Efficacy of Oral Alitretinoin Versus Oral Cyclosporine a In

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Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from Study protocol: efficacy of oral alitretinoin versus oral cyclosporine A in patients with severe recurrent vesicular hand eczema (ALICsA): a randomised prospective open-label trial with blinded outcome assessment

Jart Ate Franke Oosterhaven, Marie Louise Anna Schuttelaar

To cite: Oosterhaven JAF, Abstract Strengths and limitations of this study Schuttelaar MLA. Study Introduction Systemic treatment with alitretinoin protocol: efficacy of oral is registered for all clinical types of severe chronic alitretinoin versus oral ►► This study compares two systemic drugs for severe hand eczema. However, it is especially effective in cyclosporine A in patients with recurrent vesicular hand eczema head-to-head and severe recurrent vesicular the hyperkeratotic subtype and less effective in non- aims to answer both a relevant clinical and econom- hand eczema (ALICsA): a hyperkeratotic forms. Cyclosporine A (cyclosporine) is ical question. randomised prospective open- prescribed for hand eczema in daily practice as well. ►► A strength of the study is that blinded assessment label trial with blinded outcome It has shown to be particularly effective in patients of severity will be performed in order to obtain an assessment. BMJ Open with vesicular hand eczema. The primary objective objective result for efficacy, despite the open-label 2018;8:e020192. doi:10.1136/ of this study is to compare efficacy of alitretinoin and design. bmjopen-2017-020192 cyclosporine in the treatment of severe recurrent vesicular ►► The study is limited by the fact that there will be no ►► Prepublication history for hand eczema. follow-up after the end of treatment at 24 weeks, this paper is available online. Methods and analysis This is an investigator-initiated meaning that this study will not address the long- To view these files, please visit

randomised prospective open-label trial with blinded term efficacy of both drugs. http://bmjopen.bmj.com/ the journal online (http://dx.doi. outcome assessment. Severity assessments and org/10. 1136/bmjopen- 2017- laboratory measurements will be conducted corresponding 020192). to daily practice. The study population will consist of 72 Received 24 October 2017 adult patients (age 18–75 years) with severe recurrent Introduction Revised 12 March 2018 vesicular hand eczema. Patients are treated with either Hand eczema is a common condition. It can Accepted 14 May 2018 (group I) alitretinoin 30 mg once daily or (group II) have far-reaching personal, psychological and cyclosporine with a starting dose of 5 mg/kg/day and a occupational consequences that may have a decrease in dosage after 8 weeks to 3–3.5 mg/kg/day. drastic impact on the life of those affected. A The treatment period is 24 weeks for both drugs. Primary point prevalence of 4% and a 1-year-period on September 30, 2021 by guest. Protected copyright. endpoint for efficacy is response to treatment, defined prevalence up to 10% in the general popula- as an improvement of ≥2 steps on a Physician Global tion in Sweden have been reported.1 A Danish Assessment, using a validated Photoguide, after 24 weeks study in young adults showed an incidence of of treatment. Secondary endpoints are improvement 8.8 per 1000 person-years, a point prevalence of Hand Eczema Severity Index, Quality of Life in Hand Eczema Questionnaire and a Patient Global Assessment. of 7.1% and a 1-year-period prevalence of Adverse events and time to response will be registered. 14.3%. Women are significantly more often 2 Furthermore, cost-utility, quality-adjusted life years and affected than men. cost-effectiveness will be assessed with the EQ-5D-5L The clinical presentation of severe hand questionnaire while monitoring costs. eczema varies widely, ranging from chronic Department of Dermatology, Ethics and dissemination This protocol was reviewed fissured skin to a vesicular eruption or palmar University of Groningen, and approved by the Medical Ethical Review Board of the University Medical Center hyperkeratosis. The disease could also be University Medical Centre Groningen (reference METc Groningen, Groningen, The approached aetiologically, considering Netherlands 2015/375). The study will be conducted according to the exogenous factors causing allergic contact principles of the Declaration of Helsinki, in accordance dermatitis (eg, nickel, perfumes) and irri- Correspondence to with the Dutch Medical Research Involving Human tant contact dermatitis (eg, water, soap) in Dr Marie Louise Subjects Act. addition to endogenous factors like atopic Anna Schuttelaar; Trial registration number NCT03026946; Pre-results. m. l.a. schuttelaar@umcg. nl dermatitis.3

Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 1 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from There is general consensus concerning the first-line however, its action was less convincing. Cyclosporine on treatment of hand eczema in various guidelines. Emol- the other hand showed good response in vesicular hand lients and topical corticosteroids are considered to be eczema. This trial aims to compare alitretinoin with cyclo- the mainstay of treatment in mild and moderate forms. sporine in the treatment of severe chronic recurrent If these fail, secondary options like phototherapy and vesicular hand eczema. The study assesses the efficacy of systemic treatment are available. However, to date, an both treatments and will show head-to-head results, which evidence-based recommendation regarding the treat- should contribute to uncovering the best treatment ment of more severe hand eczema cannot be made. strategy for hand eczema. Particularly, more head-to-head trials are needed.4 Alitretinoin is the only registered systemic treatment option for all clinical types of severe chronic hand Objectives eczema. It is currently the most investigated drug in Primary objective: to compare the efficacy of alitretinoin terms of patient numbers in the second-line treatment of and cyclosporine in patients with severe recurrent vesic- severe chronic hand eczema. In well-designed, pharma- ular hand eczema. ceutical sponsored trials, 30 mg alitretinoin a day resulted Secondary objectives: in a clear or almost clear response in 48% of the partic- ►► To compare time to response. ipants, compared with 17% in placebo. In the hyperker- ►► To compare health-related quality of life atotic subtype 54% responded, compared with 12% in ►► To compare improvement in severity of hand eczema, the placebo group. In two non-hyperkeratotic subgroups as assessed by the patient. (defined as pompholyx (vesicular) and fingertip in the ►► To compare safety. study), only 33% and 44% of participants reached clear- ►► To compare cost-utility and cost-effectiveness. ance or almost clearance, compared with 12%–30% in the placebo group.5 6 Methods and analysis In our clinical experience, cyclosporine has beneficial Study design effects on hand eczema in daily practice. This concerns This study is designed as a randomised prospective open- mainly the vesicular subtype in which a response of 68% label study. Assessment of disease severity, laboratory was estimated in a retrospective drug survival study.7 measurements and quality of life in this study will be Other small studies have also shown that cyclosporine conducted comparable with daily practice assessments. may have a beneficial effect on hand eczema. In a case The duration of the study for an individual patient is 24 study, Reitamo and Granlund reported that 87.5% of the weeks. Planned inclusion period is 2 years. patients with a chronic dermatitis on the hands responded 8 to cyclosporine treatment within a few weeks. In a study Study population http://bmjopen.bmj.com/ by Granlund et al, 41 patients were treated with cyclo- The study population will consist of adult patients with sporine for chronic hand eczema; 50% of the patients severe recurrent vesicular hand eczema. Recurrent vesic- reported a beneficial effect of the treatment.9 In a second ular hand eczema will be diagnosed following the criteria open-label study, 27 patients treated for 6 weeks with of the Danish Contact Dermatitis Group.13 The definition oral cyclosporine 3 mg/kg/day showed a 1-year success of recurrent vesicular hand eczema is recurrent eruptions rate of 74% for chronic hand eczema.10 A previous trial of vesicles on the palms and/or on the sides of the fingers comparing alitretinoin with cyclosporine in atopic hand and possibly also on the palmar aspects of the fingers and

