Long-term Improvement of Psoriasis Patients' Adherence to Topical Drugs: Testing a Patient-supporting Intervention Delivered by Healthcare Professionals
Phase: NA
Conditions: Psoriasis Vulgaris
Sponsor: Odense University Hospital

 
Page 1 of 35 
Study protocol and statistical analysis plan 
Title: 
Improvement of Psoriasis Patients’ Adherence to Topical Drugs 
 
NCT number: 
NCT04220554 
 
Document date: 
Protocol version 1.4., dated October 5, 2020. 
 
 

 
Page 2 of 35 
Title  
Improvement of Psoriasis Patients’ Adherence to Topical Drugs 
Trial registration 
Trial registration no. on Clinicaltrials.gov: NCT04220554 
Protocol version 
Protocol version 1.4 dated October 5, 2020.  
Funding 
Financial 
donations 
from: 
LEO 
Foundation, 
Odense 
University 
Hospital Free Research Fund, Robert Wehnerts and Kirsten Wehnerts 
Foundation, Psoriasis Research Foundation, and the Jeweler A.L. 
Rasmussen Memorial Foundation. 
Name and contact information for 
the trial sponsor 
Klaus Ejner Andersen  
Department of Clinical Research 
University of Southern Denmark 
Winsløwparken 19 
Odense C, DK-5000 
e-mail: KEAndersen@health.sdu.dk 
Role of sponsor 
The sponsor conceived and designed the study, and will participate in 
the management, analysis, and interpretation of data; the writing of the 
report; and the decision to submit the report for publication. However, 
the sponsor will not have ultimate authority over any of these activities. 
The funders had no role in the study design; data collection, 
management, analysis, and interpretation; in the writing of the report; 
or the decision to submit the report for publication.  
 
 
 

 
Page 3 of 35 
Introduction 
Background and rationale 
Psoriasis is a chronic inflammatory skin disease affecting 2-4% of the adult Western population (1). It is 
associated with many comorbidities, negatively affects quality of life (2) and is a socio-economic burden for 
patients and society (3). Topical drugs are the recommended first-line treatment for mild-to-moderate psoriasis, 
but patient’s adherence to treatment is low, which is a barrier to treatment success (4). Poor outcomes result 
in the need for systemic or biologic treatments that are associated with potential severe adverse events and 
are often more expensive than topical drugs. Nevertheless, since improved adherence to topical drugs is 
associated with improved efficacy, there is a need for patient-supporting interventions that improve psoriasis 
patients’ adherence to topical drugs (5, 6). 
Patient support by telephone or smartphone applications (apps) may improve adherence to topical 
treatment, but the effect is small and has only been studied with a short-term follow-up period (7, 8). 
Furthermore, not all patients have access to a smartphone, and technologies may fail to be sufficiently 
individualized for all patients’ needs.  
To improve the effect of topical therapy in psoriasis patients, there is a need for studies on how to 
optimize the use of available healthcare professionals (9-11). Since dermatologists are a limited resource, the 
use of dermatology nurses, who are trained to support psoriasis patients in their use of topical drugs, may be 
a practical solution for improved health outcomes, which can be measured by an objective reduction in the 
severity of skin disease and may also be reported by patients in patient-reported outcomes (PROs) (in regard 
to overall health-related quality of life and dermatology-specific quality of life) (12). This is supported by clinical 
trials and focus group studies suggesting that improved support benefits adherence to topical drugs (13-15).  
Improved support from dermatology nurses, with specialist training in supporting psoriasis patients may include 
1) individualizing treatment plans, 2) providing easy access to dermatology consultation in case of flare-up, 
and 3) motivating patients to use the medication. 
 
Objectives 
The study investigates if the use of topical corticosteroids and/or calcipotriol with a patient-supporting 
intervention delivered by dermatology nurses supports psoriasis patients’ adherence to topical drugs 

 
Page 4 of 35 
significantly 1) reduces the severity of psoriasis, 2) improves health-related quality of life, 3) improves long-
term adherence to prescribed topical drugs and 4) is cost-effective compared to use of topical corticosteroids 
and/or calcipotriol with standard patient support. 
The null hypothesis is there is no difference in reduction in severity of psoriasis (objectively as 
measured by the Lattice-System Physician’s Global Assessment [LS-PGA]) among psoriasis patients who 
receive patient-supporting interventions versus those who do not receive the patient-supporting intervention 
(the non-intervention group). The purpose of the trial is to test the null hypothesis in a superiority setting.  
Furthermore (beside the null hypothesis for the primary outcome), the study will also investigate if 
there is a difference in quality of life (as measured by the PRO  Dermatology Life Quality Index [DLQI]), 
adherence to medication (as measured by filled prescriptions, amount of medication used and reported by 
patients in a study-specific questionnaire) and health-care costs among those receiving psoriasis patient-
supporting interventions versus those who do not receive patient-supporting interventions (the PRO  European 
Quality of life 5 Dimensions [EQ-5D] questionnaire will be obtained in order to answer this research question).  
 
Trial design 
The study is a randomized, controlled, investigator-initiated, parallel group with 1:1 allocation ratio, superiority 
trial (RCT) with an intention to treat (ITT) analysis.  
 
Methods: Participants, interventions, and outcomes 
Study setting 
The study setting is a single-site study at the outpatient clinic at the Department of Dermatology at Odense 
University hospital in Denmark. Psoriasis patients who are either already patients at the clinic or newly referred 
to the clinic will be considered for inclusion.  
 
 
 
 

 
Page 5 of 35 
Eligibility criteria  
All eligible participants will be informed about the study purpose and must consent to participate. Participants 
will answer questions regarding their socio-demographics and use of medication and will answer 
questionnaires about their health-related quality of life. Participants are allowed to be in a stable treatment 
phase with systemic drugs prescribed for dermatological disease. 
 
Inclusion criteria: 
• 
Legally competent patients between 18 and 85 years of age 
• 
Mild to severe plaque psoriasis (psoriasis affecting ≥ 4% of the total body surface area) 
• 
Access to a telephone  
• 
Ability to read the Danish language and basic internet technology skills 
 
During the trial, fertile women need to use a reliable form of contraception, i.e., intrauterine device (IUD), or 
hormonal contraception (including vaginal ring or birth control injection, implant, transdermal contraceptive 
patch, or birth-control pill), have a sterile partner, or use dual barriers during the trial period and for at least 14 
days after the study ends. Prior to inclusion in the trial, evidence of a negative pregnancy test must be given 
to the investigator.  
 
Exclusion criteria: 
• 
Patients who cannot read or understand the Danish language 
• 
Breastfeeding or pregnant patients or fertile women who do not use reliable contraception 
• 
Patients who are allergic to all the potential topical drugs that can be prescribed during the trial 
 
Criteria for exclusion during the trial period:    
There are six events that will cause removal from the study: 1) Withdrawal of consent at the last study visit in 
week 48, which entails that the data will not be included in the study analysis 2) A serious adverse event (SAE) 
related to the intervention or prescribed drugs 3) for fertile women, the occurrence of pregnancy 4) change of 
diagnosis 5) prescription of systemic antipsoriatic drugs for a dermatological indication during the trial period 
and 6) failure to keep several follow-up appointments. 

 
Page 6 of 35 
 
Eligible criteria for individuals who perform the intervention: 
Experienced dermatology nurses will perform the intervention.  
 
Who will take the informed consent?  
The investigator’s first contact with potential participants will take place in an individual face-to-face 
consultation prior to the baseline visit. Prior to presenting information about the study, the investigator will 
inform potential participants of their right to make another appointment at which a companion (lay 
representative) can be present. Potential participants will be provided with oral and written information about 
the study. The consent will also grant the authorities (the regional Data Protection Agency and the Committee 
on Health Research Ethics) the right to monitor and check the patients’ trial-related data obtained in the 
electronic research data capture and from the patients’ medical chart. 
 
