Effectiveness and safety of addition binahong extract 2.5% on saline nasal irrigation for allergic rhinitis patients: protocol for randomized controlled trial investigator-blinded

Introduction

Background

Allergic rhinitis (AR) is a chronic inflammation of the nasal mucosa. Inhaled allergens cause AR through an immunoglobulin E (IgE)-mediated hypersensitivity response (1). Experts consider the pathophysiology process of AR complex. It is associated with genetic and environmental factors in etiology (2). In atopic individuals, re-exposure to allergens activates mucosal mast cells. They release arachidonic acid metabolites, histamine, and other vasoactive and inflammatory mediators. This causes AR symptoms, include an itchy nose, sneezing, nasal congestion, eye symptoms, and rhinorrhea (3). The global AR and its Impact on Asthma (ARIA) guideline developed clinical practice guidelines for AR management. The guidelines involve diagnosis, allergen avoidance, pharmacotherapy, biologic, probiotic, and immunotherapy (4). Evaluating quality of life, organ function, and exacerbation forms the basis for management guidelines for allergic diseases. They also consider the need for rescue medicine. They also reinforce the importance of achieving disease control and reducing future risk (5).

It is not possible to avoid inhalant allergens that trigger AR symptoms. Up to 20% of AR patients may still have symptoms despite using many therapies (6). For long-term usage, intranasal application therapies offer many advantages over oral therapy. A large nasal mucosa surface delivers greater drug concentration to the inflammation site. This avoids first-pass metabolism and reduces systemic side effects (7).

There is a need to look for safer and more effective treatments. Many available treatments still have side effects. In the last decade, medicinal plants have become more popular. This is due to their natural origin, low price, and fewer side effects. Researchers agree that quercetin is a plant metabolite. Some fruits and vegetables that contain quercetin (3,31,41,5,7-pentahydroxyflavone), a naturally occurring polyphenolic flavonoid, include capers, tea, onions, berries, apples, Brassica vegetables, grapes, tomatoes, onions, and also various types of grains, nuts, bark, leaves, and flowers. Previous studies reported that plant metabolites can reduce the production and expression of inflammatory mediators and their receptors. Some of these metabolites can also inhibit the expression of transcription factors that promote mediator secretion (8). Before, people have used medicinal plants as traditional medicine to relieve AR symptoms. There are several potential herbal medicines to treat AR in the world to date. But, their mechanisms of action, such as anti-allergic, immunological, and anti-inflammatory effects, still need scientific proof (9,10). Previous reports suggest that plant samples can suppress the production of eosinophils, IgE, and cytokines. They can also inhibit the release of histamine. These medicinal plants may provide lead molecules for developing therapeutic agents. This is attractive for treating AR (10).

Rationale and knowledge gap

Epithelial cells form the first physiological barrier against the infiltration of allergens. The epithelial barrier’s impaired tight junction (TJ) structures might play a role in starting or worsening allergic diseases. This could happen by increasing antigen passage. It would expose underlying tissue to these stimuli. Protease-containing allergens and environmental pollutants enhance paracellular transport in epithelial cells. They do this by disrupting the function of the epithelial barrier (11). This proves that disrupting TJ will increase allergen delivery to the subepithelium. It will cause allergic diseases (12). Nasal washing is a simple, inexpensive procedure. It involves flushing the nasal cavity with saline solution. This moisturizes the mucosa, improves mucociliary clearance, and removes encrusted material (13).

Mast cells are effector cells of the innate immune system. They play an essential role in innate immunity and also modulate adaptive immunity. This makes them an essential cell in inflammation in allergies and allergic diseases. Mast cells are generally located on body surfaces exposed to the external environment. For example, the nasal mucosa contains them. This is why mast cells are the first line of defence. They protect against inhaled substances, such as allergens (14). The nasal mucociliary clearance system is one of the most essential nonspecific defense mechanisms in the nasal mucosa. This system consists of mucus from goblet cells and epithelial cilia. Under normal conditions, epithelial cilia pulsate in a unidirectional and coordinated manner. They aim to transport mucus through the epithelium to various drainage sites. This removes inhaled particles and irritants from the airway. It is essential to assess the positive effects and safety of additives and intranasal drugs on mucociliary function (15).

Herbal medicines have become a new trend in Indonesia lately, one of which is binahong leaves. The binahong plant [Anredera cordifolia (Tenore) Steen] contains ascorbic acid, protein, oleanolic acid, flavonoid triterpenoid saponins, and antimicrobials (16). Based on recent research, flavonoids have the potential to regulate or inhibit inflammation. Flavonoids have anti-oxidative, anti-inflammatory, and immune-modulatory properties. These properties make flavonoids invaluable for medicine, pharmaceuticals, and nutraceuticals. Flavonoids have the potential to be antiallergic. They interfere with T helper cell activation. This is a significant mechanism in inhibiting allergic responses. Flavonoids can also reduce allergic exposure. They suppress IgE and IgG1 levels. Flavonoids also drop Th-2 cytokines and inhibit peripheral basophil cell adhesion (17).