eczema ended prematurely due to the inability to include around the fingernails. Eruptions may occur at intervals on September 30, 2021 by guest. Protected copyright. the total number of participants.11 of weeks or months. The severity of the hand eczema at In several European countries, cyclosporine is regis- screening will be graded by means of a Physician Global tered for use in patients with atopic dermatitis. Schmitt Assessment using a validated Photoguide.14 Woman in the et al performed a meta-analysis of controlled and uncon- fertile age will be required to use proper contraception trolled trials of cyclosporine treatment in patients with methods. Men and women of all ethnicities of 18 years atopic dermatitis. Fifteen studies including 602 patients and older will be recruited. Patients meeting all inclusion were analysed. All studies reported a decrease in the criteria, while not meeting any of the exclusion criteria, mean severity of atopic dermatitis with a relative effective- will be asked to participate. See figure 1 for a study flow ness of 55% (95% CI 48% to 62%) after 6 to 8 weeks of chart. cyclosporine treatment.12 Although alitretinoin is the only registered systemic Inclusion criteria treatment for severe chronic hand eczema, this treatment In order to be eligible to participate in this study, a subject has never been compared with immunomodulating/ must meet all of the following criteria: immunosuppressive systemic drugs that are currently ►► Age ≥18 years and ≤75 years. considered to be a third-line alternative treatment for this ►► Severe or very severe recurrent vesicular hand eczema condition.4 Since alitretinoin showed a good response in for a minimum duration of 3 months as defined by a hyperkeratotic subtypes, the drug should be used as first Physician Global Assessment (PGA) using a validated systemic choice in this subtype. In the vesicular subtype, Photoguide.14

2 Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from http://bmjopen.bmj.com/

Figure 1 Study flow chart. *Lack of efficacy defined as no improvement assessed by the Physician Global Assessment (Photoguide) (at least one step improvement is necessary to continue treatment after 12 weeks). on September 30, 2021 by guest. Protected copyright.

►► Refractory to standard therapy, defined as: Exclusion criteria –– Patient received treatment with topical cortico- A potential subject who meets any of the following criteria steroids of class II or higher for at least 8 weeks will be excluded from participation in this study: within 3 months before enrolment, with either no response or a transient response. General criteria prior to randomisation –– Patient has also received standard skin care, includ- ►► Treated with alitretinoin or cyclosporine in the ing emollients and barrier protection as appropri- previous 3 months. ate, without significant improvement. ►► Other morphological types of hand eczema as defined –– Patient has avoided irritants and contact allergens, by the Danish Contact Dermatitis Group.13 if identified, without significant improvement. ►► Patients with predominantly atopic dermatitis, in ►► Women of childbearing potential are required to use whom the hands are also involved, but no main at least two forms of contraception for at least 1 month before starting treatment, during treatment and for at concern. (Patients with controlled atopic dermatitis, least 1 month after finishing treatment; these women in which the hands are mainly affected, are eligible are required to take monthly pregnancy tests. for inclusion.) ►► Able to provide written informed consent. ►► Psoriasis of the hands. ►► Able to speak and read the Dutch language. ►► Active bacterial, fungal or viral infection of the hands.

Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 3 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from

