Comparison of Efficacy of Methotrexate and Azathioprine in Patients With Chronic Actinic Dermatitis
Phase: EARLY_PHASE1
Conditions: Chronic Actinic Dermatitis
Sponsor: Pak Emirates Military Hospital

Comparison of efficacy of methotrexate and azathioprine in patients with 
chronic actinic dermatitis: A randomized controlled trial   
                                    (Trial no: NCT06476366) 
 
                                               Date: 14/06/2024 
                               
 
 
 
 
 
 
 
 
 
 
 
 

 
 
                             SYNOPSIS &TRIAL PROTOCOL 
                                                    For 
                                    Ethical Review Committee 
By 
Dr Ahsan Tameez Ud Din 
RTMC #: DER-2024-124-19481 
Email: ahsantameezuddinmalik@gmail.com 
Mobile No:  
 
Supervisor 
Brig. Aisha Akhtar 
Associate Professor and head of dermatology department 
Pak-Emirates Military Hospital, Rawalpindi 
 
 

 
 
                 NON-DUPLICATION CERTIFICATE 
 
It is to certify that Dr. Ahsan Tameez Ud Din is doing her FCPS training in 
Dermatology at Pak-Emirates Military Hospital, Rawalpindi under my 
supervision. The topic “Comparison of efficacy of methotrexate and 
azathioprine in patients with chronic actinic dermatitis: A randomized 
controlled trial” which he has selected for his synopsis has not been done 
previously within the last 5 years at Pak-Emirates Military Hospital, Rawalpindi. 
The synopsis study design has no ethical concerns. 
 
Supervisor 
Brig. Aisha Akhtar 
Professor and head of dermatology department 
Pak-Emirates Military Hospital, Rawalpindi. 
 
 
 

SUPERVISOR CERTIFICATE 
 
I hereby certify that Dr. Ahsan Tameez Ud Din, Postgraduate Trainee 
Dermatology, RTMC # DER-2024-124-19481 has been working under my direct 
supervision from 18-01-2024 to date in Pak-Emirates Military Hospital, 
Rawalpindi. The enclosed synopsis titled: 
 
“Comparison of efficacy of methotrexate and azathioprine in patients with 
chronic actinic dermatitis: A randomized controlled trial” 
 
will be prepared according to “FCPS Research Synopsis Guidelines” under my 
direct supervision. I have read the synopsis and have found it satisfactory. 
 
Supervisor 
Brig. Aisha Akhtar 
Professor and head of dermatology department 
Pak-Emirates Military Hospital, Rawalpindi. 
 
 
 
 
 

Comparison of efficacy of methotrexate and azathioprine in patients with 
chronic actinic dermatitis: A randomized controlled trial 
 
Introduction: 
 Chronic actinic dermatitis (CAD) is a recurrent hypersensitivity dermatitis of photo-exposed 
areas, predominantly affecting the elderly population 1-3. It is a relatively common 
photodermatitis and is clinically characterized by vesiculation and erythema in acute phase 
while the chronic lesions present with a more characteristic, infiltrated and lichenified 
appearance. There is a sharp cut-off at the non-exposed areas of the body along with the sparing 
of facial skin creases and folds 1,4. CAD is associated with a lower age of onset and in a higher 
proportion of females as compared to male in skin of color which highlights the need to be 
cognizant of such subtle differences while treating the local populations with a diverse range 
of skin tones 4,5.  
Photoprotection is the cornerstone of treatment but potent topical corticosteroids are frequently 
required 1,6. Courses of systemic corticosteroids may be required to treat or prevent acute flares, 
but considering the side effects of this modality in elderly population, there is a palpable need 
for a safer alternative 7. Azathioprine (AZP) is an immunosuppressant which has been used 
successfully as a steroid sparing agent in the treatment of CAD 1,2,8. Methotrexate (MTX) is a 
folic acid analogue which exerts its action through the inhibition of DNA synthesis. It is used 
in a variety of inflammatory dermatoses ranging from psoriasis to eczema and it is logical to 
assume that the efficacy of this drug extends to CAD which has similar underlying pathological 
bases 2,9-11.  
There is a scarcity of evidence regarding MTX efficacy in patients with CAD and very few 
head to head comparisons between MTX and AZT have been published. The aim of this study 

is to evaluate the efficacy of AZT and MTX in patients with CAD. These drugs have been used 
successfully as steroid-sparing alternatives in a variety of related dermatoses and this trial may 
help in paving the path towards the ubiquitous use of these cost-effective and relatively safer 
drugs in CAD patients of our population. 
 
