Safety and benefit of Eczefolia Supplementation as an adjunct in management of atopic dermatitis: A randomized, double-Blind, placebo-controlled Trial
ECZEFOLIA-AD TRIAL
General Information
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease affecting up to 10% of adults and 15% to 20% of children worldwide.1 About 13.4% of Malaysian children aged between one to six years old were reported to suffer from AD.2 Malaysia reported the highest prevalence of AD in Asia.3 Topical corticosteroids (TCS) and emollients are the main therapy to combat mild AD. Systemic agents and phototherapy are advocated in moderate to severe AD. Systemic treatments include corticosteroids, immunosuppressants (methotrexate, azathioprine, cyclosporine), janus kinase (JAK) inhibitors (baricitinib, upadacitinib, abrocitinib) and the biological agent dupilumab. Long-term topical and systemic corticosteroid therapy leads to various cutaneous and systemic adverse effects. Immunosuppression, risk of infection, marrow suppression, liver and renal toxicity, lung fibrosis, high lipids, increased blood pressure and high cost are some of the factors limiting systemic therapies use. Therefore, there is a high demand for safer management of AD. Inflammatory immune response mechanism is involved in the main pathogenesis of AD, it is postulated that an anti-inflammatory supplementary agent is beneficial to help in improving the signs and symptoms of AD.
A popular herb with a long history of ethnopharmacological use is Melicope ptelefolia (MP), locally known as ‘Tenggek burung’. It is often consumed as salad and used as a natural remedy for ailments such as fever, pain, stomachache, wounds, and itches. MP leaf extracts have demonstrated anti-inflammatory, analgesic, antipyretic, antioxidant and antimicrobial properties.4,5,6 Several molecular pathways have been studied as MP’s potential targets for anti-inflammatory activities: nitric oxide (NO), TNF-α, IL-6, PGE2, COX2 and nuclear factor kappa B (NF-κB).4,5 MP was reported to ameliorate NO in RAW264.7 murine macrophages.4 MP act as powerful anti-inflammatory agent by blocking the activation of NF-кB, a transcription factor that plays a central role in mediating and maintaining AD via Th1/Th2-driven skin inflammation.5,6 Extract of MP has showed significant reduction of oedema in rats compared to indomethacin.7 EczefoliaTM was formulated with MP extract, Arabic gum and β-cyclodextrin. Initial investigations on EczefoliaTM showed significant reduction in histamine levels in RBL-2H3 cells. In vivo evaluation in murine AD model revealed significant reductions of key markers including serum IgE, skin tissue IL-4, IL-13, TNF-alpha, IFN-gamma, eosinophils, mast cells, epidermal thickness, spleen size, scratching latency and dermatitis severity.8 Clinical observations and organ weight did not show any signs of toxicity. EczefoliaTM at ≤ 50 µg/mL statistically matches the effectiveness of dexamethasone. EczefoliaTM showed no significant effect on RBL-2H3 cell viability implying that the formulation is safe and non-toxic. These findings supports EczefoliaTM's potential as a supplementation to aid in improving the signs and symptoms of AD.
Hypotheses
The study hypotheses are: i. EczefoliaTM is safe with no adverse effects on peripheral blood count, renal profile and liver function as well as patient-reported symptoms and signs. ii. EczefoliaTM reduces TEWL and restores epidermal hydration. iii. EczefoliaTM improves AD, reduces skin itchiness and improves overall quality of life.
Objectives
The primary objective of the study is to determine the safety and benefits of EczefoliaTM supplementation in patients with moderate to severe AD.
The secondary objectives are i. to determine the effect of EczefoliaTM on peripheral blood count, renal profile, liver function and patient-reported symptoms and signs. ii. to determine the effects of EczefoliaTM on parameters of skin barrier function. iii. to determine the effect of EczefoliaTM on AD severity.
Methodology
Study design: A randomized, double-blind, placebo-controlled clinical trial. The first 6 weeks of the study is a RCT where patients with receive EczefoliaTM or placebo, following that all patients will receive Eczefolia for 6 weeks in an open label phase.
Study dite: Dermatology Clinic, Department of Medicine, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia (HCTM).
Study population: Adult patients diagnosed with AD attending Dermatology Clinic, Hospital Canselor Tuanku Muhriz during the study period.
Study duration: Patient recruitment is expected to commence on 11 September 2024 and data collection completed by 10 May 2025.
Ethical consideration: The study will be conducted in accordance with Good Clinical Practices and the Declaration of Helsinki (WMA, 2008). The study has received approval from Research Ethics Committee University Kebangsaan Malaysia, reference number JEP-2024-528. Written informed consent is obtained from the patients before recruitment.
Randomization and double blinding: Subjects will be randomly assigned in a ratio of 1:1 to receive EczefoliaTM or placebo. Randomisation will be conducted using Stat Trek random number generator software (http://www.stattrek.com). The capsules and packaging of EczefoliaTM and placebo hydrogels will be similar in appearance and labelled with a unique identification code. Both investigators and patients are blinded and the code will only be revealed at the end of the study.