►► Pregnant/lactating or planning to become pregnant ►► Uraemia. during the study period. ►► Hyperkalaemia. ►► Treatment with systemic immunosuppressive medica- ►► Hyperuricaemia in patients with a medical history of tion or UV radiation within the previous 4 weeks. gout. ►► Mentally incompetent. Recruitment and consent ►► Immunocompromised status (to be determined by investigator or treating physician). Recruitment takes place at a university centre Derma- tology department, during specialised eczema consulting ►► Uncontrolled arterial hypertension (minimally three measurements). Systolic pressure >160 mm Hg or sessions every week. Several Dermatology departments diastolic pressure >95 mm Hg, despite starting antihy- in hospitals in the region are provided with the study pertensive medication.15 protocol and asked to refer eligible patients. All referred hand eczema patients (by general practitioner or derma- ►► Known or suspected allergy to ingredients in the study medications. tologist) will visit the department several times for diag- nostics (patch testing) and initial therapy. Only when ►► Inclusion in a study of an investigational drug within these patients have a diagnosis of severe or very severe 60 days prior to start of treatment. recurrent vesicular hand eczema, prove refractory to ►► Current malignancy (other than successfully treated standard therapy, and avoidance of irritants and allergens non-metastatic cutaneous squamous cell or basal cell does not give significant improvement (ie, meet the key carcinoma and/or localised carcinoma in situ of the inclusion criteria), they will be approached at the outpa- cervix). tient clinic to participate in the study. Patients will be ►► Current active pancreatitis. extensively informed about the trial. ►► Evidence of alcohol abuse or drug addiction. It is the responsibility of the investigator, or a person ►► Malabsorption. designated by the investigator, to obtain written informed ►► Currently active gout. consent from each individual participating in this study ►► Recurring convulsions/epilepsy. after adequate explanation of the aims, methods, objec- ►► Living vaccine (including BCG, varicella, measles, tives and potential hazards of the study. It will also be mumps, rubella, yellow fever, oral polio and oral explained to patients that they are completely free to typhoid) in the last 2 weeks or the planned applica- refuse to enter the study or to withdraw from it at any tion of such a vaccine during the study period. time for any reason. Patients will be given a period of ►► Chronic or recurrent infectious diseases. 1 week to consider participation before they are asked to ►► Contact sensitisations with clinical relevance to the sign the informed consent form. hands, in which exposure to allergens is not avoided. ►► Hypervitaminosis A due to the use of vitamin A supple- http://bmjopen.bmj.com/ Treatment of subjects ments containing >2000 IU. Interventions ►► Use of drugs with potential to change the effective Group I will receive an oral alitretinoin capsule of 30 mg dose of study drugs within the previous 2 weeks. once daily for a total of 24 weeks. In a dose-finding study, Laboratory exclusion criteria post-randomisation the effectiveness and tolerability of this dose was estab- ►► Alanine aminotransferase (ALAT) and/or aspartate lished and it is recommended to use this as the stan- aminotransferase (ASAT) values >200% of the upper dard dose for the prescription of alitretinoin in hand 5 6 16 limit of normal. eczema. on September 30, 2021 by guest. Protected copyright. ►► Impaired renal function as indicated by a clinically Group II will receive oral cyclosporine tablets twice daily relevant abnormal creatinine value (to be determined in a dose of 5 mg/kg/day (split in two doses) and decrease this dose after 8 weeks to 3–3.5 mg/kg/day (split in two by investigator or treating physician). 17 ►► Anaemia as indicated by a clinically relevant lowered doses). haemoglobin value (to be determined by investigator Dosage reduction is allowed in both groups in case or treating physician). of abnormal findings on physical examination, laboratory markers and/or adverse events. For alitretinoin, Alitretinoin specific dose can be reduced from 30 mg/day to 10 mg/day, in ►► Triglycerides >200% of the upper limit of normal. accordance with the Summary of Product Characteristics 16 ►► Cholesterol or low-density lipoprotein cholesterol (SPC) text. For cyclosporine, in case of increased creat- values >200% of the upper limit of normal. inine levels >30% of baseline, laboratory measurement ►► Uncontrolled hypothyroidism (to be determined by should be repeated after 2 weeks. If creatinine levels are investigator or treating physician). still increased at least >30%, dosage will be reduced with the recommended 30%–50%.15 Developing hypertension Cyclosporine specific should be re-evaluated with at least three measurements ►► Impaired renal function as indicated by a clinically (if necessary by the general practitioner). If repeated relevant abnormal creatinine value (to be determined values of a systolic pressure >160 mm Hg or diastolic pres- by investigator or treating physician). sure >105 mm Hg are found, the general practitioner will

4 Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from be requested to start an antihypertensive drug (preferably and lercanidipine. Furthermore, grapefruit and grape- calcium channel blockers).15 18 fruit juice can have an increasing effect on cyclosporine Preparation and labelling of the study drugs will be plasma concentration. carried out according to usual practice by the commu- Also prohibited are drugs that result in an increased nity pharmacy, honouring Good Manufacturing Prac- risk for nephrotoxicity when combined with cyclospo- tice guidelines. Medication will be dispensed and rine, such as aminoglycosides (including gentamycin, used in the same way as in routine clinical practice, tobramycin), amphotericin B, ciprofloxacin, vancomycin, according to (among other regulations) their marketing trimethoprim (+sulfamethoxazole); fibric acid derivatives authorisations. (eg, bezafibrate, fenofibrate); non-steroidal anti-inflammatory drugs (including diclofenac, naproxen, sulindac); Use of concomitant medication melphalan, histamine H2-receptor antagonists (eg, All patients will be given an emollient cream with instruc- cimetidine, ranitidine), methotrexate. tions to apply it frequently (advice: minimum two times The dosage of statins needs to be decreased when treat- a day). One week before the first intake of study drugs, ment with cyclosporine is started because of a possible concomitant treatment with a topical class II corticoste- increase in plasma concentration of statins.17 roid (eg, triamcinolone acetonide ointment 0.1%) at maximum is permitted when needed, with a maximum Escape medication application of one finger-tip-unit (FTU) for each hand In case of an exacerbation or postponed treatment effect, daily.19 This also applies for concomitant topical cortico- patients are allowed to receive a maximum of three steroid therapy during the study period. High-potency courses of rescue medication: mometasone furoate oint- topical corticosteroids are not allowed as maintenance ment once daily for 1 week, with a maximum application therapy. of one FTU for each hand daily.19 Generally prohibited concomitant treatments during therapy comprise systemic corticosteroids, other reti- Outcome measures noids, any other systemic or topical anti-eczema therapy, Primary outcome measure phototherapy, immunosuppressive or cytostatic drugs. Severity of hand eczema Alitretinoin specific prohibited concomitant treatment: The PGA, based on a validated Photoguide developed vitamin A supplements, tetracyclines and azole antimy- by Coenraads et al, covers five degrees of severity (clear, cotics. St John’s wort should not be taken because of a almost clear, moderate, severe, very severe) and takes into possible interaction with hormonal contraceptive drugs. account the intensity of clinical signs and percentage of This could possibly result in a pregnancy, which is abso- hand surface involved.14 Response to treatment is defined

lutely contraindicated because of the teratogenic nature as an improvement of ≥2 steps on the PGA. Very severe http://bmjopen.bmj.com/ of alitretinoin.16 hand eczema is defined as responding to treatment if Cyclosporine specific prohibited concomitant treat- a status of at least ‘moderate’ is achieved. Severe hand ment: medicines that are substrates for the multidrug eczema is defined as responding to treatment if a status efflux transporter P-glycoprotein or the organic anion of at least ‘almost clear’ is achieved. transporter proteins. This could result in elevated plasma In this study, the main endpoint is the between-group concentrations, which are associated with serious and/ difference in response to treatment between baseline and or life-threatening events, for example, bosentan, dabiga- 24 weeks of treatment.