OBJECTIVE: 
To compare the safety and efficacy of AZT and MTX in the treatment of CAD by using Eczema 
Area and Severity Index (EASI) and Investigator Global Assessment (IGA) scores (Annexures 
B and C). 
Outcome measures 
 Primary: A reduction of 50% in the EASI score as compared to baseline score (EASI-50) 
Secondary: An IGA score of 0-2 will be considered as a secondary outcome measure.  
 
 
OPERATIONAL DEFINITIONS: 
Severity of eczema: 
Severity of CAD will be defined with regards to the Eczema Area and Severity Index (EASI) 
score. In clinical trials, the EASI is a scale used to evaluate the degree and severity of 
eczema.  The investigator rates the severity of the four disease features of eczema (erythema, 
infiltration and/or papulation, excoriations, and lichenification) on the EASI using a scale from 
"0" (absent) to "3" (severe). Each of the four body regions, the head, arms, trunk, and legs, has 
its scores tallied together. Additionally, each body region's percentage of the afflicted area is 

converted to a score ranging from 0 to 6, and the affected area is multiplied by each body area 
score.  The total EASI score is between 0 and 72 . 
Mild disease:  Patients with a score of 1.1-7.0 on the EASI scale will be classified as having 
mild disease. 
Moderate disease:  Patients with a score of 7.1 to 21.0 on the EASI scale will be classified as 
having moderate disease. 
Severe disease:  Patients with a score of 21.1-50.0 on the EASI scale will be classified as 
having severe disease. 
 
Very Severe disease:  Patients with a score of 50.1-72.0 on the EASI scale will be classified as 
having very severe disease. 
Disease flare: 
Disease flare will be defined as the worsening of the existing lesions or the appearance of new 
lesions with symptoms that result in a hospital visit or increase in the frequency of 
topical/systemic medications used for eczema control. 
Disease Remission: 
Disease remission will be defined as the resolution of all the lesions of CAD and appearance 
of no new lesions for at least 4 weeks. 
 
NULL HYPOTHESIS: 
There is no difference in the efficacy of AZT and MTX in the treatment of CAD. 
 

MATERIAL AND METHODS 
Setting  
Department of Dermatology, Pak Emirates Military Hospital (PEMH)  
Duration 
One year after the approval of research proposal (or until the completion of sample size) 
Study Design 
Non-blinded, parallel group, Randomized Controlled Trial 
Sample Size 
Sample size (n) was calculated to be 33 by using WHO sample size calculator by using 
following formula and parameters as per study outcomes reported by Verma et al 12   
                       
n = 
{Z1-α/2√2𝑃(1 −𝑃) + Z1-β√𝑃1 (1 −𝑃1) + (𝑃2(1 −𝑃2)}2 
 
                            (P1-P2)2 
 
Power of test (α): 95% 
Level of significance (1-β): 5% 
Proportion of population achieving primary outcome with azathioprine (P1): 47.5%  
Proportion of population achieving primary outcome with methotrexate (P2): 85%  
 
Trial Registration 

The study will be registered with the international clinical trials registry of United states 
National library of Medicine at clinicaltrials,gov.  CONSORT guidelines will be followed 
while conducting the study . 
Patient selection and Funding 
Only the patients entitled for treatment in PEMH will be enrolled in the study. The availability 
of the drugs will be ensured through coordination with the hospital pharmacist. No external 
funding is planned for conducting the trial. 
Sampling Technique 
Consecutive sampling technique will be employed.  
   Inclusion Criteria 
   All newly as well as already diagnosed patients with CAD (male or female), aged 30-80 
years, presenting to the outpatient department or the emergency department of PEMH or CMH 
will be included in the study. 
   Exclusion Criteria 
  Following patients will be excluded: 
 Patients with coexisting conditions requiring immunosuppressants, preexisting liver 
disease, dementia, any other neuropsychiatric disorder. 
 Patients with known hypersensitivity to AZT or MTX. 
 Patients with active infections 
 
