Effectiveness and safety of crisaborole 2% ointment versus betamethasone valerate 0.1% cream in atopic dermatitis: observer-blind non-inferiority randomized controlled trial in a tertiary care centre of eastern India

RESEARCH TOPIC:

Effectiveness and safety of crisaborole 2% ointment versus betamethasone valerate 0.1% cream in atopic dermatitis: observer-blind non-inferiority randomized controlled trial.

AIMS AND OBJECTIVES:

Aims: To determine effectiveness and safety of crisaborole in atopic dermatitis.

Primary objective:

To determine the effectiveness and safety of crisaborole 2% ointment in comparison with betamethasone valerate 0.1% cream in atopic dermatitis patients.

Secondary objective:

a) To evaluate the effectiveness and safety of crisaborole 2% ointment in comparison with betamethasone valerate 0.1% cream as maintenance therapy in prevention of atopic dermatitis.

b) To assess the comparative change in quality of life with treatment in both the groups.

c) To assess whether there is any difference in the effectiveness and safety of crisaborole 2% ointment among children, adolescent and adults.

BACKGROUND OF RESEARCH:

A) RATIONALE OF STUDY:

Atopic dermatitis is a common chronic skin disease characterized by type 2 helper T cell-mediated immune reaction resulting in impaired cutaneous barrier, intolerable pruritus and susceptibility to skin infections. The commonly used topical agents are emollients, topical corticosteroids (TCS) and calcineurin inhibitors. (TCI) [1] In spite of having efficacy, long-term use of these agents is associated with adverse effects. TCS is known to have local side effects like skin atrophy, striae (particularly on the face and groins) besides having systemic side effects on long-term use. On the other hand, crisaborole is a low molecular weight compound that penetrates effectively through the skin and controls inflammation by inhibiting phosphodiesterase-4 (PDE4). Moreover, it could do the job of targeted inhibition of inflammation with avoidance of the unwanted side effects of TCS. [2]

 B) INTRODUCTION:

Atopic dermatitis is a severely pruritic, chronic inflammatory skin disease which affects a large number of individuals all over the world. It is prevalent among all the age-groups. It negatively affects the health-related quality of life of pediatric patients including disturbance of sleep, mood alteration, and disturbed psychosocial functioning; it also results in psychological distress of the caregivers.[3]

The commonly used topical agents are emollients, topical corticosteroids (TCS) and calcineurin inhibitors. (TCI) [1]TCS is known to have local side effects like skin atrophy, striae (particularly on the face and groins) besides having systemic side effects on long-term use.[2]

The novel boron-containing low molecular weight compound – crisaborole – effectively penetrates the skin and reduces inflammation by inhibiting PDE-4 and thereby decreasing the degradation of cyclic adenosine monophosphate (cAMP). Then it regulates the nuclear factor-κβ and nuclear factor of activated T-cell – this causes decreased cytokine production. It successfully controls inflammation in atopic dermatitis with improvement in investigator’s static global assessment score. But, the adverse effects are few and mild-to-moderate in severity. [2]

As the comparative studies of crisaborole and topical steroids are few, there is necessity of a randomised controlled trial to look for the efficacy and safety profile of crisaborole-tretaed patients in comparison with betamethasone so that crisaborole can replace betamethasone in future for long-term management of atopic dermatitis.

C)REVIEW OF LITERATURE:

Atopic dermatitis is a common chronic skin disease characterized by type 2 helper T cell-mediated immune reaction resulting in impaired cutaneous barrier, intolerable pruritus and susceptibility to skin infections. The commonly used topical agents are emollients, topical corticosteroids (TCS) and calcineurin inhibitors. (TCI) [1]

In 2014, Beck et al. studied the role of dupilumab in a double-blind placebo-controlled randomised controlled trial in moderate-to-severe atopic dermatitis adult patients and found it to be efficacious without any dose-limiting side effect. [1]

In spite of having efficacy, long-term use of these agents is associated with adverse effects. TCS is known to have local side effects like skin atrophy, striae (particularly on the face and groins) besides having systemic side effects on long-term use. [2]

In 2016, Palleret al. found that twice daily application of crisaborole for 28 days was safe and improved all the measures of efficacy that included overall disease severity, pruritus, and other signs of AD. They compared crisaborole against vehicle in atopic dermatitis patients with age ≥2 years and found crisaborole to be more effective in improving ISGA (Investigator’s Static Global Assessment Score) score and degree of pruritus than the vehicle itself. [2]

In 2016, Zane et al did an open-label maximal-use systemic exposure study on crisaborole 2% ointment in patients aged 2-17 years. They found it to be well-tolerated with minimal systemic exposure under maximal-use circumstances and efficacious in improving mean ISGA score. Treatment success was achieved by 47.1% patients; and ISGA score of 0-1 (clear-almost clear) was achieved by 64.7% patients. [4]