tranetexilate and aliskiren. on September 30, 2021 by guest. Protected copyright. Inductors of CYP3A4 and/or P-glycoprotein will prob- Secondary outcome measures ably lead to a decrease of cyclosporine plasma concentra- Severity of hand eczema tions. Examples of these are barbiturates, carbamazepine, ►► Between-group difference in response to treatment oxcarbazepine, phenytoin, nafcilline, intravenous sulfad- between baseline and 12 weeks of treatment. imine, probucol, orlistat, St John’s wort (Hypericum ►► Between-group difference in mean change between perforatum), ticlopidine, sulfinpyrazon, terbinafine and baseline and weeks 4, 8, 12 and 24, assessed by the bosentan. Rifampicine induces metabolism of cyclospo- Hand Eczema Severity Index (HECSI) score.20 The rine in the intestines and liver. Octreotide decreases oral HECSI is a physician-rated measurement instru- absorption of cyclosporine. ment for severity, based on clinical symptoms only. It Inhibitors of CYP3A4 and/or P-glycoprotein can includes erythema, fissures, vesicles, scaling, oedema, increase cyclosporine plasma concentrations. Exam- papules and measurement of the affected area. The ples of these are nicardipine, metoclopramide, methyl- score ranges from 0 to 360, with a higher score indi- prednisolone (high doses), allopurinol, cholic acid and cating more severe hand eczema. derivatives, protease inhibitors, imatinib, colchicine and ►► Between-group difference in time to response (time nefazodon. to first PGA improvement of ≥2 steps). This is only Other drugs that increase cyclosporine plasma concen- measured at control visits so possible outcome is tration are macrolide antibiotics, azole antimycotics, limited to 4, 8, 12 and 24 weeks. This will be corrected verapamil, telaprevir, amiodarone, danazol, diltiazem using statistical methods (see statistical paragraph).

Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 5 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from Patient-reported outcome measures (PROMs): Other study parameters Quality of life The following parameters will be registered: age, sex, ►► Between-group mean change in quality of life between body mass index, current and/or previous atopic derma- baseline and 12 and 24 weeks, assessed by the Quality titis (both defined by U.K. Working Party criteria),26 age Of Life in Hand Eczema Questionnaire (QOLHEQ). of onset of atopic dermatitis, age of onset of hand eczema, The QOLHEQ is a multi-domain disease-specific work/activities (based on risk professions as named in the instrument for hand eczema assessing impairments in European Guideline on hand eczema),4 current use of quality of life. The score ranges from 0 to 120, with statins, current use of thyromimetics, currently smoking 120 indicating worst quality of life.21 22 and amount of pack-years. Pack-years are calculated by multiplying the total years smoked with the average packs Patient-reported improvement per day smoked over these years.27 For this, the online ►► Between-group difference in patients reporting Smoking Pack Years Calculator, created by Dr N J Masters improvement as ‘clear or almost clear’ compared with and C Tutt, will be used.28 baseline at weeks 12 and 24, assessed by Patient Global Assessment (PaGA). The PaGA takes signs and symp- Study procedures and overview toms into account. It covers six degrees of improve- Procedures part of standard medical treatment ment: ‘clear or almost clear’ (at least 90% clearing According to daily practice, a detailed patient history is of disease signs and symptoms compared with base- obtained of all newly referred patients with hand eczema line), ‘marked improvement’ (at least 75% clearing), and they are planned for patch testing to exclude contact ‘moderate improvement’ (at least 50% clearing), allergy. During this first period, patients are treated with ‘mild improvement’ (at least 25% clearing), ‘no topical corticosteroids and emollients. A structured educa- change’ or ‘worsening’.6 tion programme by a nurse on provoking factors and treatment is provided. If a relevant contact allergy is ruled out Safety and tolerability and the hand eczema proves to be refractory to topical ►► Adverse events in both groups will be registered. therapy and/or UV therapy, the next step is systemic therapy. These patients are a candidate for the current study if they Cost-utility and cost-effectiveness are diagnosed with severe or very severe recurrent vesicular ►► Between-group difference in mean quality-adjusted hand eczema. life years (QALYs) will be measured by the EQ-5D-5L Laboratory analysis is performed to verify contraindi- score at baseline, week 12 and week 24. The EQ-5D-5L cations for alitretinoin or cyclosporine. During therapy, is a measure for health-related quality of life (HRQoL) standard monitoring of blood values is carried out, and utility values. The EQ-5D-5L questionnaire according to SPC texts and current guidelines. At every http://bmjopen.bmj.com/ includes a descriptive system, which comprises five visit, the PGA for severity is determined and the hand dimensions of health: mobility, self-care, usual activi- eczema is scored using the HECSI, corresponding to daily ties, pain/discomfort and anxiety/depression. More- practice. Furthermore, HRQoL is scored with a Dutch over, it includes a visual analogue scale (VAS), which version of the QOLHEQ at the start of therapy, at week records the respondent’s self-rated health status on a 23 12 and week 24. graduated (0–100) scale. Standard laboratory tests to be performed include: ►► Direct medical costs will be determined using stand- Alitretinoin: at weeks 0, 4, 8, 12 and 24, laboratory tests ardised prices for consultation, treatment (medica- are carried out, including full blood count, ASAT, ALAT, on September 30, 2021 by guest. Protected copyright. tion; alitretinoin or cyclosporine, topical treatment alkaline phosphatase (ALP), gamma-glutamyltransferase with corticosteroids and emollients, if necessary oral (γ-GT), serum creatinine, cholesterol, triglycerides, or topical treatment with antibiotics), diagnostic tests, high-density lipoprotein, thyroid-stimulating hormone laboratory measurements, visits to the general prac- (TSH), T4 and glucose. Also, a urine pregnancy test will titioner for hand eczema and hospital admissions be carried out. (inpatient and/or daycare). Included patients will be Cyclosporine: at weeks 0, 4 and 12, laboratory tests are asked to keep track of how much they spend on over- carried out, including full blood count, potassium, magne- the-counter medication and other products for their sium, ASAT, ALAT, ALP, γ-GT, bilirubin, LDH, albumin, hand eczema (out-of-pocket costs). Direct non-med- serum creatinine, uric acid, cholesterol and triglycerides. ical costs, consisting of travel costs, will be determined At weeks 4 and 12, cyclosporine trough levels will be using average travel costs to the hospital as deter- determined. mined by relevant Dutch guidelines on cost-studies in At weeks 8 and 24, serum creatinine will be determined. healthcare.24 25 ►► Indirect costs, consisting mainly of productivity loss, Procedures extra for this study will be also be calculated using tables from the guide- Patients will be given 1 week to consider participation. lines with average income of Dutch workers stratified Due to this, a maximum of one extra visit is needed to by age and gender, corrected for shift working/irreg- randomise the patient and obtain baseline data. The ular working hours.24 PaGA one-item questionnaire will be obtained at weeks 12

