP has been demonstrated havinga moderate anti-inflammatory effect associated with good compliance among patients, a low incidence of cross-sensitivity reactions and a weak atrophogenicity.

FP does not show a significant effect on the hypothalamic pituitary axis (HPA), due to its lipophilicity, and its rapid hepatic biotransformation, reflecting a favourable ratio between topical and systemic activity. The results from a clinical trial with moderate to severe AD demonstrate that FP does not cause any major local side-effect. First-line therapy of AD in paediatric patients consist of the application of a mildly to moderately potent topical glucocorticoid combined with emollients . FP cream 0.05% has also been proven safe for the treatment of moderate to severe AD for up to 4 weeks in children 3 months of age and older.

More than one study has been demonstrated the efficacy and safety of FP 0.05% cream for proactive therapy of AD. A large multicentre study compared an intermittent dosing regimen of FP 0.05% cream (twice per week) with its drug-free vehicle in reducing the risk of relapse in adults and children (44% and 66% respectively) aged 3 months to 65 years with moderate or severe, but stabilized AD. Both regimens were added to regular daily emollient. The results showed patients receiving intermittent FP cream in the maintenance phase were 7.7 times (paediatric patients even 8.1 times) less likely to have an AD relapse compared with patients under vehicle cream. And the maintenance therapy with FP turned out to be safe and well-tolerated.

Subsequent similar large scale study was to compare the efficacy and safety of both FP 0.05% cream and 0.005% ointment in reducing the risk of relapses. The difference was that only patients aged 12-65 years with moderate to severe AD who were experiencing a flare were enrolled. FP 0.05% was more effective in reducing relapses than FP 0.005%: the former reducing the risk of relapses six fold and the latter two fold compared with emollient alone. Median time to relapse was 6 weeks for emollient alone compared with more than 16 weeks for additional FP. Both medications were well-tolerated with a low risk of local adverse effects.

First-line therapy of AD in paediatric patients consist of the application of a mildly to moderately potent topical glucocorticoid combined with emollients . Except for topical glucocorticoid, emollients are the basic treatment of AD, which have been recommended and emphasized by almost all the AD guidelines. PHYSIOGEL lotion, as a hypoallergenic emollient, contains physiological lipids, which mimics the structure and composition of the skin's protective lipid barrier with DMS (Dermal Membrane Structure) technique. PHYSIOGEL lotion provides immediate and long lasting moisture to prevent skin dryness, which has been recommended by dermatologists in AD adjunctive daily care. It is advised to apply a thin film of PHYSIOGEL lotion once to twice daily ideally for people of all ages with dry, sensitive and barrier dysfunction skin (including people suffering from AD).

In summary, a superiority of a proactive therapy with combination of FP and emollient over the drug-free vehicle or emollient alone has been demonstrated. Proactive therapy with FP prevented, delayed, and reduced the occurrence of exacerbations and AD relapses without any obvious safety concerns. Besides, PHYSIOGEL lotion, an emollient with physiological lipids and DMS technology, has good efficacy in repairing skin barrier. In this regard, it is possibly meaningful to demonstrate the efficacy and safety of a FP and PHYSIOGEL lotion combination in reducing AD relapse.

OBJECTIVE(S) This study is aimed to demonstrate the risk of AD relapse can be significantly reduced by extended intermittent dosing with Fluticasone propionate (FP) 0.05% cream in addition to regular emollient therapy (PHYSIOGEL lotion) in the maintenance treatment (20 weeks) of atopic dermatitis (AD) as compared with application of emollient alone.

The secondary objective is to evaluate the safety of FP 0.05% cream and emollient combination usage in AD maintenance treatment and determine the optimal treatment regimen in Chinese paediatric patients with AD.

Study Design This is an open-label, randomized, comparative study. The study includes 4 phases: SCREENING, ACUTE, MAINTENANCE and FOLLOW-UP.

After subjects sign the written informed consent form (Visit 1), they will enter the SCREENING phase to check the eligibility within 7 days before the 1st dose of FP 0.05% cream. During SCREENING phase, investigator will collect subjects' demographic data, medical history, Atopic Dermatitis' diagnosis and treatment history, concomitant medications. Investigator needs to assess AD Severity and conduct physical examination. Substance abuse will be evaluated. And pregnant test must be conducted to check for Women of childbearing potential (WOCBP).

-Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 6 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized.

WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.

Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or here their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.

The Visit 2 will be occurred before the 1st dose of FP 0.05% cream. At Visit 2, investigator needs to evaluate Eczema Area, AD Severity and Visual Skin Assessment. Vital signs will be measured and recorded. Subjects need to complete the questionnaire of QoL under the investigator's instruction. Investigator must confirm subjects' eligibility for ACUTE phase after all of inclusion and exclusion criteria have been checked.

All subjects eligible for ACUTE phase will receive twice daily FP 0.05% cream. FP 0.05% cream will be applied to affected sites and any newly occurring AD sites.

The efficacy and safety in ACUTE phase will be assessed every 2 weeks up to 4 weeks or until Treatment Success dependent on which time point comes first. At each visit (Visit 3, W-2±2days; Visit 4, W0±2days) in ACUTE phase, investigator needs to assess Eczema Area, AD Severity, Visual Skin Assessment, and conduct physical examination, vital sign measurement. Randomization will be processed once investigator confirms the subject's eligibility for MAINTENANCE phase.

The day of randomization is D0 in MAINTENANCE phase. If patients achieve Treatment Success and meet the criteria of MAINTENANCE phase during the visit intervals of ACUTE phase, Visit 4 can be moved earlier than scheduled date. If the time of treatment success is within 2 weeks after Visit 2, the subject can enter Visit 4 directly by skipping Visit 3.