The patient information mentions that the study purpose is to investigate the efficacy of topical drugs, 
indicates that some participants receive additional nurse-support, stipulates the risks and benefits of the study, 
potential side-effects, treatment plan, precautions, recording of study relevant data and duty of confidentiality, 
linkage with register data, audit by authorities (the regional Data Protection Agency and the Committee on 
Health Research Ethics), access for study personnel (the investigator and study nurses) to enter patients’ 
medical chart and research data tool while the blinded assessor has limited access to the research data tool, 
compensation and grievance options, finances, voluntary nature of participation, informed consent, and the 
possibility of withdrawal from the trial. Lastly, the patient will be informed of the availability of treatment if the 
patient does not wish to participate in the study. Participants shall be made aware of their right to deliberate 
for 14 days and shall be given the opportunity to have any doubts resolved.  
If the patient has decided to participate in the study, the patient in question will date and sign the 
informed consent and deliver it personally to the investigator. The informed consent is then to be dated and 
signed by the attesting investigator on the day the patient is informed. The original consent form will be stored 
in the patient’s case report form (CRF). 
 
 
 

 
Page 7 of 35 
Additional consent provisions for the collection and use of participant data and 
biological specimens 
The informed consent grants researchers the right to obtain data for research use from the participants medical 
chart and to link study data to central health registers (for use of medication and other health services) over a 
two-year period prior to inclusion in the trial and during the trial period. 
 
Interventions 
Explanation for the choice of comparators  
The non-intervention group receives the standard-of-care treatment for clinical practice at Danish dermatology 
outpatient clinics. Psoriasis patients are typically seen by a dermatologist at first visit and instructed by a nurse, 
and every third month thereafter they consult a dermatologist at the outpatient clinic.  
 
Intervention description  
Intervention group: Detailed description of the improved patient-support  
The intervention group will include support delivered by three experienced dermatology nurses. Each patient 
will be supported by the same dermatology nurse throughout the entire study period. The intervention is 
expected to encourage psoriasis patients to apply the topical drugs on a regular basis  by 1) ensuring that 
patients have a reminder system (16, 17), 2) making patients accountable (18-20), 3) providing support (21), 
4) building trust in the treatment and healthcare-provider (10, 13, 22, 23), and 5) by increasing perceived ease 
of use via favourable comparisons to other treatment options (18, 24). Participants in the intervention group 
will be seen by a nurse in the dermatology clinic at baseline and weeks 12, 24, 36 and 48. Furthermore, the 
participants will either be seen in the dermatology clinic or receive follow-up from the nurse by telephone at 
weeks 1, 4, 8, 16, 20, 28, 32, 40 and 44. 
 
Intervention group: description of study visits 
Baseline visit (expected duration: 60 min.) (physician 20 min. and nurse 40 min.): participants are first met by 
a physician in the dermatology clinic. After obtaining informed consent, patient history and making an objective 
assessment of the skin, the physician will instruct the patient about topical treatment options and prescribe a 

 
Page 8 of 35 
topical treatment after shared decision-making (25). Then, a nurse will instruct the patient on how to use the 
prescribed topical drugs. 
Consultation by nurse in the clinic or digital follow-ups at weeks 1, 4, 8, 16, 20, 28, 32, 40 and 44 
(expected duration: 20 min.) (nurse): Participants choose whether they wish to meet the nurse in the clinic or 
be contacted via telephone, where they may ask questions regarding their treatment and receive further 
instructions. 
Visits at weeks 12, 24, 36 and 48 (expected duration: 30 min.). Participants are seen by the dermatologist 
and a nurse in the clinic, questions are answered, and adjustment of topical treatment is introduced as needed.  
 
Non-intervention group: standard-of-care patient support 
The non-intervention group gets the standard-of-care treatment for clinical practice at Danish dermatology 
outpatient clinics. Psoriasis patients are typically seen by a dermatologist at first visit and instructed by a nurse, 
and thereafter every third month they consult a dermatologist at the outpatient clinic.  
Visit at baseline and weeks 12, 24, 36 and 48: At baseline, the participant receives 20 min. instruction from 
the dermatologist and a possible 15 min instruction from the nurse. Subsequent visits consist of a 15 min 
dermatologist consultation. 
 
Study drugs 
In both groups, the participants will be prescribed topical drugs based on a shared decision between the 
prescriber and patient, since preferences for topical drugs differ between patients and there is no single topical 
drug that is suitable for all psoriasis patients (26). For both groups, one of the topical drugs containing 
corticosteroids or calcipotriol registered in Denmark for psoriasis patients will be prescribed, since these drugs 
are the most frequently prescribed topical drugs in Denmark (27) and have a clear dose recommendation (28).  
All participants will be instructed how to use the medication according to “the fingertip unit for topical steroids”, 
i.e., 0.5 gram per day per BSA, for as long as a rash is present (28). No placebo or reference compounds will 
be used in the trial.  
 
The treatment is not prescribed in accordance with a study protocol, but in accordance with common 
practice. No extra diagnostic or safety measures will be conducted other than standard care, where the 

 
Page 9 of 35 
physician informs the patient about common, non-serious as well as rare, serious adverse events and about 
how to act if these are found.  
 
Description and justification of dose level, dose regimen and frequency plus treatment period 
Patients will be treated once daily as long as a flare is present. When calcipotriol-containing topical drugs are 
prescribed, maximum consumption will be 15 g/day. Since all patients will be prescribed the same group of 
recommended standard drugs, it is estimated that there are no increased risks connected with participating in 
the trial.  
 
Criteria for discontinuing or modifying allocated interventions  
Modifications to allocated interventions will not be permitted. 
 
Strategies to improve adherence to interventions 
On a weekly basis, the investigator will check if the nurses are providing the planned patient-support and are 
adhering to the protocol. If the nurses do not adhere to the study protocol, the investigator will immediately 
contact the study nurse and arrange a meeting, where the study nurse will be instructed about the study 
intervention guide and asked the reason for non- adherence to the study protocol. Furthermore, participants’ 
adherence to prescribed medication will be monitored at visit week 48. Visit adherence may be improved by 
sending SMS reminders to all study participants a few days before each visit. Adherence to treatment is not 
improved besides the study intervention allocated to the intervention group.  
 
Relevant concomitant care permitted or prohibited during the trial  
Participants are not allowed to start systemic antipsoriatic drugs prescribed on dermatological indication during 
the intervention period, since systemic drugs will influence the primary outcome (change in LS-PGA). However, 
participants who are in a stable phase of prescribed systemic drugs prescribed on dermatological indication at 
baseline are allowed to be included and kept on the systemic drugs. 
 

 
Page 10 of 35 
Provisions for post-trial care 
Participants discontinued from the study due to the occurrence of an SAE will be followed in the relevant 
medical department. Participants who participate in the study are covered by the Danish Health Authorities via 
the Danish Act on the right to Complain and Receive Compensation. 
 
Outcomes 
Outcome measures will be either assessor-blinded LS-PGA and secondary adherence measures of weight of 
topical drugs used or patient-reported (for patient-reported adherence, DLQ, and EQ-5D). Below, five elements 
are specified in full for each outcome: i) domain, ii) specific measure, iii) specific metric, iv) method of 
aggregation, and v) time-points) (29, 30). 
 
Adherence measures 
Primary adherence 
Specific measure: 
Primary adherence will be measured by the proportion of patients who collect their prescribed topical drug 
(containing corticosteroid or calcipotriol in the trial period within a certain Anatomical Therapeutic Chemical 
[ATC] class) from a pharmacy during the study period.  
 
Specific metric: 
Value at last patient visit.  
 
Method of aggregation:  
Mean. 
 
Time point:  
Investigated at visit in week 48.  
 
Secondary adherence  
Specific measure: 

 
Page 11 of 35 
Secondary adherence will be calculated by combining measured amount of medication used (determined by 
the weight of the remains in the used medication packages) per body surface area unit affected.  
 
 Estimated recommended consumption of medication will be 0.5 gram per day multiplied by the 
estimated mean BSA during the whole study period, calculated from BSA measures at baseline and at weeks 
12, 24, 36 and 48. 
 