Study intervention:
Subjects will be randomised into two groups:
i. Group 1 will receive 1 capsule of 200mg/day EczefoliaTM
ii. Group 2 will receive 1 capsule of placebo
Patients will be on EczefoliaTM or placebo for 6 weeks. After 6 weeks, all patients will enter an open-label phase and receive EczefoliaTM for another 6 weeks. Compliance will be determined by counting remaining capsules at each visit. Subjects will continue their standard AD therapy for the 3-month duration of the study. Change in standard AD therapy is not allowed during the study.
Assessments: will be performed at baseline, week 6 and week 12. These are blood for serum IgE, renal profile, liver function, full blood count and urinalysis. Skin measurements are TEWL and hydration. AD severity is determined by EASI, SCORAD, VAS for itch and DLQI questionnaire for quality of life.
Investigational product(s):
Eczefolia™ is a product derived from Tenggek burung extract that has undergone meticulous manufacturing process. The raw materials are subjected to organic solvent ultrasonic-assisted extraction, followed by filtration and concentration to remove solid particles and excess solvent. The filtered extract is then enriched with microporous resin and spray-dried with white dextrin to form a brownish powder. The final product, Eczefolia™ undergoes rigorous quality control analysis to ensure compliance with required standards. For the placebo, arabic gum and beta-cyclodextrin powder are microencapsulated and spray-dried into powder form. Both ingredients for the placebo are safe for consumption with no significant toxicity to humans reported.8,9 All equipments, machinery and both investigational products are food grade and halal. The equipments and machinery are primarily made of stainless steel, ensuring the safety and quality of the product.
Primary endpoint:
i. 50% reduction in AD severity at week 6. ii. No serious adverse events throughout the study. Serious adverse events are those that would require discontinuation of the investigational product e.g liver or kidney impairment, bone marrow suppression and infections.
Secondary end point: improvement in serum IgE, skin hydration, TEWL, itch score and quality of life at week 12
Safety and adverse events: Unblinding is allowed in events concerning patient safety. All adverse event or intercurrent illnesses will be reported and documented. Patients who developed adverse effect would be followed up until the symptoms resolved or to a certain duration. Referral to specialties is considered depending on the severity of adverse events.
Subject withdrawal and dropout:
Subjects will be withdrawn from the study in the event of:
i. Consent is withdrawn by the patient
ii. Patients develop moderate to severe side effect to the study intervention.
iii. Patients who developed moderate or severe Ad flare.
iv. Patients who developed severe infections.
Rescue therapy: Patients with moderate or severe flare of AD during the study will be treated according to standard clinical management and discontinued from the study.
Discontinuation criteria:
i. moderate or severe flare of AD
ii. deranged FBC, RP or LFT or abnormal urinalysis at any point during the study.
iii. allergic reactions to the investigational products.
iv. other adverse signs and symptoms which may be attributed to the investigational products; at the discretion of the investigator.
The sample size is calculated based on an estimate of 56% improvement of AD symptoms after Lactobacillus probiotic supplementation versus 15% improvement with placebo.10 With consideration of a 20% drop out, the total number of subjects required is50 (25 subjects for each arm). The calculation was based a formula from https://clincalc.com/stats/samplesize.aspx website.
References
1. Schuler et al. Novel insights into atopic dermatitis. The Journal of allergy and clinical immunology. 2023;151(5):1145-1154.
2. Goh YY et al. Prevalence of Atopic Dermatitis and Pattern of Drug Therapy in Malaysian Children. Dermatitis : contact, atopic, occupational, drug. 2018;29(3):151-161.
3. Langan S et al. Trends in eczema prevalence in children and adolescents: A Global Asthma Network Phase I Study. Clinical & Experimental Allergy. 2023;53.
4. Yao Q et al. The phytochemistry, pharmacology and applications of Melicope pteleifolia: A review. Journal of Ethnopharmacology. 2020;251:112546.
5. Johnson AJ et al. Antipyretic, analgesic, anti-inflammatory and antioxidant activities of two major chromenes from Melicope pteleifolia. J Ethnopharmacol. 2010;130(2):267-71.
6. Dajee M et al. Blockade of Experimental Atopic Dermatitis via Topical NF-κB Decoy Oligonucleotide. Journal of Investigative Dermatology. 2006;126(8):1792-1803.
7. Mahadi M et al. The potential effects of Melicope ptelefolia root extract as an anti-nociceptive and anti-inflammatory on animal models. Bulletin of Faculty of Pharmacy, Cairo University. 2016;54(2):237-241.
8. Gonzalez Pereira A et al. Main Applications of Cyclodextrins in the Food Industry as the Compounds of Choice to Form Host-Guest Complexes. International journal of molecular sciences. 2021;22(3).
9. Anderson DM. Evidence for the safety of gum arabic (Acacia senegal (L.) Willd.) as a food additive--a brief review. Food additives and contaminants. 1986;3(3):225-230.
10. Rosenfeldt V et al. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. The Journal of allergy and clinical immunology. 2003;111(2):389-395.
Study Information
Inclusion & Exclusion Criteria
Study Timeline