If patients don't achieve Treatment Success for 4-week FP 0.05% cream treatment, they will be discontinued study treatment and conduct End of Therapy Visit. The subjects eligible for MAINTENANCE phase will be 1:1 randomized to receive either emollient twice daily plus FP 0.05% cream once daily twice a week (Group A), or emollient twice daily (Group B). FP 0.05% cream will be applied to all healed sites and any newly occurring sites.

The efficacy and safety in MAINTENANCE phase will be assessed every 4 weeks up to 20 weeks or until AD relapse dependent on which time point comes first. At each visit (V5, W4±2days; V6, W8±2days; V7, W12±2days; V8,W16±2days;V9,W20±2days), Investigator needs to evaluate Eczema Area, AD Severity, Visual Skin Assessment, and conduct physical examination, vital sign measurement. The questionnaire of QoL needs to be completed by subjects at the end of maintenance phase.

In MAINTENANCE phase, once subjects experience AD Relapse, they will be discontinued study treatment and conduct End of Therapy Visit.

On the contrary, if subjects don't experience relapse during MAINTENANCE phase, all of them will enter FOLLOW-UP phase applying emollient twice daily.

The efficacy and safety in FOLLOW-UP phase will be assessed every 4 weeks up to 12 weeks or until AD relapse dependent on which time point comes first. At each visit (V10, W24±5days; V11, W28±5days; V12, W32±5days), investigator needs to evaluate Eczema Area, AD Severity, Visual Skin Assessment, and conduct physical examination, vital sign measurement.In FOLLOW-UP phase, once subjects experience AD relapse, they will be discontinued study treatment and conduct End of Therapy Visit.

At End of Therapy Visit, investigator needs to evaluate Eczema Area, AD Severity, Visual Skin Assessment, and conduct physical examination, vital sign measurement. Subjects need to complete the questionnaire of QoL and Subjects' post-study evaluation to drug.

Subjects need to conduct Early Withdrawal Visit once they meet Withdrawal Criteria. At Early Withdrawal Visit, investigator needs to evaluate Eczema Area, AD Severity, Visual Skin Assessment, and conduct physical examination, vital sign measurement. Subjects need to complete the questionnaire of QoL and Subjects' post-study evaluation to drug.

At each study visit, concomitant medications will be collected after receiving subject's written informed consent form, and AEs should be collected and documented after the first dose of FP. For the female subjects who has experienced menarche, urine pregnant test need to be done when subjects enter the study and be repeated at the end of the entire study. If the result is positive, the subject will quit from the study. The treatment compliance will be evaluated at each visit after the 1st dose of FP 0.05% cream.

Total study duration is up to 37 weeks.

Eligibility Criteria:
Inclusion Criteria:

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the package insert of CUTIVATE and PHYSIOGEL Lotion.

Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. Subjects eligible for enrolment in the study must meet all of the following criteria:

1. male or female patients age between 1 to 18 years old (including 1 year and excluding 18 years old);
2. Diagnose atopic dermatitis according to criteria of Williams;
3. Mild to moderate AD on the head/neck, trunk, upper limbs or lower limbs and PSGA scores 2-3;
4. The informed consent must be signed before any study specific tests or procedures are initiated;

   Subjects eligible for enrolment in the MAINTENANCE phase of the study must meet all of the following criteria:
5. Achieve treatment success after receiving Fluticasone propionate 0.05% cream twice daily up to 4 weeks in ACUTE phase

Exclusion Criteria:

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects meeting any of the following criteria must not be enrolled in the study:

Acute phase:

1. Dermatitis of only the face, feet or hands;
2. The involved area has exceeded 10% of the whole body area;
3. Diagnosed contact dermatitis at predilection sites of AD;
4. Atrophy, telangiectasia, extensive scarring lesions in the area or areas to be treated;
5. Had topical therapies including but not limit to calcineurin inhibitors (topical tacrolimus or topical pimecrolimus), corticosteroids, antihistamines within 14 days prior to screening;
6. Has accepted nonsteroidal immunosuppressants (eg cyclosporine, methotrexate), or ultraviolet light treatments including ultraviolet-A and ultraviolet-B, or systemic corticosteroids regardless administration by oral, intramuscular, or intravenous within 4 weeks prior to screening;
7. Pregnant or breast-feeding. Women of Childbearing Potential (WOCBP) with a positive urine pregnancy test performed within 7 days before the start of treatment;
8. Has immunocompromised disease (e.g. lymphoma, AIDS, Wiskott-Aldrich syndrome) or have a history of malignancy (including basal cell carcinoma, squamous cell carcinoma, melanoma);
9. Has open skin infections (bacterial, viral or fungal) if at the application site;
10. Has head lice or scabies;
11. Present with clinical conditions other than AD that may interfere with the valuation (e.g. generalized erythrodema, toxicoderma, acne, Netherton's Syndrome, psoriasis);
12. Require systemic therapy for the treatment of atopic dermatitis, or had systemic therapy including but not limit to antihistamines within 14 days prior to screening;
13. Has accepted any experimental or investigational drug or therapy within 6 weeks prior to screening;
14. Has known hypersensitivity to Fluticasone Propionate 0.05% cream, or PHYSIOGEL lotion, or relate drugs;
15. Non-compliance with general medical treatment, or are known to miss appointments, or don't intend to comply with the protocol for the duration of the study;
16. Drug abuse, mental dysfunction, or other factors limiting the subject's ability to cooperate fully with study-related procedures;
17. Know to be unreliable or may be unable to complete the study;
18. Any condition or prior/present treatment that would render the subject not eligible for the study;

    Maintenance phase:
19. Accepted topic therapies other than Fluticasone propionate 0.05% cream and emollients during the ACUTE phase;
20. Has active skin infection (bacterial, viral or fungal).