Rate of secondary adherence = 
!"#$%&'( *&"%#+ ", +"-./*0 (1%2$
34-'/+'( *&"%#+ %$'(
 
 
Consumed amount of topical drugs = Sum of weight of prescribed topical drugsa – sum of weight of all 
prescribed medication packages returned at visit week 48b. 
 
a: As weighed from representative full medication packages of the prescribed topical drugs. 
 
b: By weight of medication packages returned by blinded assessor when weighed in the outpatient clinic. 
 
Topical drugs (expected amount used) =  
0.5 g/day * 48 weeks * 7 days/week *( 
567(9*$'0.#');<=567(>?<);567(><@);567(>AB)C;567(>@D)
D
) 
 
Specific metric:  
Value at last patient visit. 
 
Method of aggregation:  
Mean. 
 
Time point: 
The rate of secondary adherence will be assessed at week 48. The measures used to calculate secondary 
adherence will be obtained as follows: the BSA (1 BSA equals 1% of a person’s total body surface area) will 
be assessed at each visit (baseline, week 12, 24, 36 and 48) while weight of consumed drugs will be obtained 
at the last visit in week 48.  

 
Page 12 of 35 
 
Patient-reported adherence 
Specific measure:  
Patients will fill out a study-specific PRO questionnaire, where they report their self-reported adherence (as 
measured by rate of days where a rash was apparent and the patient applied the prescribed topical preparation 
(from grade 1-4; 1: applied 0-25% of days, 2: applied 26-50% of days, 3: applied 51-75% of days, 4: applied 
76-100% of days)). The study-specific adherence measure has previously been used by the research group 
(8).     
 
Specific metric: 
Value at time-point at last patient visit.  
 
Time point: 
At last study visit at week 48. 
 
Disease severity measures 
Severity of psoriasis 
Specific measure: 
Disease severity will be objectively measured by BSA (an interval scale from 0-100; 0, no involvement; 100, 
full body involvement) and LS-PGA (an ordinal scale from 1-8: 1, clear; 8, severely affected) (31).  
Disease severity measures will be obtained by a blinded data assessor (a skilled nurse or a 
qualified trained research assistant). At the appointment the patient is put into a room; the blinded assessor 
sees the patient first and fills out the scoring (BSA and LS-PGA) – the patient is instructed not to talk except 
to exchange greetings. The person providing the rating inserts the scoring in the electronic research data 
capture system. 
 
Specific metric: 
Change from baseline.  
 

 
Page 13 of 35 
Method of aggregation:  
Mean. 
 
Time-point: 
Baseline and weeks 12, 24, 36 and 48.  
 
Dermatology specific quality of life measure 
Specific measure:  
The patient fills out a Danish translation of the PRO DLQI questionnaire (an ordinal scale from 0-30: 0, not 
affected by psoriasis; 30, severely affected by psoriasis) (32) questionnaire on a tablet, that synchronizes data 
into the data capturing tool.   
 
Specific metric: 
Change from baseline.  
 
Method of aggregation:  
Mean. 
 
Time-point: 
Baseline and weeks 12, 24, 36 and 48.  
 
Generic health-related quality of life measure 
 
Specific measure: 
The patient fills out a Danish translation of the PRO EQ-5D-3L questionnaire on a tablet, that synchronizes 
data into the data capture tool. EQ-5D-3L comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and 
extreme problems. The EQ-5D-3L health profiles are converted into a value based on the danish societal value 
sets (33). The EQ-5D value is on a scale where 1 represents full health and 0 represents being dead; the 

 
Page 14 of 35 
higher the value, the better the health state. The scale allows negative values to be assigned to health states 
that are considered worse than dead.  
 
Specific metric:  
Change from baseline.  
 
Method of aggregation: 
Mean. 
 
Time point:  
Baseline and week 48.  
 
Participant timeline 
The study will be concluded when the last included participant has completed the study.  
Regarding PRO assessments, the initial PRO will be collected prior to randomization. PROs will be collected 
after the clinical assessments. At the visit at baseline and week 48, DLQI questionnaires will be obtained before 
the EQ-5D questionnaire. At visit week 48, patient-reported adherence will be reported after the EQ-5D 
questionnaire.  
 
Study plan and design 
At an ordinary consultation with patients referred to the dermatology department, the investigator will screen 
for suitable participants according to the inclusion criteria. Before patients are included in the study, informed 
consent will be obtained at the baseline visit.  
 
Information obtained and provided throughout the study 
At the baseline visit, the investigator will collect information from the patient on 1) current and previous use of 
medicine, 2) length of illness, 3) socio-economic status (marital status, educational level, days of sick leave 
and income), and 4) severity of disease and disease duration. The information will be used to check that the 

 
Page 15 of 35 
non-intervention and intervention groups are comparable. In addition, after visit week 48, data from the Danish 
Health Registries will be obtained in order to have outcomes for primary adherence and costs of health service 
use.   
 
Sample size  
The null hypothesis is that there is no difference in the primary outcome (LS-PGA) between the intervention 
and non-intervention groups. The sample size was calculated based on data from a previous project obtaining 
LS-PGA data from 134 patients randomized to intervention (an adherence-supporting app) or non-intervention 
(receiving standard-of-care support) (8), where an over 20% LS-PGA improvement in favour of the adherence-
support intervention was observed between non-intervention and intervention group. A relative 20% difference 
in mean scale on the LS-PGA is expected, and a power of 80%, two-sided significance level of 95%, and 1:1 
allocation is desirable, considering a maximum expected dropout rate of 80%. Based on mean and standard 
deviations of LS-PGA from the previous study this results in a maximum sample size for a two-sided t-test 
consisting of 115 participants before drop-out. The sample size was calculated using Stata 15 (StataCorp, 
College Station, TX, USA (34). 
The sample size is not calculated for the secondary PRO outcomes. However, the principal 
PRO hypotheses are that the intervention will improve quality of life. A previous RCT conducted by members 
of our research group (8) had a comparable sample size and was able to detect an improvement in quality of 
life in favour of the intervention.   
  
Recruitment  
The Dermatology Department will be the primary recruitment and trial site until the maximum planned number 
of 115 psoriasis patients has been included. Supplemental patient recruitment may be used by contact with 
dermatologists in practice or by advertisements in local newspapers, at public institutions or social media on 
the internet.  
 
 

 
Page 16 of 35 
 
Assignment of interventions: allocation 
Sequence generation 
After baseline data has been entered in REDCap, participants will be allocated parallel-assigned 1:1 in random 
blocks to either the intervention or the non-intervention arm via pre-specified computer-generated block 
randomization in the REDCap randomization module. 
 
Concealment mechanism 
The randomization code will be stored by a data manager. Furthermore, participants are informed that the 
purpose of the study is to investigate the effect of the prescribed topical drugs.  
 
Implementation 
After informed consent has been obtained, the investigator obtains baseline data from the study participants, 
which will be entered in the randomization module in the electronic data collection program REDCap. The 
investigator will assign participants to the intervention based on the results of the randomization.  
 
Assignment of interventions: Blinding 
Who will be blinded 
The data assessor (who measures LS-PGA and the weight of returned medication packages) will be blinded 
to the allocation.  
 
Procedure for unblinding if needed 
Participants are not blinded to the intervention. All participants are informed that some receive additional nurse-
support while others are followed by the doctor. However, the investigator tells patients the main purpose of 

 
Page 17 of 35 
the trial is to study use of topical drugs, thus partially concealing the fact that this is an adherence study. 
Limiting participants’ awareness that the main aim is to study adherence will reduce any positive effect on 
adherence in the non-intervention group.  
 