 
 

Consent: 
Written informed consent will be taken by the patients on a printed form of their preferred 
language (Urdu/English). Patients will be made fully aware of all their rights, possible benefits 
and risks of participation and will be explained regarding the right to withdraw from treatment 
at any point during the trial. English and Urdu versions of the consent form are attached as 
Annexure-D. 
 
Randomization and Allocation 
After the enrolment of patients and taking informed consent, participants will be randomly 
allocated in a 1:1 ratio in two treatment groups via lottery method. The allocation will be 
concealed using sequentially numbered, opaque envelopes. Owing to the nature of the 
treatment groups, the blinding of neither the investigators nor the participants will be feasible. 
Intervention protocol 
After confirming the results of the baseline blood tests, treatment will be initiated as per 
following protocol: 
 Group A will be administered tablet azathioprine at a dose of 0.3mg/kg daily after 
testing for thiopurine methyltransferase (TPMT) levels.  
 Group B will be administered oral methotrexate starting from 5mg/week and increasing 
the dose by 2.5mg/week to the final dose of 10mg/week. Daily 0.5mg folic acid tablets 
(excluding the day of the MTX) will be administered.  
Both treatments will be continued for 24 weeks and monitoring and dose adjustment will be 
done according to clinical protocol. 
 

Follow-up and Outcome assessment 
Weekly complete blood picture (CBC) will be done until the last dose escalation for group B 
patients. Both group of patients will be advised regarding strict sun protection measures 
(sunblock, hats, sunglasses). The baseline investigations for both groups included CBC, liver 
function tests (LFTs), renal function tests (RFTs), electrocardiogram, chest X-ray and urine 
analysis while TPMT levels will be assessed specifically for group B patients. The patients will 
be followed up at week 4, 12 and 24. CBC, RFTs and LFTs will be done at each follow-up. 
EASI score will be calculated at baseline and at subsequently at each follow-up visit.  
A comparison from the EASI score from the last visit will be made at each follow-up to assess 
whether any patient achieved the primary outcome of EASI-50 (50% improvement in EASI 
score from baseline). Investigator global assessment (IGA) score will be used as a secondary 
outcome measure. It is a subjective measure of disease severity which is assessed by the 
physician on patient’s every visit. It ranges from 0 to 4 (0-clear, 1-almost clear, 2-mild, 3-
moderate, 4-severe). An IGA score of 0-2 will be considered as the outcome measure. Patients 
will be also asked for any specific side-effects of the treatment at every follow-up. The data 
including the demographic profile of the participants will be recorded on a printed form. The 
data will be kept under lock and key and will be available only to the treating physician and 
the research team. 
Monitoring of side-effects during the trial period: 
The patients will be kept under close surveillance and will be contacted by phone in case of 
failure to follow at the given dates. Any reported side-effects will be carefully documented and 
if required, patients will be admitted and and alternate treatment will be started after stopping 
the culprit drug. The patients will have a freedom to choose to withdraw from the trial even in 
the absence of any side-effect. 

Post-trial care: 
The patients will be kept under regular, 3 monthly follow-ups and any side-effects will be 
reported. In case of adverse events, patient would be admitted and alternate treatment will be 
started after stopping the culprit drug. 
 