6 Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from

Table 1 Study schedule V1 V0 Visit Screening Baseline V1 V2 V3 V4 Week −1 0 4 8 12 24 Screening/baseline Check for clinical eligibility (inclusion/exclusion) x Sign informed consent x Randomisation x Baseline data/demographics/medical history/ x baseline costs Laboratory exclusion criteria post-randomisation x Start medication x Treatment Escape medication assessment x x x x If applicable: dosage alteration assessment x x x x Efficacy Severity scoring x x x x x PGA/HECSI Quality of life questionnaire x x x QOLHEQ PaGA of improvement x x Costs Cost assessment x x x x x Cost-utility questionnaire x x x EQ-5D-5L Safety Laboratory control x x x x x Concomitant medication x x x x x http://bmjopen.bmj.com/ Adverse events x x x x Blood pressure measurement (cyclosporine only) x x x x x If applicable: premature withdrawal assessment x x x x x

Patients are permitted to deviate from the schedule with a maximum of 7 days during weeks 0–8. From week 9, a maximum deviation of 14 days is permitted. HECSI, Hand Eczema Severity Index; PaGA, Patient Global Assessment; PGA, Physician Global Assessment; QOLHEQ, Quality of Life in

Hand Eczema Questionnaire. on September 30, 2021 by guest. Protected copyright. and 24. This procedure is only extra in terms of obtaining Safety a quantitative assessment of the qualitative report that a Alitretinoin patient provides in daily practice. Main risks in the alitretinoin group are16: Patients will be asked to keep track of out-of-pocket ►► Teratogenicity of the study drugs. costs on products for their hand eczema. During each ►► Occurrence of allergic/anaphylactic reactions. visit, patients will be asked for direct and indirect medical ►► Depression with anxiety, mood changes and suicidal and non-medical costs. Furthermore, the EQ-5D-5L ques- tendencies. tionnaire is obtained at weeks 0, 12 and 24, which is extra ►► Sunburn. compared with daily practice. ►► Xerostomia, xerosis cutis. Serum Thymus and Activation-Regulated Chemokine ►► Keratoconjunctivitis sicca, keratitis, blurred (night) (TARC/CCL17) will be determined at all visits to study vision, cataract. Care must be taken when driving a whether this chemokine is a suitable biomarker for hand vehicle or when operating machines. eczema severity and/or disease activity over time. ►► Myalgia, arthralgia, increase of creatine kinase (CK) No diagnostic procedures or other treatments will be values. postponed for patients participating in this study. ►► Exostosis, ankylosing spondylitis. In table 1, a systematic overview of the study is presented. ►► Headache.

Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 7 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from

►► Blushing. Experience with acute overdosage of cyclosporine is ►► Increase of cholesterol and triglycerides, with ulti- limited. Oral doses of cyclosporine of up to 10 g (about mately pancreatitis. 150 mg/kg) have been tolerated with relatively minor ►► Decrease of TSH and T4. clinical consequences, such as vomiting, drowsiness, ►► Increased liver transaminases. headache, tachycardia and in a few patients moder- ►► Decrease in effective dose of simvastatin. ately severe, reversible impairment of renal function. ►► Change at scarring or dermatitis during therapy and However, serious symptoms of intoxication have been 6 months after in case of aggressive dermabrasion or reported following accidental parenteral overdosage epilation. with cyclosporine in premature neonates. ►► Anaemia. In all cases of overdosage, general supportive measures ►► Epistaxis. should be followed and symptomatic treatment applied. ►► Alopecia. Forced emesis and gastric lavage may be of value within ►► Benign intracranial hypertension (rare and most seen the first few hours after oral intake. Cyclosporine is not in combination with tetracyclines). dialysable to any great extent, nor is it well cleared by ►► Inflammatory bowel disease (rare). charcoal haemoperfusion. ►► Vasculitis (rare). It can be concluded that the (reversible) effects can be Alitretinoin is a derivative of vitamin A. Alitretinoin properly managed. has been administered in oncological clinical studies at dosages of more than 10 times the therapeutic dosage Withdrawal of individual subjects given for chronic hand eczema. The adverse effects Subjects can leave the study at any time for any reason observed were consistent with retinoid toxicity and if they wish to do so, without any consequences. The included severe headache, diarrhoea, facial flushing investigator can decide to withdraw a subject from the and hypertriglyceridaemia. These effects were reversible. study, or to stop treatment, for medical reasons. Specific It can be concluded that the (reversible) effects can be criteria for withdrawal are: properly managed. ►► Evidence of pregnancy. ►► Occurrence of serious adverse events. Cyclosporine ►► Lack of efficacy at 12 weeks, defined as no improve- Main risks in the cyclosporine group are17: ment assessed by the PGA (at least one step improve- ►► Renal toxicity. ment is necessary to continue treatment after 12 ►► Hepatotoxicity. weeks). ►► Hypertension, flushing. ►► Use of prohibited concomitant therapy, or a need for

►► Nausea/vomiting, abdominal discomfort. their use. http://bmjopen.bmj.com/ ►► Headache. ►► The need for more than three courses of rescue ►► Diarrhoea. medication. ►► Anaemia, thrombocytopenia. ►► Anaphylactic reaction or other severe systemic reac- ►► Leucopenia. tion to study drug intake. ►► Hyperlipidaemia. ►► Diagnosis of malignancy during study, excluding ►► Hyperkalaemia, hypomagnesaemia, hyperuricaemia, non-metastatic cutaneous squamous cell or basal cell hyperglycaemia. carcinoma and/or localised carcinoma in situ of the