Data collection and management 
Plans for assessment and collection of outcomes 
Outcomes 
Specification and justification of effect parameters  
LS-PGA is a validated outcome measure for the estimation of the disease activity of mild-to-moderate psoriasis 
(35, 36).  
DLQI is a licensed validated PRO questionnaire that was first published in 1994 and has been 
widely used for clinical and research purposes. It has been translated into Danish (37). The domains include 
symptoms and feelings, work and school, daily activities, personal relationships, leisure, and treatment. The 
domains are divided into 10 items. Each item has a score from 0-4. The scores are added together and produce 
a final score from 0-30 (0, QOL not affected by skin disease, to 30, QOL severely affected by skin disease). 
The questions are designed to be completed within a one-week recall period (i.e., last seven days). It is 
designed for use in adults, i.e., patients aged 16 years and over. The average completion time of the 
questionnaire is two minutes, and an electronic version will be used. Usually, no assistance is required. The 
DLQI is self-explanatory and can be simply handed to the patient who is asked to fill it in. There is no need for 
detailed explanation. The DLQI will be used in accordance with its user manual. There will be no deviations 
from its use. The instrument has been reported to have good content and construct validity, and 
responsiveness in the assessment of psoriasis in adults, and can feasibly be used in clinical trials and practice 
(37).  
EQ-5D is a validated generic licensed questionnaire for quality of life (38). There are 243 
possible health states defined by combining one level from each dimension, ranging from 11111 (full health) 
to 33333 (worst health). Patients answer how their perceived health is on the day they complete the 
questionnaire. The EQ-5D-3L questionnaire also include the EQ visual analogue score (EQ VAS). The EQ 

 
Page 18 of 35 
VAS records patient’s self-rated health on a vertical visual analogue scale, where the endpoints are ´Best 
imaginable health state´ and ´Worst imaginable health state´. The average completion time of the 
questionnaire is few minutes, and the questionnaire is cognitively undemanding. A Danish language electronic 
version will be used. The questionnaire will be used in accordance with the manual and no deviations from its 
use will be made.  
Obtaining LS-PGA and DLQI five times during the study gives extra support to the analysis 
phase, so a smaller difference can be detected, if this is stable over time.  
 
Primary adherence will be assessed using data from the high-quality Danish National 
Prescription Registry (39), which is considered valid and reliable. Using package weight to obtain an estimate 
of secondary adherence is considered acceptable (40). The patient-reported adherence scale has previously 
been used in another adherence-trial (8).     
All data fields in the REDCap tool are validated: All fields have a minimum and maximum value 
which helps to narrow down the input options. This means that REDCap prompts an error if a field entry does 
not meet certain expectations. Furthermore, at end of the trial, all fields will be validated via visual checking by 
a member of the research staff, in order to ensure accuracy and check that all data are within the prespecified 
minimum and maximum values. Proxy-reported outcomes will not be used.  
 
The REDCap data collection tool has a built-in function that issues an immediate warning if all fields in the 
questionnaire have not been completed. At each visit, the investigator will check that no warnings have been 
issued. Furthermore, PRO assessments will not be taken from participants who discontinue or deviate from 
the assigned intervention protocol.   
 
Data that is considered to be source data 
The following source data will be recorded from the patients’ medical chart or from an interview and stored in 
REDCap (41): Duration of psoriasis, previous and current systemic, biologic, and topical treatment for psoriasis 
(in a two-year period prior to inclusion in the study) and socio-demographic data (relationship status, education 
and job status, municipality, and national origin). During the study, LS-PGA (including BSA) and the weight of 
consumed topical medication will be assessed by the blinded assessor. DLQI and EQ-5D will be reported by 
patients. The investigator will obtain data regarding the antipsoriatic drugs prescribed during the study period, 

 
Page 19 of 35 
and the rate of filled first prescriptions for antipsoriatic drugs during the study period will be obtained. The trial 
personnel will note down the time used for consultations.   
 
Plans to promote participant retention and complete follow-up 
All participants receive an automatically generated notification a week prior to attending in the outpatient clinic. 
In case of non-attendance, the investigator will contact the participant by telephone and suggest a new 
consultation.  
 
Data management 
Study-relevant clinical data will be stored in REDCap hosted at OPEN (Open Patient data Exploratory 
Network). Furthermore, data obtained in the clinic will be analysed for missing data and transferred to Scientific 
Services at the Danish Health Data Authority for use in the economic analysis.  
When participants have returned all the medication packages prescribed during the study period at 
week 48, the medication packages will be weighed by a blinded assessor and returned to study participants.  
 
After the end of the study and after the reports have been submitted and approved by the authorities 
(the Committee on Health Research Ethics), the sponsor will ensure that the study data are deleted.   
 
Confidentiality 
All data concerning participant information will be stored in REDCap and will only be accessible for staff 
members. All collected data will only be traceable by a code.  
 
Plans for collection, laboratory evaluation and storage of biological specimens for 
genetic or molecular analysis in this trial/future use 
Not applicable since no biological specimens are used. 
 

 
Page 20 of 35 
 
Statistical methods 
Statistical methods for primary and secondary outcomes  
Analysis of the primary outcome: changes in LS-PGA 
Changes in LS-PGA measures from baseline to week 12 and from baseline to weeks 24, 36 and 48 will be 
compared between the two groups by linear mixed model for longitudinal data. LS-PGA will be presented in 
box plots and bar charts.  
  Two sensitivity analyses on LS-PGA data will be carried out in which all study participants will be 
included: i) a complete case analysis, and ii) an imputed analysis (after 100 times multiple imputations by 
multivariate normal regression on LS-PGA data) with all covariates.  
 
Analysis of secondary outcomes: changes in DLQI value and adherence 
Changes in DLQI measures from baseline to weeks 12, 24, 36 and 48 will be compared between the two 
groups by linear mixed model for longitudinal data. DLQI will be presented in box plots and bar charts.  
For separate analyses of the three adherence measures (by filled prescriptions, weight of medication 
and patient reported adherence, respectively), the adherence rate is dichotomized with a selected cut-off of 
80%, with adherence rates above 80% considered adherent (a cut-off typically used when studying adherence 
in chronic diseases) (8, 42). Dichotomized adherences are compared by using logistic regression.  
Statistical analysis will be conducted by an experienced statistician. The statistician will not be blinded 
to the intervention, as any blinding would be difficult to obtain because the participants in the intervention group 
are subdivided in three different subgroups (grouped according to the nurse delivering the intervention), while 
the non-intervention group is kept in one group. However, the analysis will comply with the statistical methods 
outlined in the study protocol. An interim analysis is not planned.  
Obtaining LS-PGA and DLQI five times during the study gives extra strength to the analysis, so 
a smaller difference can be detected, if this is stable over time.  
  
 

 
Page 21 of 35 
Interim analyses 
No interim analyses are planned, since there are no anticipated problems that are detrimental to the 
participants, as all topical drugs prescribed in the trial are well-known manufactured drugs.  
Criteria for formally halting the trial will be when the last patient visit has taken place.  
 
Methods for additional analyses (e.g., subgroup analyses)  
Subgroup analyses of the primary and secondary outcomes by interaction terms in regression models are 
planned, to investigate if the dermatology nurses or the percentage of nurse-contacts made by telephone affect 
the intervention.  
 
Analysis methods to handle protocol non-adherence and any statistical methods to 
handle missing data  
Missing data on the primary outcome will be evaluated to assess the occurrence of specific missing data 
patterns, and if necessary, missing data will be handled by using multiple imputation. Missing effectiveness 
values are imputed at missing time points using values from available time points. Furthermore, missing data 
will not be imputed for PRO outcomes or adherence measures. 
 
Plans to give access to the full protocol, participant level-data and statistical code  
Access to the full dataset (participant-level dataset and statistical code) obtained in the clinical trial is not 
planned. The datasets analysed during the current study are available from the corresponding author on 
reasonable request. After the end of the study and after the reports have been submitted and approved by the 
authorities (the Committee on Health Research Ethics), the sponsor will ensure the study data are deleted.   
 