Data Analysis 
Statistical analysis will be performed using SPSS version 23.0. Mean and standard deviation 
or median will be calculated for age and duration of symptoms. Frequency and percentage will 
be calculated for gender (male/female), marital status (yes/no), place of living (rural/urban), 
and achievement of EASI-50 score (yes/no). Comparison of efficacy between both groups will 
be compared by chi square test and p-value ≤0.05 will be taken as significant. Effect modifiers 
like age, gender, marital status, duration of symptoms, place of living (rural/urban) will be 
controlled through stratifications. Post-stratification chi square test will be applied to see their 
effects on efficacy and p value ≤ 0.05 will be considered as significant. 
 
Dissemination of findings 
The findings of the study will be shared with the medical community through presentation in 
research conferences and through publication in national/international medical journal. The 
participants of the study will be entitled to ask for the study findings at any time and will be 
provided with a written/printed form on demand. 
 
 

 
 
 
 
 
 
REFERENCES: 
1. Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D. Rook’s Textbook of 
Dermatology. Chichester, West Sussex: John Wiley & Sons, Ltd; 2016. 
2. Paracha MM, Zahoor H, Khan AQ, Noor SM, Sagheer F. Efficacy Of Methotrexate 
Versus Azathioprine In The Treatment Of Chronic Actinic Dermatitis: A Randomized 
Control Trial. J Ayub Med Coll Abbottabad. 2022; 34(S1): S644-S648 
3. Gu Q, Zhang Z, Yang J, Gao H, Hu Y, Xu Y, et al. Chronic actinic dermatitis: A 5‐
year clinical analysis of 488 patients in China. Photodermatol. Photoimmunol 
Photomed. 2023; 39(3): 263-8. 
4. Tan KW, Haylett AK, Ling TC, Rhodes LE. Comparison of demographic and 
photobiological features of chronic actinic dermatitis in patients with lighter vs darker 
skin types. JAMA dermatol. 2017; 153(5): 427-35. 
5. Passeron T, Lim HW, Goh CL, Kang HY, Ly F, Morita A, et al. Photoprotection 
according to skin phototype and dermatoses: practical recommendations from an 
expert panel. J Eur Acad Dermatol Venereol. 2021; 35(7): 1460-9. 

6. Krutmann J, Passeron T, Gilaberte Y, Granger C, Leone G, Narda M, et al. 
Photoprotection of the future: challenges and opportunities. J Eur Acad Dermatol 
Venereol. 2020; 34(3): 447-54. 
7.  Yasir M, Goyal A, Sonthalia S. Corticosteroid adverse effects [Internet]. U.S. National 
Library 
of 
Medicine; 
2023 
[cited 
2024 
May 
13]. 
Available 
from: 
https://www.ncbi.nlm.nih.gov/books/NBK531462/ 
8. Naqqash S, Asad F, Pal SS. Efficacy and safety of azathioprine in the treatment of 
chronic actinic dermatitis. J Pak Assoc Dermatol. 2010; 20(4): 222-6. 
9. McFeely O, Doyle C, Blasco MC, Beatty P, Murphy L, O'Mahony S, et al. Chronic 
actinic dermatitis successfully treated with methotrexate and dupilumab. 
Photodermatol Photoimmunol Photomed. 2023; 39(2): 172-174. 
10. Ghosh N, Nasrin T, Mahmud H, Paul HK. Efficacy and safety of low dose 
Methotrexate in the treatment of chronic hand eczema. J Pak Assoc Dermatol. 2020; 
30(1): 3-8. 
11. Paracha MM, Noor SM, Khan AQ. Efficacy and safety of methotrexate in chronic 
actinic dermatitis: a pilot study. Khyber Med Univ J. 2018; 10(3): 124-26. 
12. Verma KK, Kumar P, Bhari N, Gupta S, Kalaivani M. Azathioprine weekly pulse 
versus methotrexate for the treatment of chronic plaque psoriasis: a randomized 
controlled trial. Indian J Dermatol Venereol Leprol. 2021;87(4):509-514. 
 