In 2018, Lonndahl et al. studied the role of substance P antagonist Aprepitant in atopic dermatitis. They found that Aprepitant had no additive effect compared with standardized topical treatment alone (TCS + moisturizer) in atopic dermatitis. [5]

In 2019, Bissonnette et al. did an intrapatient double-blind randomised controlled trial to compare the effect of crisaborole in improving the cutaneous biomarkers of inflammation versus vehicle alone. They found that crisaborole reversed the biomarker profiles of barrier function and cutaneous inflammation (epidermal hyperplasia, TH2 and TH17/TH22 cytokines), along with improvements in the measures of clinical efficacy. [6]

In 2019, Woo et al. found crisaborole was effective topical medication in mild to moderate atopic dermatitis with favourable safety profile.[7]

In 2020, Schlessinger et al. found that crisaborole was well-tolerated and efficacious topical agent for children aged 3-24 months with mild-to-moderate atopic dermatitis. Safety and efficacy were similar to that of previous studies of crisaborole in patients elder than 2 years. The minor adverse effects were application site pain and discomfort. [3]

Gap in existing research -

The
afore-mentioned studies showed crisaborole to be an effective and safe
compound in the treatment of atopic dermatitis. But, long-term use of potent
topical steroid was associated with some local and, in few cases, systemic
adverse effects. These were more common when applied to the face, groins etc[2]. So,
there is need of an equally effective topical agent with less adverse effects,
in comparison with betamethasone valerate 0.1% cream.

As the comparative studies of crisaborole and topical steroids are few, there is necessity of a randomised controlled trial to look for the efficacy and safety profile of crisaborole-tretaed patients in comparison with betamethasone so that crisaborole can replace betamethasone in future for long-term management of atopic dermatitis – not only for initial control, but also for prevention of relapse as preventive maintenance therapy.

  MATERIALS AND METHODS:

STUDY DESIGN: This will be institution-based observer-blind non-inferiority randomized controlled trial.

STUDY SETTING AND TIMELINES: The study will be conducted at Dermatology Outdoor of Bankura Sammilani Medical College & Hospital, a tertiary care hospital in Eastern India.

 TIMELINE

Timeline

Development of Case record form (CRF)  and questionnaires and validating the questionnaires in local language

Recruitment of patients, drug administration, follow up and data collection

Data entry, analysis, report writing and submission

|December 2023-March 2024

    |April 2024 – March 2025

    |April 2025-May 2025

PLACE OF STUDY: The study will be conducted at Dermatology outpatient department of Bankura Sammilani Medical College &Hospital.

PERIOD OF STUDY: December 2023 to May 2025 (duration - 18 months) after obtaining Institutional Ethics Committee permission.

STUDY POPULATION: All the atopic dermatitis patients (with age >5 years)diagnosed by Hanifin and Rajka criteria attending Dermatology outpatient department of Bankura Sammilani Medical College & Hospital.

SAMPLE SIZE/DESIGN:

The calculated sample size is 33 per group considering the percentage success in control group (Ï€s) (betamethasone) (27.84%)[5] and the experimental group (Ï€e) (crisaborole) (47.1%)[4] with 5% significance level, 80% power, non-inferiority limit (d) of 10%. Considering 10% drop out the target sample size is 37 in each group which translates to 74 total study participants.

 The sample size is calculated using the formula

n = f(α, β) × [πs × (100 − πs) + πe × (100 − πe)] / (πs − πe − d)2

where, f(α, β) = [Φ-1(α)

• Φ-1(β)]2 with Φ-1 is the cumulative distribution function of a standardised normal deviate.

The sample size calculation was done online using sample size calculator available at https://www.sealedenvelope.com/power/binary-noninferior/

INCLUSION CRITERIA

·         Atopic dermatitis patients diagnosed by Hanifin and Rajka criteria.

·         Age more than 5 yrs up to 80 years.

EXCLUSION CRITERIA

·         Patients with erythroderma resulting from atopic dermatitis.

·         Those receiving any other immunosuppressives or immunomodulators.

·         Known cases of chronic liver and kidney diseases.

·         Eczema herpeticum cases

·         Patients with psychiatric disorders.

·         Participation in any clinical trial within the last 3 months.

·         Non-consenting patients or parents

RANDOMIZATION AND BLINDING:

The eligible participants, after screening, will be randomized into either group A (receiving crisaborole 2% ointment) or group B (receiving betamethasone valerate 0.1% cream) with allocation ratio 1:1 as per randomization sequence.Allocation will be concealed by SNOSE (Sequentially Numbered Opaque Sealed Envelope) technique. Card with the treatment name will be inserted in an opaque sealed envelope as per randomization and the envelope will be numbered sequentially. The treating physician will render the therapy as per the card contained in the envelope.