 
 
 

 
Page 22 of 35 
 
Supervision and monitoring 
Composition of the coordinating centre and trial steering committee 
There is no trial steering committee.  
The coordinating centre is responsible for overall data management, monitoring and communication at the 
study site and among the researchers, and general supervision of the conduct of the research project. 
The composition of the coordinating centre is as follows:  
• 
Principal investigator: MTS  
o 
Design and conduct of the study 
o 
Administration of research grants 
o 
Handling cooperative agreements 
o 
Drafting contracts in compliance with applicable laws and regulations 
o 
Publication of study reports 
o 
Preparation of protocol and revisions and case report forms 
o 
Recruitment of participants 
• 
Sponsor: KEA 
o 
Design and conduct of the study 
o 
Publication of study reports 
o 
Preparation of protocol and revisions  
o 
Recruitment of participants 
• 
Three dermatology nurses 
o 
Supporting the principal investigator during patient consultations and providing the study 
intervention  
• 
Two blinded assessors 
o 
Measuring severity of psoriasis (primary outcome) and weighing study medication  

 
Page 23 of 35 
 
Composition of the data monitoring committee, its role and reporting structure  
To the best of our knowledge, the patient supporting intervention delivered by dermatology nurses 
 in itself does not carry any risks for participants. Therefore, a data monitoring committee is not required. The 
study is a smaller-size study without critical safety concerns and addresses less-essential outcomes (relief of 
symptoms and adherence to medication). The Danish Medicines Agency was consulted and concluded the 
study was not a pharmaceutical trial and, furthermore, a data monitoring committee was not needed to audit 
the trial.  
The principal investigator and sponsor guarantee data and participant safety. 
 
Adverse event reporting and harms  
PRO data will not be monitored during the study for the purposes of providing information about the clinical care 
of individual trial participants, since patients’ awareness of any fluctuations may impact on the study outcomes.  
Screening for AEs will be conducted at baseline and weeks 12, 24, 36 and 48. At each visit, the investigator 
will systematically screen for all known side effects listed in the product summary for prescribed topical drugs 
both by interviewing the participants, inspecting the skin surface and by reading through all files in the patient 
chart. The investigator will adhere to instructions for post marketing reporting of adverse drug experiences. 
Furthermore, a table with all AEs will be published along with study outcomes according to instructions for 
reporting adverse events (AEs), SAEs, serious adverse reactions (SARs), and suspected unexpected serious 
adverse reactions (SUSARs). A table summarizing the number of adverse events in the non-intervention vs. 
intervention group will be used to compare if there are any group-related differences in terms of AEs, and to 
investigate any potential increased use of topical drugs if one of the groups is associated with an increased 
risk of AEs.  
A table summarizing number of adverse events in the non-intervention vs. intervention group will be used to 
compare if there are any differences between the groups in regard to AEs and to investigate if any increased 
use of topical drugs in one of the groups is associated with an increased risk of AEs. 
If there is a suspicion of a SAE, the study investigator must immediately be contacted, arrange for 
relevant inquiries, ensure SAE reporting, and assess if the participant should cease participating in the trial. 

 
Page 24 of 35 
If participants discontinue the study as a result of an SAE, the following action will be taken: an objective 
examination of the skin will be undertaken; if hypercalcemia or hypercalciuria is suspected in patients treated 
with calcipotriol, it must be confirmed by blood test as well as by objective neurological investigation in the 
neurological department at the nearby university hospital. If the SAE is adrenal suppression or weakening of 
glycaemic control by diabetes mellitus is suspected in patients treated with topical corticosteroids, it must be 
confirmed by blood test and by an objective investigation in the endocrinology department at the nearby 
university hospital. If the SAE indicates a suspicion of a cataract or increased intraocular pressure arises in 
patients treated with topical corticosteroids, this must be confirmed by an objective ophthalmological 
investigation in the ophthalmology department at the nearby university hospital.  
 
Participants discontinued from the study due to the occurrence of an SAE will be followed in the relevant 
medical department.   
Participants who participate in the study are covered by the Danish Health Authorities via the Danish 
Act on Complaints and Compensation. 
 
Frequency and plans for auditing trial conduct  
At all times, the investigator will provide direct access to monitoring, auditing and/or inspection by the 
Committee on Health Research Ethics, the regional Data Protection Agency, national health authorities or 
health authorities from other countries. This auditing will be independent of the investigator and the sponsor. 
The investigator will allow the authorities (and the Committee on Health Research Ethics) access to monitor 
and quality check the data. Furthermore, the investigator will provide an annual report to the regional 
Committee on Health Research Ethics reporting any adverse events occurring during the trial period.  
All data used in the analysis will be stored in REDCap, OPEN Analyze or Scientific Services at The 
Danish Health Data Authority.   
 
 
 
Plans for communicating important protocol amendments to relevant parties (e.g., 

 
Page 25 of 35 
trial participants, ethical committees) 
Important protocol amendments will be reported to the relevant parties (i.e., the Regional Committees on 
Health Ethics for Southern Denmark, Denmark, the trial participants, and trial registries) by e-mail. Substantial 
amendments are only implemented after approval of the Regional Committees on Health Ethics for Southern 
Denmark, Denmark. All non-substantial amendments are communicated to the Regional Committees on 
Health Ethics for Southern Denmark, Denmark and within the Annual Safety Report. 
 
Economic evaluation 
 
To assess the effectiveness of the intervention a cost-effectiveness/utility analysis will be performed. The effect 
measures are Quality adjusted life years (QALY), DLQI and LS-PGA. EQ-5D values (based on danish societal 
weights) (43) will be used to calculate QALYs (44). The intervention has numerous potential short-term 
economic benefits within the study period, primarily a reduction of the need for prescribing narrow-band 
ultraviolet B (UVB) treatment, biologic treatment, systemic antipsoriatic drugs and laboratory analyses used to 
monitor the use of drugs. Furthermore, the intervention may reduce patients’ need for consulting the general 
practitioner or private dermatologists to obtain a prescription for antipsoriatic treatment. As the intervention 
may improve patients’ well-being, there is likely to be a reduced need for psychological or psychiatric treatment. 
The intervention is not expected to reduce the incidence of other psoriasis co-morbidities, except for improved 
well-being. Adverse events will be recorded but not included in the economic evaluation model, as they are 
assumed to be mild for both groups, thus not incurring relevant costs. Costs and resources will be calculated 
from a healthcare sector perspective including healthcare system costs. The total healthcare costs (measured 
in GBP in 2021 prices) for participants will be obtained to compare costs for the intervention group and non-
intervention. Cost data for the economic evaluation will be compiled by i) registration at each outpatient visit 
during the trial period of the time spent by the nurse delivering dermatology support to patients in the 
intervention group (study personnel will receive a fixed payment per work hour), ii) registration of cost for drugs 
delivered free-of-charge (by searching the patient medical charts, estimating drugs linked to a unique 
pharmaceutical item number (45), and iii) extraction of data from the Danish Health registries to compile total 
healthcare costs, linked to participants’ personal identification number, in a two-year period prior to inclusion 
in the study and during the study period (48 weeks). Data from the Danish Health registries contain real-life 

 
Page 26 of 35 
pseudonymized individual-level data for study participants. Data will be collected by Scientific Service (Danish: 
Forskerservice) at The Danish Health Data Authority via joint port access (46) linked with study data using the 
civil registration number. All analyses will be conducted on Scientific Service’s secure server, using encrypted 
civil registration numbers. Data will include the total cost of prescription medication (data from The Danish 
National Prescription Registry (47)) and hospital procedures, including in- and outpatient treatments (data from 
National Patient Register (LPR (Landspatientregistret)) and the Diagnosis Related Group (DRG)-grouped 
National Patient Register (48)). Visits in the primary sector, including those of the general practitioner and 
practicing dermatologist, will be extracted from the National Health Service Register (49).  
 
Cost-effectiveness analyses 
The analysis of resource use and costs will be conducted on individual partients’ aggregated cost measures 
during the observation period (48 weeks) from the inclusion date for each individual patient. Regression 
analyses will be used to estimate incremental cost and QALYs. Because costs are normally right-skewed and 
QALY left-skewed, generalized linear models are considered. As the intervention and non-intervention might 
have different resource use at baseline, an adjustment is made for baseline costs (cost of the previous two 
years). QALYs are adjusted for baseline utility values (50). If appropriate, an adjustment for baseline covariates 
in the regression analysis of QALY will also be applied. Baseline covariates (self-reported) will be age, gender, 
marital 
status, 
education, 
psoriasis-age, 
smoking-status, 
labour 
market 
participation, 
income, 
and 
absenteeism. Models are estimated with and without adjustment for covariates. Missing effect data will be 
evaluated to assess the occurrence of specific missing data patterns and, if necessary, Multiple Imputation will 
be used. 
 