►► Tremor, convulsions, paraesthesia. cervix. on September 30, 2021 by guest. Protected copyright. ►► Hirsutism/hypertrichosis. ►► Any infection that is opportunistic and other infec- ►► Acne. tions whose nature or course may suggest an immuno- ►► Myalgia. compromised status. ►► Muscle cramps. ►► Administration of a living vaccine. ►► Tiredness. ►► Developing hypertension (minimally three measure- ►► Gynaecomastia. ments). Systolic pressure >160 mm Hg or diastolic ►► Occurrence of allergic/anaphylactic reactions. pressure >95 mm Hg, despite starting antihyperten- 15 ►► Pre-existing infections may also be aggravated and sive medication. reactivation of polyomavirus infections may lead to ►► Severe laboratory abnormalities including: polyomavirus-associated nephropathy or to John –– ALAT and/or ASAT values >300% of the upper Cunningham (JC) virus-associated progressive multi- limit of normal. focal leukopathy. Serious and/or fatal outcomes have –– Triglycerides >9 mmol/L. been reported. –– Creatinine increase of >30%, despite dose ►► Increased risk of lymphomas and other malignancies reduction. (mainly when combining multiple immunosuppres- ►► Intercurrent severe illness or major surgery. sive drugs). ►► Protocol violations or if the requirements of the ►► Increased risk of infections. protocol are not respected. ►► Decreased effect of live vaccinations. ►► Patient lost to follow-up.

8 Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from Serious adverse events and suspected unexpected serious adverse difference between alitretinoin and cyclosporine, using reactions a χ2 test with a two-sided 0.05 significance level. In this A serious adverse event (SAE) is any untoward medical calculation, we use the following assumptions: rando- occurrence or effect at any dose that: misation ratio is 1:1, and we expect the percentage of 6 ►► Results in death. responders in the alitretinoin group to be 33%. From ►► Is life threatening (at the time of the event). a retrospective study and other case studies, we esti- 7 ►► Requires hospitalisation or prolongation of existing mate 68% responders in the cyclosporine group. We inpatients’ hospitalisation. anticipate a drop-out of maximally 15% of randomised ►► Results in persistent or significant disability or patients; a small percentage prior to first application of incapacity. study drugs due to excluding laboratory measurements ►► Is a congenital anomaly or birth defect. and a larger percentage during follow-up, mainly due Any other important medical event that may not to subjective side effects. We therefore plan to include result in death, be life threatening or require hospital- 72 patients in total, 36 in the alitretinoin group and 36 isation may be considered a serious adverse experience in the cyclosporine group. when, based on appropriate medical judgement, the This was calculated with the sample size calculator event may jeopardise the subject or may require an inter- of the Department of Statistics, University of British vention to prevent one of the outcomes listed above. Columbia, Canada, available online (http://www.stat. Unexpected adverse reactions are suspected unex- ubc.ca/~rollin/stats/ssize/b2.html). pected serious adverse reactions if the following three For all analyses, we will use Bonferroni adjustment if conditions are met: necessary. 1. The event must be serious (see SAE). 2. There must be a certain degree of probability that the Primary analysis event is a harmful and an undesirable reaction to the Severity of hand eczema medicinal product under investigation, regardless of Between-group difference in response to treatment the administered dose. between baseline and 24 weeks of treatment. For compar- 3. The adverse reaction must be unexpected, that is to ison of proportions in the alitretinoin and cyclosporine say, the nature and severity of the adverse reaction are group, a χ2 test, or Fisher’s exact test if appropriate, will not in agreement with the product information as re- be used. Presenting the data as ORs derived from logistic corded in the SPC texts. regression analysis will be considered as an alternative Randomisation, blinding and treatment allocation reporting method. Randomisation is carried out by a computer program http://bmjopen.bmj.com/ (ALEA, http://www.aleaclinical.eu). Patients will be Secondary analyses randomly assigned in a 1:1 ratio to the two treatment Severity of hand eczema arms. We will use block randomisation with a random ►► Between-group difference in response to treatment block size of 4 or 6 (random generated blocks). No strati- between baseline and 12 weeks of treatment. For fication will be done. This is a study with blinded efficacy comparison of proportions in the alitretinoin and assessors, who are unaware of treatment allocation. The cyclosporine group, a χ2 test will be used. participants and treating physician will be aware of treat- ►► Between-group difference in mean change between ment allocation. Efficacy assessment will be carried out by baseline and weeks 4, 8, 12 and 24, assessed by the on September 30, 2021 by guest. Protected copyright. one main blinded assessor and a second assessor in case HECSI score. This will be reported graphically. For the first assessor is unable to be present. These assessors comparison of mean change between the alitretinoin are trained by the primary investigator and are experi- and cyclosporine group at weeks 12 and 24, Student’s enced in assessing hand eczema by PGA and HECSI in t-test or Mann-Whitney U test will be used, depending daily practice. The first assessor is expected to perform on distribution of data. around 95% of all assessments. Blinding will be broken ►► Between-group difference in time to response (time after analysing the data. to first PGA improvement of ≥2 steps compared with baseline). Because this outcome measure is inter- Statistical analyses val-censored, the cumulative incidence of ‘response’ Hypothesis and sample size calculation will be analysed using actuarial life table analysis and This trial is designed to demonstrate a superior response weighted log-rank tests for interval censored data; in to cyclosporine compared with alitretinoin in the particular the group proportional hazards model29 treatment of severe recurrent vesicular hand eczema. and a generalised Wilcoxon-Mann-Whitney test,30 Response to treatment is defined as an improvement which emphasises early events. The exact permutation of ≥2 steps on the PGA, based on a validated Photoguide value for the scores of the group proportional hazards developed by Coenraads et al14 at 24 weeks of treat- model will be calculated, along with Wilcoxon-Mann- ment. A sample size of 31 in each group will have 80% Whitney tests and the non-parametric maximum-like- power to be able to reject the null hypothesis of no lihood estimate of the survival distribution function.31

Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 9 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from Patient-reported outcome measures (PROMs): will be coded using sequential administration numbers. A Quality of life subject identification code list is used to link the data to ►► Between-group mean change in quality of life the subjects. The code is not based on the patient initials between baseline and 12 and 24 weeks, assessed by the and birth date. The code will be safeguarded by the prin- QOLHEQ. Clinically relevant improvement is defined cipal investigator (MLAS). The documents will be stored as an absolute improvement of 15 points (theoreti- in a locked room. The digital source data will be saved in cally corresponding to an improvement of ≥1 point on subsections of the subject’s medical file. These data will 50% of the questions) compared with baseline. For be accessible to the principal investigator and the investi- comparison of proportions of patients rated as having gator, and also to other treating physicians. Data will not clinically relevant improvement in the alitretinoin be accessed by the blinded efficacy assessors. All data will and cyclosporine group, a χ2 test will be used. be recorded in electronic case report forms (eCRFs) in Utopia (software for electronic data capture) developed Patient-reported improvement by the Trial Coordination Centre, linked to the University ►► Between-group difference in patients reporting Medical Centre Groningen. The eCRFs will only be acces- improvement as ‘clear or almost clear’ at weeks 12 sible with the username and password of the responsible and 24, assessed by PaGA. For comparison of propor- investigator. tions of patients rated as ‘clear or almost clear’ in the Data will be saved for 15 years after completion of this 2 alitretinoin and cyclosporine group, a χ test will be study. used. All the data will be saved in accordance with the Dutch Personal Data Protection Act. Safety and tolerability ►► Descriptive statistics will be used to present adverse Monitoring events. A certified monitor will carry out monitoring of this study. Cost-utility and cost-effectiveness The monitor will get read-only access to the digital and ►► For both groups (alitretinoin and cyclosporine), the paper documents of participants. The goal of this moni- mean EQ-5D scores overall and of each dimension toring is to review if will be reported. Results from the descriptive system ►► The rights and well-being of subjects are being of the EQ-5D-5L will be converted to a utility index protected. value, a population-based (social) value specific for ►► The reported data are right and fully reproducible. the Netherlands. With this value, Dutch utility values ►► The execution of the study is in accordance with this will be calculated in order to determine the QALYs protocol and relevant legal requirements.

over the study period. Mean values of the EQ-VAS will http://bmjopen.bmj.com/ Data safety monitoring board be reported with a 95% CI. For comparison of means, Student’s t-test or Mann-Whitney U test will be used, No data safety monitoring board (DSMB) is established depending on distribution of data. since this study will be conducted corresponding to daily practice. In case of life-threatening diseases, usually the ►► The incremental cost-effectiveness ratio will be calcu- implementation of a DSMB is indicated from an ethical lated and reported as €/QALY. point of view. However, hand eczema is a non-critical indi- ►► A regression model will be used to estimate the association between QALYs and the PGA. cation. Frequent laboratory assessments will reduce the

possibility of SAEs to a minimum. The patient population on September 30, 2021 by guest. Protected copyright. Handling of missing data in this clinical trial exists of legal competent adults and All analyses will be based on the intention-to-treat prin- the study drugs alitretinoin and cyclosporine are well-in- ciple to guard against attrition bias. Subjects might want vestigated, well-characterised drugs. to withdraw because the study drug works insufficient and they might also want to withdraw when their hand eczema Patient and public involvement is cured. In the Netherlands, there is no patient association exclu- Missing values will be handled in a way that is depen- sively for patients with hand eczema. However, multiple dent on assumptions about the missing data. If the extent patients with hand eczema are members of the associa- and pattern of missing data is known (eg, missing at tion of atopic dermatitis patients (‘De Vereniging voor random, missing completely at random, missing not at Mensen met Constitutioneel Eczeem’, www.vmce.nl). random), an analysis will be chosen that is valid under This association has 1500 members and a website with a plausible assumption about the missing data (probably up to 2000 hits a day. One committee member and two mixed models). This is according to a strategy proposed patients from this organisation contributed to our study by White et al.32 design by participating in a focus session concerning all aspects of our study, but in particular PROMs, logistics Data handling from a patient perspective and patient-friendliness of the Data will be handled confidentially. Data derived from study. These patients also participated in composing and the questionnaires and other paper source documents refining the patient information material. Before and