Objective

The content in binahong is also shown to have anti-fever, anti-parasitic effects and anti-inflammatory (18). This can be an alternative treatment, as nasal saline irrigation only has cleaning effect but does not have anti-inflammatory content. Nevertheless, no clinical trial have evaluated the effectiveness and safety of binahong extract 2.5% as nasal irrigation for adults with AR, and we also need the evidence of binahong extract 2.5% anti-allergic mechanism in modulation of mediator inflammation biomarker. Thus we designed a prospective open label, parallel randomized controlled trial to confirm the hypothesis. We present this article in accordance with the SPIRIT reporting checklist (available at https://jxym.amegroups.com/article/view/10.21037/jxym-23-33/rc) (19).

Methods

Study design and setting

We registered the study at clinicaltrials.gov (unique identifier: NCT05960526) in July 2023. This is a single-blind, parallel randomized controlled trial. In total of 80 participants will be recruited from otorhinolaryngology clinic PKU Muhammadiyah Gamping Hospital Yogyakarta Indonesia. The flow chart and study period are shown in Figure 1 and Table 1 respectively. After obtaining written informed consent, eligible participants will be randomly assigned to a binahong extract 2.5% nasal irrigation group or control saline nasal irrigation group in a 1:1 ratio. Patients in the intervention group were instructed to carry out intranasal irrigation 2 times daily using the solution from 1 sachet of NaCl 0.9% powder and binahong extract solution 2.5% added with drinking water until 300 mL, administered using bottled water pulse (150 mL each nostril).

Figure 1 Trial flowchart (primary data).

Ethics

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study protocol has been approved by Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, Indonesia number: KE/FK/0419/EC/2023. The protocol will be explicitly explained to all participants orally and using flyer that the trial involves two groups of intervention or control according to randomization, with 2 weeks period treatment and 4 weeks follow-up. All participants will be given sufficient time to decide whether to sign the informed consent form. Written informed consent must be obtained from each participant before they are randomized to a group. If any modification of the protocol which impact on the study, patient benefit or safety, changes of intervention, population, study procedures and significant administrative will applay a formal amendment to Ethics Committee/institutional review board.

Participant recruitment

Participants will be recruited via a local advertisement, social media open recruitment and doctor referral from otorhinolaryngology clinic at PKU Muhammadiyah Gamping Hospital Yogyakarta Indonesia. Information about the study will be carefully explained before enrollment. Participants must meet the diagnostic criteria of AR, have of a personal or family history of allergy, have score screening using Score Allergic for Allergic Rhinitis (SFAR) 7 or more. From physical examination is pale gray, pale blue, nasal turbinate congested and water discharge, and immunological test using skin prick test result at least one positive for inhalant allergen.

Inclusion criteria

• Eligibility criteria according to ARIA the diagnostic criteria of AR from history, physical examination and immunological test.
• Age 18 to 65 years old, with no gender limitation.
• Agree to participate in the research by written informed consent.

Exclusion criteria

• Pregnant or breastfeeding women.
• Active smoker.
• Local AR.
• Patients with autoimmune diseases.
• Chronic rhinosinusitis with or without nasal polyps.

Randomization

Randomization will be performed by third-party using computer-generated random number, the randomization number will fill in sequentially numbered, opaque sealed envelopes (SNOSE). Envelopes are opened sequentially by research assistant only after the participant given written informed consent.

Blinding

Research assistants and participants were aware of the groupings in this study due to the different nasal irrigation solutions used. The laboratory team or researchers were not informed of the study grouping. Research assistants and participants will be instructed to refrain from communicating group allocation to researchers.

Intervention

During the 2-week treatment period, participant performed nasal irrigation using 300 mL solution in WaterPulse nasal bottle wash YT-300 device, for both nasal cavity twice daily. Isotonic saline solution for control group was prepared by adding 1 sachet of ENT Clear powder into 300 mL boiled water, and for intervention group the solution was prepared by adding 1 sachet of ENT Clear powder and binahong extract 2.5% into 300 mL boiled water. The standard procedure of instilling nasal irrigation was demonstrated to each participant and the same process was repeated by participant in front of researcher to confirm uniformity in technique of nasal administration.

Concomitant treatment

There will be no others treatment for participants, but if during intervention participant take any medicine will be report in evaluation.

Outcome measures

The primary outcome is a change in the messenger RNA (mRNA) expression of mediator inflammation, the secondary outcomes indicators are change of symptoms (SNOT-22 score), quality of life [mini Rhinoconjunctivitis Quality of Life Questionnaire (mini-RQLQ)] and nasal physiology [mucociliary transport time (MCT), nasal patency].

Adverse events and termination of trial

We will record all adverse reactions for safety reasons related to the study treatment with a detailed description. The researcher will provide phone numbers and advice to all participants. This is for participants to consult in case of adverse reactions, whether related to the study treatment or not. The researcher will decide to discontinue the study when >25% of participants discontinue the intervention due to adverse reactions.