The total costs from baseline to 48 weeks after baseline (end of trial) is compared between the two groups and 
divided by the difference in gain in effect, resulting in an incremental cost-effectiveness ratio (ICER). The ICER 
is measured as the total cost per QALY gain from baseline to the end of the trial. For this trial, the ICER is a 
summary measure representing the economic value of the intervention compared to the standard care 
procedure. A positive ICER reflects the additional costs per one additional unit of the measure of effect. A 
negative ICER reflects that one of the treatment strategies is dominant. Similarly, an ICER will be computed 
using DLQI and LS-PGA effect measures. Dominance in the results exists if one strategy is found to be both 

 
Page 27 of 35 
cheaper and more effective than the other. The clinical relevance of the analysis will be improved if the ICER 
reflects what is considered a minimal clinically important difference (MCID) in the DLQI and LS-PGA (that is, 
at least a two-point difference in the DLQI (37) as well as the LS-PGA (36)). Results will be bootstrapped to 
obtain confidence limits around the estimate (51, 52). Furthermore, conventional methods to examine the 
sensitivity of the cost-effectiveness analysis, such as cost-effectiveness acceptability curves (CEAC), will be 
applied. All analyses will be performed using STATA 16. 
 
Dissemination plans 
Trial participants and the general population will be informed about the results of the study by means of 
publication of results on ClinicalTrials.gov. Furthermore, a scientific publication of study results in a peer-
reviewed scientific journal is intended.  
 
Discussion 
This study aims to demonstrate whether individualized, optimized patient support (delivered by dermatology 
nurses) to dermatological patients can optimize the use of topical treatment, reduce the severity of psoriasis, 
be cost-effective and have a modest value for improved health outcome compared to standard treatment.  
This study is limited by a study sample size calculated on the primary outcome alone (that is, reduction 
in LS-PGA). Due to the limited sample size, it may be difficult to detect any significant differences between the 
two groups in terms of secondary outcomes and economic analysis. Since it is felt unlikely for the intervention 
to have a long-term post-interventional effect on outcomes, the analysis is limited to the intervention period. 
Data checking will be done by visual checking, which is time-consuming compared to double data entry, for 
example, but less accurate (53). 
The study intervention will be delivered by three dermatology nurses, introducing a risk that the benefits 
of the intervention are driven (positively or negatively) by a small number of nurses. Development of a detailed 
study guide, to which the investigator will ensure that study personnel adhere, is a method of reducing the risk 
that any effect is driven by the dermatology nurses and not the intervention program itself.  
The knowledge of participating in an adherence-improving intervention may in itself improve adherence 
and introduce a risk of reporting bias, in particular when the participants’ use of medication is measured and 

 
Page 28 of 35 
they report DLQI and EQ-5D. However, it is difficult to blind participants to the intervention given or to obtain 
approval from the ethics committee for masking participants to the fact that they are in a trial until the end of 
the study, which has been used in other studies involving adherence-interventions (54).  
Patients’ self-reported adherence will be obtained using a study-specific adherence scale, which limits 
the internal and external validity of the study. It was not considered an option to introduce a placebo-
intervention, in order to have blinded patients in the non-intervention arm. This is a limitation of the study 
design. At the very least, the lack of blinding of the investigator and study nurse introduces a risk of attrition 
bias while the lack of blinding of the data analyst and health economist introduces a risk of performance bias 
(55).  
A strength of the study is that participants are blinded to one of the facts, namely that a main purpose 
of the study is to investigate adherence, since the awareness of being in an adherence-improving trial could 
in itself influence adherence. The study design is based on systematic literature searches and use of a 
participatory study design, where the opinions of psoriasis patients and dermatology nurses have been 
considered. The study aims to provide effective, long-term follow-up and to use a clinically relevant primary 
endpoint (severity of disease), to collect and compare different adherence measures as well as be relevant for 
potential future implementation of the study (economic analysis). Patient-reported outcomes (DLQI and EQ-
5D)) as well as the physician-obtained outcome (LS-PGA) are obtained, which is an advantage of the study 
since patients’ perception of severity of disease and physicians’ objective measures do not always correlate 
(56).  To reduce the impact of participants’ awareness of being in an adherence-study, a measure of 
participants’ estimated adherence is not obtained at baseline (as would have been necessary if, for example, 
the validated adherence-measure Morisky Medication Adherence Scale 4-item (MMAS-4) was applied at the 
baseline study visit and at week 48 (57)).  
If the intervention is significantly superior compared to standard patient support, there is potential for 
implementing the patient-support intervention in the dermatology clinic. Results from the study may also be 
applied to other chronic dermatological diseases. At the very least, the study may be used methodically as a 
model for research projects investigating other chronic diseases. 
 
 

 
Page 29 of 35 
Trial status 
Study schedule 
Protocol version 1.4 dated October 5, 2020. The study included its first participant on June 19, 2020. The study 
is to be completed by summer 2022 at the latest. 
 
Abbreviations 
AE: Adverse Event; ATC: Anatomical Therapeutic Chemical; BSA: Body Surface Area; CEAC: Cost-
Effectiveness Acceptability Curve; CRF: Case Report Form; DDPA: Danish Data Protection Act; DLQI: 
Dermatology Life Quality Index; DRG: Diagnosis Related Group; EQ-5D: European Quality of life 5 
Dimensions; EQ VAS: European Quality Visual Analogue Score; ICER: Incremental Cost-Effectiveness Ratio; 
ITT: Intention to Treat; IUD: intrauterine device; LPR: Landspatientregistret; LS-PGA: Lattice System 
Physician's Global Assessment; MCID; Minimal Clinically Important Difference; MMAS-4: Morisky Medication 
Adherence Scale 4-item; OPEN: Open Patient data Exploratory Network; PRO: Patient Reported Outcome; 
REDCap: Research Electronic Data Capture; RCT: Randomized Controlled Trial; SAE: Serious Adverse 
Event; 
SAR: 
Serious 
Adverse 
Reaction; 
SPIRIT: 
Standard 
Protocol 
Items: 
Recommendations 
for 
Interventional Trials; SUSAR: Suspected Unexpected Serious Adverse Reaction; UVB: Ultraviolet B; WHO: 
World Health Organization; QALY: Quality Adjusted Life Years.   
 
Declarations 
Acknowledgements 
Assistant Professor, Psychologist, PhD E.J. Masicampo critically commented on the study protocol and 
suggested the guide for the patient-supporting consultations. Professor Charles N. Ellis, MD critically 
commented on the blinding procedure. The trial personnel are acknowledged for their suggestions for 
improvements in the trial design and intervention.  
 
 

 
Page 30 of 35 
Funding 
The trial is investigator-initiated. The trial has received funding from LEO foundation, Odense University 
Hospital Free Research Fund, Robert Wehnerts and Kirsten Wehnerts Foundation, Psoriasis Research 
Foundation, and Jeweler A.L. Rasmussens Memorial Foundation. The foundations have no role in the design 
of the study or the collection, analysis, or interpretation of data.  
Amount of support from each donor 
Payments from LEO Foundation: 2,200,000 DKK. Payments from Odense University Hospital Free Research 
Fund: 100,000 DKK. Payments from Robert Wehnerts and Kirsten Wehnerts Foundation: 25,000 DKK. 
Payments from the Psoriasis Research Foundation: 125,000 DKK. Payments from Jeweler A.L. Rasmussens 
Memorial Foundation: 20,000 DKK.  
Funding will be used solely for paying research staff and covering expenses for the trial during the trial 
period. There will be no payments to trial participants. Participants will, however, receive a minor gift (e.g., a 
small box of chocolates, maximum value 100 DKK) at week 24, as a reward. Providing participants with a small 
gift meets the requirements of the National Committee on Health Research Ethics, since the small gift will be 
given after consent has been signed and participants will not be aware of the opportunity to receive a gift at 
the time, they sign the consent form. 
The funding body will not have any influence on the design of the study or the collection, analysis, and 
interpretation of data or on writing the manuscript. 
 