Randomization will be done by a computer generated random number table by balanced unstratified randomization using www.graphpad.com.

Blinding: The study will be rendered observer-blindsince the assessing physician will be different than treating physician and will be unaware of the treatment. Observer-blinding will be done to remove observer bias.

 TREATMENT GROUPS:

The eligible participants will be randomized into -

i.            Group A (receiving crisaborole 2% ointment)

ii.            Group B (receiving betamethasone valerate 0.1% cream)

 STUDY VARIABLES:

1.      Demographic profile

2.      Serial digital imaging

3.      Validated Investigator’s Global Assessment- Atopic dermatitis (vIGA-AD)

4.      SCORing Atopic Dermatitis (SCORAD)

5.      Eczema Area and Severity Index (EASI)

6.      Dermatology Life Quality Index (DLQI)

7.      Pruritus Numerical rating scale (NRS)

8.      Cost of therapy

 DATA COLLECTION AND INTERPRETATION:

This study will be conducted after getting permission from Institutional Ethics Committee. All the atopic dermatitis patients attending Dermatology OPD will be included in the study based on inclusion and exclusion criteria. Proper written informed consent from each patient or caregiver shall be obtained after explaining the study procedure in their own language.

STUDY TOOLS:

·         Clinical history

·         General survey and systemic examination

·         Case record form (CRF)

·         Adverse effect checklist.

·         Complete hemogram (Hb, TC, DC, ESR, Platelets)

·         Urea, creatinine, liver function test

·         Digital camera

·         Pencil, rubber and pen

·         SCORAD form

·         vIGA-AD form

·         EASI score form

·         DLQI form

·         Treatment medications (Moisturizers- coconut oil, crisaborole/betamethasone, cetirizine tablet/syrup)

VISITS AND FOLLOW-UPS:

Baseline (week 0):

1.      The patients will be enrolled based on inclusion and exclusion criteria.

2.      Written informed consent will be obtained from the patients or care-givers.

3.      Randomization will be done.

4.      Detailed history taking and meticulous clinical examination will be done.

5.      Laboratory parameters of routine hemogram, serum urea, creatinine and liver function tests will be done.

6.      CRF will be filled.

7.      Photograph will be taken.

8.      SCORAD, EASI and vIGA-AD forms will be filled.

9.      Pruritus score will be calculated.

10.  DLQI will be calculated.

11.  Topical crisaborole or betamethasone will be provided as per randomization.

12.  Tablet or syrup cetirizine will be added (dose according to age).

13.  The patients will be advised to apply moisturizers and come after 2 weeks.

 1st follow-up (2 weeks):

1.      Photograph will be taken.

2.      CRF will be filled.

3.      SCORAD, EASI and ISGA forms will be filled.

4.      Pruritus score will be calculated.

5.      DLQI will be calculated.

6.      Any adverse events noted.

7.      Treatment modality will be replaced or adjunctive treatments will be given to patients with relapse or not controlled despite the afore-mentioned treatment regimen.

8.      Topical crisaborole or betamethasone will be provided as per randomization.

9.      Tablet or syrup cetirizine will be added (dose according to age).

10.  The patients will be advised to apply moisturizers and come after 2 weeks.

 2nd follow-up (4 weeks):

1.      Photograph will be taken.

2.      CRF will be filled.

3.      SCORAD, EASI and vIGA-AD forms will be filled.

4.      Pruritus score will be calculated.

5.      DLQI will be calculated.

6.      Any adverse events noted.

7.      Treatment modality will be replaced or adjunctive treatments will be given to patients with relapse or not controlled despite the afore-mentioned treatment regimen.

8.      Patients will be advised to apply either topical crisaborole or betamethasone twice weekly (Saturday, Sunday) as maintenance therapy.

9.      The patients will be advised to apply moisturizers and come after 4 weeks.

 3rd follow-up (8 weeks)/End of visit:

1.      Photograph will be taken.

2.      CRF will be filled.

3.      SCORAD, EASI and vIGA-AD forms will be calculated.

4.      Pruritus score will be calculated.

5.      DLQI will be calculated.

6.      Any adverse events noted.

7.      The patients will be advised based on the clinical outcome after maintenance therapy.

 The SCORAD, EASI, DLQI and vIGA-AD forms are attached below -

 

 TREATMENT PROCEDURES:All the eligible patients of atopic dermatitis will be randomized into 2 groups based on inclusion and exclusion criteria. History taking and objective examination will be done, and photograph of skin lesion of the patient will be taken for future comparison with next follow up. Routine hemogram, serum urea, creatinine and liver function tests will be done. CRF will be filled up and SCORAD, EASI, ISGA, DLQI, pruritus numerical rating scale will be calculated according to history and examination findings. Patients or their caregivers will be advised to apply crisaborole 2% ointment or betamethasone valerate 0.1% cream twice daily and coconut oil as moisturizer. Tablet or syrup cetirizine will be added (dose according to age) for symptomatic relief of pruritus.