 

                                                       ANNEXURE A 
Comparison of efficacy of methotrexate and azathioprine in patients with chronic actinic 
dermatitis 
Name                                           Age                                Sex                     Occupation 
Marital status                              Group A/B                     Residence: Urban/Rural 
Education                                    Co-morbid (HTN, DM, Smoking )                   
 Duration of disease                    EASI SCORE:                IGA score 
Baseline investigations: 
Hb               platelet count                   TLC                   BIL               ALT                    AST                 
ALP              Urea                 creatinine                             Chest Xray                                  
ECG                                                      urine RE 
Followup visits: 
 
 
 
EASI-50 achieved           yes/no               (if yes,  achieved at week:                   ) 
IGA score 0-2                 yes/no                (if yes, achieved at week                ) 
 
 
week 
Hb 
PLT 
TLC 
BIL 
ALT 
AST 
UREA 
CREAT EASI 
IGA 
4 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 

                                                       ANNEXURE B 
                                                               Eczema Area and Severity Index (EASI) score 
 
Area of Involvement: Each body region has potentially 100% involvement. Score 0 to 6 based on the 
following table: 
 
% involvement 
0 
1-9% 
10 - 29% 
30 - 49% 
50 - 69% 
70 - 89% 
90 - 100% 
Region score 
0 
1 
2 
3 
4 
5 
6 
 
Severity of Signs: Grade the severity of each sign on a scale of 0 to 3: 
 
 
 Take an average of the severity across the involved area. 
 Half points (1.5 and 2.5) may be 
used. 0.5 is not permitted – if a sign 
is present it should be at least mild 
(1) 
 
 
Scoring table: 
 
Body region 
Erythema        
(0-3) 
  Edema/ 
Papulation 
(0-3) 
Excoriation 
(0-3) 
Lichenification 
(0-3) 
Region 
score 
(0-6) 
Multiplier 
Score per body 
region 
Head/neck 
( 
+ 
+ 
+ 
                          ) 
X 
X 0.1 
Trunk 
( 
+ 
+ 
+ 
) 
X 
X 0.3 
Upper 
extremities 
( 
+ 
+ 
+ 
) 
X 
X 0.2 
Lower 
extremities 
( 
+ 
+ 
+ 
) 
X 
X 0.4 
The final EASI score is the sum of the 
4 region scores: 
(0-72) 
 
 
 
 
0 
None 
1 
Mild 
2 
Moderate 
3 
Severe 

                                                     ANNEXURE-C 
    Investigator Global Assessment scale (IGA score) 
Instructions: 
The IGA score is selected using the descriptors below that best describe the overall appearance of 
the lesions at a given time point. It is not necessary that all characteristics under Morphological 
Description be present. 
 
Score 
Morphological Description 
0 – Clear 
No inflammatory signs of atopic dermatitis (no erythema, no induration/papulation, no 
lichenification, no oozing/crusting). Post-inflammatory hyperpigmentation and/or 
hypopigmentation may be present. 
1 – Almost clear 
Barely perceptible erythema, barely perceptible induration/papulation, and/or minimal 
lichenification. No oozing or crusting. 
2 – Mild 
Slight but definite erythema (pink), slight but definite induration/papulation, and/or slight 
but definite lichenification. No oozing or crusting. 
3 – Moderate 
Clearly perceptible erythema (dull red), clearly perceptible induration/papulation, and/or 
clearly perceptible lichenification. Oozing and crusting may be present. 
4 – Severe 
Marked erythema (deep or bright red), marked induration/papulation, and/or marked 
lichenification. Disease is widespread in extent. Oozing or crusting may be present. 
 
Notes: 
1. In indeterminate cases, please use extent to differentiate 
between scores. For example: 
• 
Patient with marked erythema (deep or bright red), marked papulation and/or marked 
lichenification that is limited in extent, will be considered “3 – Moderate”. 
2. Excoriations should not be considered when assessing disease severity. 
 