Availability of data and materials 
MTS, SM and LPK will have access to the full data sets. All data collected is stored on a firewall-encrypted 
backed-up OPEN server with strictly regulated access solely for researchers directly involved in the study. 
 
Ethics approval and consent to participate  
Ethical approval has been obtained by the Regional Committees on Health Ethics for Southern Denmark, 
Denmark (S-20200031). 
 

 
Page 31 of 35 
The study is registered with ClinicalTrials.gov (NCT04380909). Written, informed consent to participate will be 
obtained from all participants. 
The investigator will ensure that the study will be conducted in accordance with the protocol, and applicable 
legislation (including the Danish Data Protection Act (DDPA) (55)) and that requirements issued by public 
authorities (the regional Data Protection Agency and the Danish the Committee on Health Research Ethics) 
have been and shall be followed. 
 
Specific ethical considerations in the study  
All participants will be informed that the purpose of the study is to investigate how psoriasis improves with 
topical drugs used in a real-life setting. The study will be performed in accordance with the ethical principles 
in the Helsinki Declaration (58).  
Participation in the study will not expose participants to more risk of side-effects than receiving standard 
of care treatment.  
Topical corticosteroids and calcipotriol are safe and effective when they are used as prescribed (59, 60). 
However, if the patient experiences lack of efficacy from the prescribed treatment with topical corticosteroids-
containing antipsoriatic drugs, this may be due to non-adherence. If the clinician is not attentive to this, the 
next step will be to subject the patient to treatments that carry a risk of skin cancer or burns (for example, 
narrow-band UVB phototherapy treatment), treatments with potentially severe side-effects such as severe 
immunosuppression, pancytopenia and liver damage (for example, methotrexate), and finally cost-intensive 
treatments without knowledge of long-term side-effects (for example, biologic treatments or apremilast).  
 
Competing interests  
MTS and KEA have received a grant from the LEO Foundation to conduct the trial. SRF is a 
speaker for Janssen and Taro; a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, 
LEO Pharma Inc.; has received grants from Galderma, Janssen, Abbott Labs, 
Amgen, Stiefel/GlaxoSmithKline, Celgene and Anacor; is a consultant for Amgen, Baxter, Caremark, Gerson 
Lehrman Group, Guidepoint Global, Hanall Pharmaceutical Co Ltd, Kikaku, Lilly, Merck & Co Inc., Merz 
Pharmaceuticals, Mylan, Novartis Pharmaceuticals, Pfizer Inc., Qurient, Suncare Research and Xenoport; is 

 
Page 32 of 35 
on an advisory board for Pfizer Inc.; is the founder of and holds stocks in Causa Research and holds stocks in 
and is majority owner of Medical Quality Enhancement Corporation; he receives royalties from UpToDate and 
Xlibris. SM and LPK declare no competing interests.  
 
References 
1. 
Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a 
systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377-85. 
2. 
De Korte J. Quality of life in dermatology: Past, present and future. Acta Dermato-
Venereologica. 2009;89 (5):560. 
3. 
Gutknecht M, Krensel M, Augustin M. Health economic analyses of psoriasis management: a 
systematic literature search. Archives of dermatological research. 2016;308(9):601-16. 
4. 
Carroll CL, Feldman SR, Camacho FT, Balkrishnan R. Better medication adherence results in 
greater improvement in severity of psoriasis. The British journal of dermatology. 2004;151(4):895-7. 
5. 
Okwundu N, Cardwell L, Cline A, Richardson I, Feldman SR. Is topical treatment effective for 
psoriasis in patients who failed topical treatment? The Journal of dermatological treatment. 2021;32(1):41-44. 
6. 
Sabaté E. Adherence to long-term therapies: evidence for action. World Health Organization; 
2003. Report No.: WHO/MNC/03.01. 
7. 
Balato N, Megna M, Costanzo L, Balato A, Ayala F. Educational and motivational support 
service: a pilot study for mobile-phone-based interventions in patients with psoriasis. British journal of 
dermatology. 2013; 168(1):201-205.. 
8. 
Svendsen MT, Andersen F, Andersen KH, Pottegard A, Johannessen H, Moller S, et al. A 
smartphone application supporting patients with psoriasis improves adherence to topical treatment: a 
randomized controlled trial. The British journal of dermatology. 2018;179(5):1062-1071. 
9. 
Caldarola G, De Simone C, Moretta G, Poscia A, Peris K. Role of personalized medication 
training in improving efficacy and adherence to a topical therapy in psoriatic patients. The Journal of 
dermatological treatment. 2017;28(8):722-5. 
10. 
Reich K, Zschocke I, Bachelez H, de Jong EMGJ, Gisondi P, Puig L, et al. A Topical Treatment 
Optimization Programme (TTOP) improves clinical outcome for calcipotriol/betamethasone gel in psoriasis: 
results of a 64-week multinational randomized phase IV study in 1790 patients (PSO-TOP). Th British journal 
of dermatology. 2017;177(1):197-205. 
11. 
de Korte J, Van Onselen J, Kownacki S, Sprangers MA, Bos JD. Quality of care in patients with 
psoriasis: an initial clinical study of an international disease management programme. J Eur Acad Dermatol 
Venereol. 2005;19(1):35-41. 
12. 
Augustin M, Langenbruch AK, Gutknecht M, RADtke MA, Blome C. Quality of Life Measures 
for Dermatology: Definition, Evaluation, and Interpretation. Current Dermatology Report 2012;1:148-159.  
13. 
Svendsen MT, Feldmann S, Tiedemann SN, Sørensen ASS, Rivas CMR, Andersen KE. 
Improving psoriasis patients' adherence to topical drugs: a systematic review. The Journal of dermatological 
treatment. 2020;31(8):776-785. 
14. 
Svendsen MT, Andersen KE, Andersen F, Hansen J, Pottegård A, Johannessen H. Psoriasis 
patients' experiences concerning medical adherence to treatment with topical corticosteroids. Psoriasis 
(Auckl.). 2016;23:113-119. 
15. 
Svendsen MT, Feldman SR, Tiedemann SN, Stochholm Sørensen AS, Rivas CMR, Andersen 
KE. Dermatology nurses view on factors related to Danish psoriasis patients' adherence to topical drugs: a 
focus group study. The Journal of dermatological treatment. 2021;32(5):497-502. 
16. 
Zhao YY, Dang FP, Zhai TT, Li HJ, Wang RJ, Ren JJ. The effect of text message reminders on 
medication adherence among patients with coronary heart disease: A systematic review and meta-analysis. 
Medicine (Baltimore). 2019;98(52):e18353. 