10 Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from after the study, the website and newsletter of the patient Data sharing statement The study is designed honouring the Centrale Commissie association is used to announce start (drawing attention Mensgebonden Onderzoek (CCMO) statement on publication policy. The results will be made public unreservedly; they will be offered for publication in a peer-reviewed to the study) and end (announce results) of the study. journal. In a publication, all data will be handled anonymously. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, Ethics and dissemination and license their derivative works on different terms, provided the original work is Ethics properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by- nc/4. 0/ The study will be conducted according to the principles of the Declaration of Helsinki (seventh revision, © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise Fortaleza, Brazil, October 2013), in accordance with the expressly granted. Medical Research Involving Human Subjects Act (WMO) and also in accordance with the International Confer- ence on Harmonisation Good Clinical Practice Guide- lines (ICH-GCP). References In this trial, both groups are treated with a drug, known 1. Thyssen JP, Johansen JD, Linneberg A, et al. The epidemiology to be beneficial to hand eczema in a considerable amount of hand eczema in the general population—prevalence and main findings. Contact Dermatitis 2010;62:75–87. of patients. So the intended benefit of both study drugs is 2. Mortz CG, Bindslev-Jensen C, Andersen KE. Hand eczema in to reduce the severity of hand eczema. The Odense Adolescence Cohort Study on Atopic Diseases and We hypothesise that cyclosporine has a superior efficacy Dermatitis (TOACS): prevalence, incidence and risk factors from adolescence to adulthood. Br J Dermatol 2014;171:313–23. compared with alitretinoin in severe chronic recurrent 3. Diepgen TL, Elsner P, Schliemann S, et al. Guideline on the vesicular hand eczema. If this hypothesis is confirmed, management of hand eczema ICD-10 Code: L20. L23. L24. L25. L30. J Dtsch Dermatol Ges 2009;7(Suppl 3):S1–16. there could be a practical as well as a financial implica- 4. Diepgen TL, Andersen KE, Chosidow O, et al. Guidelines for tion. Practically, more responding patients to cyclospo- diagnosis, prevention and treatment of hand eczema. J Dtsch Dermatol Ges 2015;13:e1–22. rine lead to a greater beneficial effect on hand eczema 5. Ruzicka T, Larsen FG, Galewicz D, et al. Oral alitretinoin (9-cis- in this patient group. Financially, cyclosporine is a lot retinoic acid) therapy for chronic hand dermatitis in patients less expensive than alitretinoin. If cyclosporine shows refractory to standard therapy: results of a randomized, double- blind, placebo-controlled, multicenter trial. Arch Dermatol superior efficacy in severe recurrent hand eczema, this 2004;140:1453–9. could lead to an official registration. This, in turn, could 6. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand mean a decrease in financial burden for the treatment of eczema refractory to topical corticosteroids: results of a randomized, patients with severe recurrent vesicular hand eczema in double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008;158:808–17. the population. 7. Christoffers WA, Politiek K, Coenraads PJ, et al. Drug survival of http://bmjopen.bmj.com/ We deem the overall risks for patients participating in cyclosporine in the treatment of hand eczema: a multicentre, daily this study to be acceptable because of the tight inclusion use study. J Eur Acad Dermatol Venereol 2016;30:63–6. 8. Reitamo S, Granlund H. Cyclosporin A in the treatment of chronic and exclusion criteria (ensuring a relatively healthy study dermatitis of the hands. Br J Dermatol 1994;130:75–8. population), combined with regular laboratory assess- 9. Granlund H, Erkko P, Eriksson E, et al. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of ments to enhance safety monitoring. Furthermore, prior severe chronic hand eczema. Acta Derm Venereol 1996;76:371–6. experience with both study drugs in daily practice has 10. Granlund H, Erkko P, Reitamo S. Long-term follow-up of eczema patients treated with cyclosporine. Acta Derm Venereol improved our capability to manage risks. The remaining 1998;78:40–3. risk is therefore small and does not differ from regular 11. Schmitt J. Ciclosporin versus alitretinoin for severe atopic hand on September 30, 2021 by guest. Protected copyright. daily practice. dermatitis (TocyDD). 2014 clinicaltrials.gov/show/NCT01231854 Last accessed 12 June 2018 12. Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment Acknowledgements The authors would like to thank K M Vermeulen for her of patients with atopic eczema—a systematic review and meta- valuable contributions to the health economics component of this protocol and the analysis. J Eur Acad Dermatol Venereol 2007;21:606–19. patient advisors who contributed to the design of the study. 13. Menné T, Johansen JD, Sommerlund M, et al. Hand eczema guidelines based on the Danish guidelines for the diagnosis and Contributors JAFO and MLAS contributed equally to this work. JAFO and MLAS treatment of hand eczema. Contact Dermatitis 2011;65:3–12. conceived this trial. JAFO drafted and MLAS revised the study protocol and this 14. Coenraads PJ, Van Der Walle H, Thestrup-Pedersen K, et al. manuscript. JAFO and MLAS read and approved the final version of the study Construction and validation of a photographic guide for assessing protocol and this manuscript. MLAS is principal investigator of this trial. severity of chronic hand dermatitis. Br J Dermatol 2005;152:296–301. 15. Nederlandse Vereniging voor Dermatologie en Venereologie. Richtlijn Funding This research is supported by a grant provided by the Netherlands constitutioneel eczeem 2006 2007. Organisation for Health Research and Development (ZonMw, project no. 16. Anonymous. SPC text alitretinoin. 2015 http://db.cbg-meb.nl/IB- 848015010). teksten/h100957. pdf Last accessed 12 June 2018 17. Anonymous. SPC text cyclosporine. 2016 http://www.medicines.or g. Competing interests Both authors have received honoraria for services rendered uk/emc/medicine/1307 (Last accessed 12 June 2018). to GlaxoSmithKline, wholly unrelated to this study. 18. Cai J, Huang Z, Yang G, et al. Comparing antihypertensive effect Patient consent Not required. and plasma ciclosporin concentration between amlodipine and valsartan regimens in hypertensive renal transplant patients receiving Ethics approval This protocol was reviewed and approved by the Medical ciclosporin therapy. Am J Cardiovasc Drugs 2011;11:401–9. Ethical Review Board of the University Medical Center Groningen (reference METc 19. Long CC, Finlay AY. The finger-tip unit—a new practical measure. 2015/375). Clin Exp Dermatol 1991;16:444–7. 20. Held E, Skoet R, Johansen JD, et al. The hand eczema severity Provenance and peer review Not commissioned; externally peer reviewed. index (HECSI): a scoring system for clinical assessment of hand

Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192 11 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020192 on 11 July 2018. Downloaded from eczema. A study of inter- and intraobserver reliability. Br J Dermatol 26. Williams HC, Burney PG, Pembroke AC, et al. The U.K. Working 2005;152:302–7. Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent 21. Ofenloch RF, Weisshaar E, Dumke AK, et al. The Quality of Life in hospital validation. Br J Dermatol 1994;131:406–16. Hand Eczema Questionnaire (QOLHEQ): validation of the German 27. Weintraub WS, Klein LW, Seelaus PA, et al. Importance of total version of a new disease-specific measure of quality of life for life consumption of cigarettes as a risk factor for coronary artery patients with hand eczema. Br J Dermatol 2014;171:304–12. disease. Am J Cardiol 1985;55:669–72. 22. Ofenloch RF, Oosterhaven JAF, Susitaival P, et al. Cross-cultural 28. Masters N, Tutt C. Smoking pack years calculator. 2017 http://www. validation of the Quality of Life in Hand Eczema Questionnaire smokingpackyears.com Last accessed 12 June 2018 (QOLHEQ). J Invest Dermatol 2017;137:1454–60. 29. Finkelstein DM. A proportional hazards model for interval-censored 23. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary failure time data. Biometrics 1986;42:845–54. testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life 30. Fay MP. Rank invariant tests for interval censored data under the Res 2011;20:1727–36. grouped continuous model. Biometrics 1996;52:811–22. 24. Hakkaart-van Roijen L, Tan S, Bouwmans C. Handleiding voor 31. Fay MP. Interval: weighted logrank tests and NPMLE for interval kostenonderzoek, methoden en standaard kostprijzen voor censored data. R package version 0.1–1.1. 2014. 2017 https://cran. r- economische evaluaties in de gezondheidszorg: College voor project.org/web/packages/interval/index.html Last accessed 12 June zorgverzekeringen. Geactualiseerde versie, 2010. 2018 25. Politiek K, Oosterhaven JA, Vermeulen KM, et al. Systematic review 32. White IR, Horton NJ, Carpenter J, et al. Strategy for intention to of cost-of-illness studies in hand eczema. Contact Dermatitis treat analysis in randomised trials with missing outcome data. BMJ 2016;75:67–76. 2011;342:d40. http://bmjopen.bmj.com/ on September 30, 2021 by guest. Protected copyright.

12 Oosterhaven JAF, Schuttelaar MLA. BMJ Open 2018;8:e020192. doi:10.1136/bmjopen-2017-020192