 
 
 
 
 

                                                 ANNEXURE-D 
Informed Consent Form 
 
Title of Study: A Non-Blinded, Parallel-Group Randomized Controlled Trial Comparing Azathioprine 
and Methotrexate in  Chronic Actinic Dermatitis Patients 
Principal Investigator: Dr. Ahsan Tameez Ud Din 
Affiliation: Pak Emirates Military Hospital 
Contact Information: ahsantameezuddinmalik@gmail.com 
Introduction 
You are being invited to participate in a research study. Please read this form carefully and ask any 
questions you may have before agreeing to take part in the study. 
Purpose of the Study 
The purpose of this study is to compare the effectiveness and safety of two medications, Azathioprine 
and Methotrexate, in the treatment of [Disease/Condition]. 
Procedures 
If you agree to participate, you will be randomly assigned to receive either Azathioprine or 
Methotrexate. You will be monitored regularly through clinical visits and laboratory tests for a period 
of [Duration]. 
Risks and Benefits 
Both medications may cause side effects. These will be explained to you. The benefit of participating 
is that you may receive improved care and contribute to medical knowledge. 

Confidentiality 
All information collected in this study will be kept confidential. Your identity will not be revealed in 
any reports or publications resulting from this study. 
Voluntary Participation 
Your participation is voluntary. You may choose not to participate or to withdraw at any time without 
any penalty or loss of benefits. 
Consent 
I have read and understood the information provided above. I have had the opportunity to ask 
questions and my questions have been answered to my satisfaction. I voluntarily agree to participate 
in this study. 
Participant Name: ______________________  Signature: _______________  Date: __________ 
Witness Name: _________________________  Signature: _______________  Date: __________ 
Investigator Name: _____________________  Signature: _______________  Date: __________ 
 
 

رضامندی کا فارم 
مطالعہ کا عنوان: ازاتھائیوپرین اور میتھو ٹریکسیٹ کے درمیان موازنہ - ایک غیر اندھا، متوازی گروپ RCT 
مرکزی محقق:  ڈاکٹر احسن تمیزالدین 
ادارہ: پاک امارات ملٹری ہسپتال  
رابطہ معلومات : ahsantameezuddinmalik@gmail.com 
تعارف 
آپ کو اس تحقیق میں شامل ہونے کی دعوت دی جا رہی ہے۔ برائے مہربانی اس فارم کو غور سے پڑھیں اور اگر آپ کے 
کوئی سواالت ہوں تو ضرور پوچھیں۔ 
مطالعے کا مقصد 
اس مطالعے کا مقصد از
اتھائیوپرین اور میتھو ٹریکسیٹ کی مؤثریت اور حفاظت کا موازنہ کرنا ہے۔ 
طریقہ کار 
اگر آپ شامل ہونے پر رضامند ہوں تو آپ کو بے ترتیب طریقے سے کسی ایک دوا (ازاتھائیوپرین یا میتھو ٹریکسیٹ) کے 
گروپ میں رکھا جائے گا۔ آپ کی باقاعدگی سے جانچ کی جائے گی۔ 
خطرات اور فوا
ئد 
دونوں دواؤں کے مضر اثرات ہو سکتے ہیں جو آپ کو بتائے جائیں گے۔ اس مطالعے سے آپ کو بہتر عالج ملنے اور طبی 
علم میں اضافہ کرنے کا موقع مل سکتا ہے۔ 
رازداری 
اس مطالعے میں آپ کی تمام معلومات کو خفیہ رکھا جائے گا۔ آپ کی شناخت ظاہر نہیں کی جائے گی۔ 
رضاکارانہ شمو
لیت 
اس مطالعے میں شمولیت مکمل طور پر رضاکارانہ ہے۔ آپ کسی بھی وقت شمولیت سے انکار یا علیحدگی اختیار کر سکتے 
ہیں۔ 

رضامندی 
میں نے اوپر دی گئی معلومات کو پڑھا اور سمجھا ہے۔ میرے سواالت کے تسلی بخش جوابات دیے گئے ہیں۔ میں اپنی مرضی 
سے اس مطالعے میں شامل ہونے رپ رضامند ہوں۔ 
شرکت کنندہ کا نام: ______________________  دستخط: _______________  تاریخ: __________ 
گواہ کا نام: _________________________  دستخط: _______________  تاریخ: __________ 
محقق کا نام: _____________________  دستخط: _______________  تاریخ: __________