NCT01231854.

Methods	Parallel‐group, randomised controlled trial This study was conducted at a single centre in Germany
Participants	The study planned on 78 participants with severe atopic hand dermatitis but ended prematurely Included: 15 Dropouts: 6 Inclusion criteria of the trial Male and female Age > 18 years and ≤ 75 years Body weight 50 to 100 kg Chronic hand dermatitis (duration > 6 months) Atopic constitution according to Erlanger Atopiescore 1 and/or positive personal history for atopic eczema, allergic rhinitis, allergic asthma, and/or elevated serum IgE Severe hand dermatitis not responding to treatment with potent topical steroids for at least 4 weeks within the past 6 months due to IGA Written informed consent Exclusion criteria of the trial Participation in another clinical trial within past 4 weeks Pregnancy/breastfeeding Women of reproductive age except those who fulfil at least 1 of the following criteria throughout the total study and until at least 5 weeks after active study treatment in case of early study termination: post‐menopausal women (12 months physiological amenorrhoea or 6 months amenorrhoea with serum FSH level > 40 mlU/mL), postoperative (6 weeks after bilateral ovariectomy with or without hysterectomy), regular and proper use of at least 2 methods of contraception, including at least 1 method of contraception with a failure rate < 1% per year (e.g. implants, depot preparations, oral contraceptives, IUD), or vasectomy of the partner. Women of reproductive age who do not meet all of the following criteria throughout the whole study or ‐ in case of early study termination ‐ up to 5 weeks after active therapy: The participant understands the teratogenic risk associated with taking the study medication The participant understands the need for strict monthly monitoring, the need for reliable, continuous contraception, and the need for regular pregnancy tests throughout the study and ‐ in case of early study termination ‐ up to 5 weeks of active therapy The participant is able to adequately and reliably apply methods of contraception The participant is informed about the possible consequences of pregnancy and knows that she must immediately contact her physician in case of suspected pregnancy The participant gives informed consent about knowing the potential risks and necessary measures to avoid pregnancy Blood and/or plasma donation during the whole study period. In case of early study termination, blood and plasma donation is not allowed until 1 month after the end of active study treatment UV therapy within the past 3 months Concurrent photo‐ and/or photochemotherapy Known hypersensitivity/intolerance against cyclosporin, alitretinoin, or any other ingredients of Immunosporin or Toctino Known allergy against peanuts or soya Known hereditary fructose intolerance Acute and/or uncontrolled chronic infectious disease Known congenital or acquired immune deficiency Malignant tumour (past or present) Uncontrolled arterial hypertension (RR systolic ≥ 160 mmHg and/or RR diastolic ≥ 90 mmHg despite anti‐hypertensive treatment) Renal insufficiency (serum creatinine above normal range) Liver insufficiency (CHILD ≥ Stadium B) Not sufficiently controlled hyperlipidaemia (LDL/HDL ratio > 4 despite medical treatment) Clinically significant thyroid hypofunction Known hypervitaminosis A Concurrent supplementation of vitamin A or treatment with other retinoids Concurrent tetracycline therapy Concurrent therapy with St. John's wort ("Johanniskraut") Known genetic diseases causing increased UV light sensitivity such as xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome Known drug and/or alcohol abuse Known significant psychiatric morbidity Study population Gender: cyclosporin group 1 female, 6 male; alitretinoin group 4 female, 3 male Age: cyclosporin group mean 42.1 years, SD 13.9 years; alitretinoin group mean 33.1 years, SD 12.7 years
Interventions	Intervention • Oral cyclosporin depending on body weight: 50 to 74.9 kg: daily dosage 200 mg; 75 to 100 kg: daily dosage 300 mg (7 participants) • Oral alitretinoin 30 mg once daily in 8 participants Duration 24 weeks
Outcomes	Primary outcome of the trial Proportion of participants with complete or almost complete clearance according to the Investigator Global Assessment (IGA) within 24 weeks of active therapy in both groups Secondary outcomes of the trial Time to complete or almost complete clearance according to IGA in both groups Proportion of participants with complete or almost complete clearance according to the Patient's Global Assessment (PGA) within 12 weeks and 24 weeks of active therapy Mean relative change in objective disease severity by means of the Hand Eczema Severity Index (HECSI) between baseline and weeks 4, 8, 12, 16, 20, and 24 in both groups Mean relative change in quality of life (Skindex 17) between baseline and week 24 in both groups Cost‐effectiveness of studied treatment options (cost/QALY gained; assessed by the EQ‐5D) Mean relative change in work productivity (assessed by the work limitations questionnaire (WLQ)) in both groups Mean utilisation of topical steroids within the follow‐up period in both groups Participant satisfaction with treatment in both groups (assessed using a 100‐mm VAS) Proportion of participants with relapse (≥ 75% of baseline HECSI) within 24‐week follow‐up after previous complete/almost complete clearance For participants with atopic dermatitis on the body: measured percentage of participants with at least 50% improvement in disease severity with active therapy using SCORAD Tolerability and safety in both study groups
Notes	The study was ended prematurely. According to the sample size calculation, 78 participants should have been included; however only 15 participants were included, and 14 were analysed. Results are not yet published. The study author released the preliminary study results in personal communication and is aware of the fact that the data are used in this review. The secondary outcome ‐ reduction in severity, investigator‐rated ‐ was included, but we were unable to reproduce the data Declarations of interest: not stated Funding: TU Dresden, Germany Sample size rationale: adequate, although the needed number of participants was not included
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "during the baseline visit patients underwent central randomization with the use of a randomization table with constant length of blocks and stratification according to the patients’ body weights (50‐74.9 kg vs. 75‐100 kg) with equal allocation to ciclosporin and alitretinoin. The allocation sequence was generated by the KKS Dresden utilizing the trial software MACRO 3.0, and stored by the clinical trials pharmacist at the Technical University Dresden" Comment: random sequence generation method was considered adequate
Allocation concealment (selection bias)	Low risk	Quote: "treatment packs were prepared and labelled at the pharmacy. The research assistants used consecutively numbered packs to allocate new participants to treatment groups" Comment: study authors declared that they were blinded during allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "participants and assessors were blinded to group assignment during collection of the data" Comment: drug dispensation was done by a third party (the pharmacist). Unclear whether drugs were identical in appearance
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "participants and assessors were blinded to group assignment during collection of the data. Database lock was on January 28, 2013. Unblinding occurred on March 07, 2013 before data analyses" Comment: the article claims that the observer had no access to the randomisation list, and a third party was used for drug dispensation. Unblinding occurred before data analyses
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "all analyses were performed on the Intention‐to‐Treat (ITT) population. This population includes all patients that completed the baseline visit and used the trial medication at least once during the study" The study aimed to include 78 participants but was terminated early due to inability to include this number of participants. Finally, 15 participants were randomised and 1 withdrew before the study drug was used. The intention‐to‐treat analysis included all participants who received the study drug (14 of 15 participants) Comment: intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	The trial was registered under NCT01231854 before it was begun. We found no major discrepancies between the trial register and the final study report
Other bias	High risk	Baseline comparison: groups were comparable at baseline with regards to disease severity Diagnostic certainty: yes The study was ended prematurely