 
Page 33 of 35 
17. 
Eicher L, Knop M, Aszodi N, Senner S, French LE, Wollenberg A. A systematic review of 
factors influencing treatment adherence in chronic inflammatory skin disease - strategies for optimizing 
treatment outcome. J Eur Acad Dermatol Venereol. 2019;33(12):2253-63. 
18. 
Oussedik E, Foy CG, Masicampo EJ, Kammrath LK, Anderson RE, Feldman SR. 
Accountability: a missing construct in models of adherence behavior and in clinical practice. Patient preference 
and adherence. 2017;11:1285-94. 
19. 
Kolli SS, Pona A, Cline A, Feldman SR. Strategies to Improve Adherence.  Treatment 
Adherence in Dermatology: Springer; 2020. p. 21-8. 
20. 
Rijsbergen M, Niemeyer-van der Kolk T, Rijneveld R, Pinckaers J, Meshcheriakov I, Bouwes 
Bavinck JN, et al. Mobile e-diary application facilitates the monitoring of patient-reported outcomes and a 
high treatment adherence for clinical trials in dermatology. J Eur Acad Dermatol Venereol. 2020;34(3):633-
639. 
21. 
Noordraven EL, Schermer MHN, Blanken P, Mulder CL, Wierdsma AI. Ethical acceptability 
of offering financial incentives for taking antipsychotic depot medication: patients' and clinicians' perspectives 
after a 12-month randomized controlled trial. BMC psychiatry. 2017;17(1):313. 
22. 
Burroni AG, Fassino M, Torti A, Visentin E. How do disease perception, treatment features, 
and dermatologist-patient relationship impact on patients assuming topical treatment? An Italian survey. 
Patient Relat Outcome Meas. 2015;6:9-17. 
23. 
Noar SM, Benac CN, Harris MS. Does tailoring matter? Meta-analytic review of tailored print 
health behavior change interventions. Psychological bulletin. 2007;133(4):673-93. 
24. 
Tversky 
A, 
Simonson 
I. 
Context-dependent 
preferences. 
Management 
science. 
1993;39(10):1179-89. 
25. 
Kircik LH, Stein LG, Pariser DM. Improving Adherence to Topical Therapies Through 
Improved Clinician-Patient Communication and Shared Decision Making. Cutis. 2019;103(4S):S13-S5. 
26. 
Svendsen MT, Feldman SR, Tiedemann SN, Sørensen ASS, Rivas CMR, Andersen KE. 
Psoriasis patient preferences for topical drugs: a systematic review. The Journal of dermatological treatment. 
2021;32(5):478-483. 
27. 
Svendsen mt, Ernst MS, Andersen KE, Andersen F, Johannesen H, Pottegård. Use of topical 
antipsoriatic drugs in Denmark: a nationwide drug utilization study. British Journal of Dermatology 
2019;180(1):157-164.  
28. 
Long C, Finlay A. The finger‐tip unit—a new practical measure. Clinical and experimental 
dermatology. 1991;16(6):444-7. 
29.  
Saldanha IJ, Dickersin K, Wang X, Li T. Outcomes in Cochrane Systematic Reviews 
Addressing Four Common Eye Conditions: An Evaluation of Completeness and Comparability. PLOS One 
2014;9(10):e109400. 
30.  
Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov Resukts Database – 
Update and Key Issues. New England Journal of Medicine. 201;364(9): 852–860.  
31. 
Langley RG, Ellis CN. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis 
Global Assessment, and Lattice System Physician's Global Assessment. J Am Acad Dermatol. 
2004;51(4):563-9. 
32. 
Zachariae R, Zachariae C, Ibsen H, Mortensen JT, Wulf HC. Dermatology life quality index: 
data from Danish inpatients and outpatients. Acta Derm Venereol. 2000;80(4):272-6. 
33.  
Wittrup-Jensen, Kim U., Jørgen Lauridsen, Claire Gudex, et al. 'Generation of a Danish TTO 
Value Set for EQ-5D Health States', Scandinavian Journal of Public Health, vol. 37/no. 5, (2009), pp. 459-
466. 
34. 
StataCorp. Stata Statistical Software: Release 16. In: College Station T, editor.: StataCorp 
LCC.; 2019. 
35. 
Svendsen MT, Andersen KE. Don't forget the Lattice-System Physician's Global Assessment 
as one of the research tools for measuring severity of mild-to-moderate psoriasis. J Am Acad Dermatol. 
2021:12;S0190-9622(21)00344-3 (Online ahead of print). 
36. 
Chow C, Simpson MJ, Luger TA, Chubb H, Ellis CN. Comparison of three methods for 
measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and 

 
Page 34 of 35 
Severity Index, Static Physician's Global Assessment and Lattice System Physician's Global Assessment. J 
Eur Acad Dermatol Venereol. 2015;29(7):1406-14. 
37. 
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically 
important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. 
Dermatology. 2015;230(1):27-33. 
38. 
Yang Y, Brazier J, Longworth L. EQ-5D in skin conditions: an assessment of validity and 
responsiveness. Eur J Health Econ. 2015;16(9):927-39. 
39. 
Pottegard A, Schmidt SA, Wallach-Kildemoes H, Sorensen HT, Hallas J, Schmidt M. Data 
Resource Profile: The Danish National Prescription Registry. Int J Epidemiol. 2017;46(3):798-798f. 
40. 
Svendsen MT, Andersen F, Hansen J, Johannessen H, Andersen KE. Medical adherence to 
topical corticosteroid preparations prescribed for psoriasis: A systematic review. J Dermatolog Treat. 
2017;28(1):32-9. 
41. 
Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, et al. The REDCap 
consortium: Building an international community of software platform partners. Journal of biomedical 
informatics. 2019;95:103208. 
42. 
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-97. 
43. 
Wittrup-Jensen, Kim U., Jørgen Lauridsen, Claire Gudex, et al. 'Generation of a Danish TTO 
Value Set for EQ-5D Health States', Scandinavian Journal of Public Health, vol. 37/no. 5, (2009), pp. 459-
466. 
44. 
Drummond, Michael, Mark J. Sculpher, Karl Claxton, et al. , 'Methods for the Economic 
Evaluation of Health Care Programmes', Anonymous Translator (Fourth edn, Oxford, Oxford University Press, 
2015). 
45. 
BEK nr 767 af 22/06/2016 (Varenummerbekendtgørelsen), (2016). 
46. 
Gregersen R, Wiingreen R, Rosenberg J. [Health-related register-based research in Denmark]. 
Ugeskr Laeger. 2018;180(43). 
47. 
Pottegård A, Schmidt SAJ, Wallach-Kildemoes H, Sørensen HT, Hallas J, Schmidt M. Data 
Resource Profile: The Danish National Prescription Registry. Int J Epidemiol. 2017;46(3):798-f. 
48. 
Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish 
National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 
2015;7:449-90. 
49. 
Andersen JS, Olivarius Nde F, Krasnik A. The Danish National Health Service Register. 
Scandinavian journal of public health. 2011;39(7 Suppl):34-7. 
50.  
Manca A, Hawkins N, Sculper MJ.  et al. Estimating mean QALYs in trial-based cost-
effectiveness analysis: the importance of controlling for baseline utility. Health economics 2005;14(5): 487-
96 
51. 
Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW. Methods for the 
economic evaluation of health care programmes: Oxford university press; 2015. 
52. 
Børlum Kristensen F, Sigmund H. Metodehåndbog for medicinsk teknologivurdering. 2007. 
53. 
Barchard KA, Verenikina Y. Improving data accuracy: Selecting the best data checking 
technique. Computers in Human Behavior 2013;29(5):1917-1922.  
54. 
Patel NU, Moore BA, Craver RF, Feldman SR. Ethical considerations in adherence research. 
Patient preference and adherence. 2016;10:2429. 
55. 
Polit DF. Blinding during the analysis of research data. International Journal of Nursing Studies 
2011;48:636-641. 
56. 
Loft ND, Egeberg A, Rasmussen MK, Bryld LE, Gniadecki R, Dam TN, et al. Patient-reported 
Outcomes During Treatment in Patients with Moderate-to-severe Psoriasis: A Danish Nationwide Study. Acta 
dermato-venereologica. 2019;99(13):1224-30. 
57. 
Tan X, Patel I, Chang J. Review of the four item Morisky medication adherence scale (MMAS-
4) and eight item Morisky medication adherence scale (MMAS-8). INNOVATIONS in pharmacy. 
2014;5(3):5. 
58. 
The Danish Data Protection Act, LOV nr. 502 (2018). 
59. 
World Medical A. World Medical Association Declaration of  : ethical principles for medical 
research involving human subjects. JAMA. 2013;310(20):2191-4. 

 
Page 35 of 35 
60. 
Castela E, Archier E, Devaux S, Gallini A, Aractingi S, Cribier B, et al. Topical corticosteroids 
in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. Journal of the 
European Academy of Dermatology and Venereology. 2012;26:47-51.