Data collection and management

We will collect some demographic information about participants, such as height, weight, age, blood pressure, previous medical history, and ENT examination at the time of enrollment. Participan fullfill evaluation of symptoms and quality of life using SNOT-22 and mini-RQLQ, investigator examine of nasal physiology using PNIF and mucociliary clearence time and nasal brush for mRNA expression of interleukin (IL)-4, IL-6, IL-13, and tumor necrosis factor (TNF)-α for baseline data. After 2 weeks of nasal irrigation treatment with daily reminder, participants invited for the same evaluation. Case report form will be used to record all participant data, and also enter the data into electronic database. All data will be kept in a locker cabinet by password for secure and control access and will be maintained in storage for a period of 3 years after completion of the study. The biologic speciments from nasal scraping will be storage in Molecular Medicine and Therapy Reseach Laboratory Universitas Muhammadiyah Yogyakarta.

Sample size calculation

This study aims to investigate the effectiveness of combining 2.5% binahong extract and saline nasal irrigation for AR patients. We determined the sample size by using a superiority test to compare two means. A prior study provided the basis for this. We proposed that the treatment group would exhibit a mean value of 150±1.60 for the IL-4 levels, while the control group would demonstrate a mean value of 6.64±3.06. To achieve a significance level of 5% and a power of 90%, a sample size of 70 participants is necessary. To ensure a potential dropout rate of 10%, we need 80 participants. The participants should be evenly distributed, with 40 individuals assigned to each group.

Statistical analysis

Qualified statisticians conducted data analysis. Also, we conducted data analysis by the intention-to-treat principle. We replaced missing data with the median or mean of the items. We used this data to fill in for a homogeneous population of participants. We used descriptive statistics to summarize the characteristics of the subjects. The presenter presented the numerical data. It represented the mean (standard deviation) of the normally distributed data. We used the median for non-normally distributed data. We presented categorical data as frequency (%). We measured the mean differences before and after the treatment for each group using a t-test. The level of significance was set at 0.05. We used an independent t-test to measure the improvement difference for each group. Adding a 2.5% binahong extract solution was more effective than using only nasal saline solution.

Trial status

The trial began recruitment in March 2023, and the last participant is expected to be included in December 2024. Currently, this trial is in the process of recruiting participants.

Discussion

Several previous studies have concluded that nasal irrigation reduces patient-reported illness severity scores in children and promotes improvement in nasal symptoms, adults and children with no reported side effects (20,21). The various mechanisms of nasal irrigation were: (I) decreasing inflammatory mediators, (II) clearing inspissated mucus and exogenous inflammatory triggers, (III) increasing mucociliary function, and (IV) decreasing mucosal edema (22). It is used alone in association with other therapies in several diseases related to upper respiratory tract including AR and post-operative nasal surgery (23).

The composition of the solution that have been studied for nasal washing in some clinical studies were various tonicities of sodium chloride (NaCl), strerile seawater, steroid active substances, hypochlorous acid, sodium hyaluronate, surfactants and lycorice. Hypochlorous acid has antipruritic, anti-inflammatory and antimicrobial properties that are safe without toxic effects (24). Sodium hyaluronate is an extracellular matrix that impprove mucociliary clearance through epithelial repair with mechanisme of wound repair and mucosal surface repair (25).

Isotonic saline irrigation (240 mL) performed twice a day for eight weeks proved to be effective and did not cause side effects in patients with AR. Adverse effects of local mucosal irritation in the form of swelling and inflammation were associated with nasal irrigation using hypertonic saline (1 mL) three times a day for one month. In addition, during the beginning of the study, patients experienced itching and burning symptoms in the nostrils. Nasal irrigation using hypertonic saline causes the release of glandular secretions and substance P through stimulation of the nociceptive nerves. This is what eventually caused the pain in the patients (26).

In this study, it was found that many natural ingredients are helpful in accelerating the wound recovery stage, one of which is Anredera cordifolia (Ten.) Steenis or binahong. This plant has many benefits, including antipyretic, helping the wound recovery process, anti-inflammatory, blood circulation, anti-bacterial, diuretic, and hemostatic (27).

Acknowledgments

We would like to thank all respondents for their participation and compliance to the study procedures.

Funding: This research received funding from Hibah Damas grants from Universitas Gadjah Mada, Yogyakarta, Indonesia (No. 2342/UN1/FKKMK.1.3/PPKE/PT/2023). The funders had no role in the design, implementation, analyses, interpretation and publication of this study.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jxym.amegroups.com/article/view/10.21037/jxym-23-33/rc

Peer Review File: Available at https://jxym.amegroups.com/article/view/10.21037/jxym-23-33/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jxym.amegroups.com/article/view/10.21037/jxym-23-33/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study protocol has been approved by Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, Indonesia number: KE/FK/0419/EC/2023. The protocol will be explicitly explained to all participants orally and using flyer that the trial involves two groups of intervention or control according to randomization, with 2 weeks period treatment and 4 weeks follow-up. All participants will be given sufficient time to decide whether to sign the informed consent form. Written informed consent must be obtained from each participant before they are randomized to a group. If any modification of the protocol which impact on the study, patient benefit or safety, changes of intervention, population, study procedures and significant administrative will applay a formal amendment to Ethics Committee/institutional review board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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