During every follow up patients will be examined for any adverse effect and looked for any improvement or worsening. CRF will be filled up and SCORAD, EASI, ISGA, DLQI, pruritus numerical rating scale will be calculated at 1st, 2nd and 3rd follow-ups and compared to baseline. The active treatment will be continued up to 2nd follow-up. Treatment modality will be replaced or adjunctive treatments will be given to patients with relapse or not controlled despite the afore-mentioned treatment regimen. Patient will be advised to continue coconut oil as moisturizer up to the last visit. After 2nd follow-up, patients will be advised to apply either topical crisaborole or betamethasone twice weekly (Saturday, Sunday) as proactive maintenance therapy for further 4 weeks. Patient may be given symptomatic treatment according to any adverse effect.

 EFFECTIVENESS PARAMETERS:

The primary effectiveness parameter is the improvement in SCORAD, EASI, ISGA, DLQI and pruritus numerical rating scale.

SAFETY PARAMETERS:

Vital signs, spontaneously reported adverse events and those elicited by the clinician will be assessed at each follow-up. Changes in laboratory values of routine hemogram, serum urea, creatinine and liver function tests will be recorded at baseline and 3rd follow-up.

 QUALITY OF LIFE PARAMETERS:

Quality of life in patients with trophic ulcer due to leprosy will be assessed by a validated vernacular (Bengali) version of Dermatology Life Quality Index (DLQI)[http://www.dermatology.org.uk/downloads/DLQI_Bengali.pdf], which consists of 10 questions, each scored between 0 and 3.

 STATISTICAL ANALYSIS:

All the data will be put into Microsoft office Excel sheet and analyzed accordingly by using appropriate statistical software (med calc @ version of Ostend, Belgium).

OUTCOME DEFINITION:

This study is conducted as non-inferiority trial design with the research hypothesis of "effectiveness and safety of crisaborole 2% ointment is not inferior to betamethasone valerate 0.1% cream in treatment of atopic dermatitis measured in terms of scoring indices (SCORAD, ISGA, EASI, DLQI, pruritus NRS) studied over a period of 8 weeks". Those achieving ISGA score 0 or 1 will be considered as successfully treated. The adverse events and cost of therapy will also be evaluated and compared between the two arms.

ETHICAL CLEARANCE:

This study will be conducted after getting due permission from Institutional Ethics Committee. Proper written informed consent from each patient or their caregiver will be obtained after explaining the study procedure in their own language. The sample consent form in English, Hindi and Bengali are given below.

WORK PLAN (ACTIVITY SCHEDULE OF RESEARCH WORK)

1.      Preparation of research proposal-title & synopsis of research.

2.      Literature review to aid in devising the aims and objectives of the study.

3.      Formulation of statistical analysis plan and study sample & design education.

4.      Obtaining ethical & other necessary clearances from requisite authorities.

5.      Preparation of patient information and consent forms.

6.      Starting the data collection once the research proposal is approved.

7.      Completing the data collection and analysis within the stipulated time frame of 12 months after approval of research proposal by the IEC.

8.      Reporting and managing any adverse events during the period of study.

9.      After completing statistical analysis, evaluation of obtained results and observations and the significance of the studyà completing the discussion and concluding the study.

10.  Final submission of the research work within stipulated time frame to IEC and peer reviewed journal.

|REFERNCES:

1.         Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis. N Engl J Med. 2014 Jul 10;371(2):130–9.

2.         Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503.e6.

3.         Schlessinger J, Shepard JS, Gower R, Su JC, Lynde C, Cha A, et al. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1). Am J Clin Dermatol. 2020 Apr;21(2):275–84.

4.         Zane LT, Kircik L, Call R, Tschen E, Draelos ZD, Chanda S, et al. Crisaborole Topical Ointment, 2% in Patients Ages 2 to 17 Years with Atopic Dermatitis: A Phase 1b, Open‐Label, Maximal‐Use Systemic Exposure Study. Pediatr Dermatol. 2016 Jul;33(4):380–7.

5.         Lönndahl L, Holst M, Bradley M, Killasli H, Heilborn J, Hall M, et al. Substance P Antagonist Aprepitant Shows no Additive Effect Compared with Standardized Topical Treatment Alone in Patients with Atopic Dermatitis. Acta Derm Venereol. 2018;98(3):324–8.

6.         Bissonnette R, Pavel AB, Diaz A, Werth JL, Zang C, Vranic I, et al. Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial. J Allergy Clin Immunol. 2019 Nov;144(5):1274–89.

7.         Woo TE, Kuzel P. Crisaborole 2% Ointment (Eucrisa) for Atopic Dermatitis. Skin Ther Lett. 2019 Mar;24(2):4–6.