Comparative Efficacy of Shirishavaleha and Intranasal Administration of Shadbindu Taila versus Shirishavaleha and Intranasal Administration of Normal Saline in the Management of Sleep-Disordered Breathing SDB in Children due to Adenoid Hypertrophy A two arm randomized clinical trial

TITLE OF THE STUDY:

 "Comparative Efficacy of Shirishavaleha and Intranasal administration of Shadbindu Taila versus Shirishavaleha and Intranasal administration of Normal Saline in the management of Sleep-Disordered Breathing (SDB) in Children due to Adenoid Hypertrophy: A two-arm randomized clinical trial”

RESEARCH QUESTION:

"What is the comparative efficacy of Shirishavaleha and intranasal administration of Shadbindu Taila for a period of 6 weeksversus Shirishavaleha and intranasal administration of Normal Saline in the management of Sleep-disordered breathing (SDB) in children of 3-12 years of age group due to adenoid hypertrophy?

 HYPOTHESIS:

Shirishavaleha daily in two divided doses with lukewarm water, as per the patient’s age, and intranasal administration of Shadbindu Taila dose as per age group once a dayfor a period of 6 weekswill be more effective compared to the Shirishavaleha and intranasal administration of Normal Saline with identical doses and period in the management of Sleep-Disordered Breathing (SDB) in children of 3-12 years of age group due to adenoid hypertrophy.

 NULL HYPOTHESIS (H0):

There is no difference in the efficacy between the oral administration of Shirishavaleha daily in two divided doses with lukewarm water, as per the patient’s age, and intranasal administration of Shadbindu Taila dose as per age group once a dayfor a period of 6 weeks and oral administration of Shirishavaleha and intranasal administration of Normal Saline with identical doses and period in the management of Sleep-Disordered Breathing (SDB) in children of 3-12 years of age group due to adenoid hypertrophy.

ALTERNATE HYPOTHESIS (H1):

Shirishavaleha daily in two divided doses with lukewarm water, as per the patient’s age, and intranasal administration of Shadbindu Taila dose as per age group once a dayfor a period of 6 weeks is more effective than Shirishavaleha and intranasal administration of Normal Saline with identical doses and period in the management of Sleep-Disordered Breathing (SDB) in children of 3-12 years of age group due to adenoid hypertrophy.

INTRODUCTION:

Sleep-disordered breathing (SDB) impacts at least 12% of otherwise healthy children, ranging from primary snoring to severe obstructive sleep apnea (OSA) with frequent apnea episodes and resultant hypoxia.1-2 SDB in children presents with symptoms like snoring, breathing pauses, restlessness, mouth breathing, daytime sleepiness, difficulty concentrating, and behavioral problems, varying in severity and frequency based on individual differences and underlying causes.3 This condition, if left untreated, leads to significant health issues, affecting cognitive function, behavior, and cardiovascular health.4 The American Academy of Pediatrics recommends referring children with habitual snoring and sleep difficulties for management, including polysomnography (PSG) to assess severity or specialist evaluation. Moderate to severe OSA (≥5 obstructive respiratory events per hour on PSG) typically warrants adenotonsillectomy (T&A).2

Sleep-Disordered Breathing (SDB) is increasingly being recognized as a cause of morbidity even in young children. With an estimated prevalence of 1 to 4 %.5

SDB in children can be caused by various factors, including anatomical abnormalities like adenotonsillar hypertrophy,6 obesity,7 Craniofacial Abnormalities,8 Neuromuscular disorders such as CP and Muscular dystrophy,9 Allergies and Nasal Congestion,10 Genetic Predisposition,11etc.

Adenotonsillar hypertrophy is considered to be the most important risk factor for the development of obstructive sleep apnea syndrome (OSAS) in children.12,13 Enlargement of the adenoids and tonsils frequently narrows the nasopharynx and oropharynx, respectively, leading to the partial or total obstruction of the upper airways.14

In addition to adenotonsillar hypertrophy, age, and obesity influence OSAS in children. Among children with tonsillar hypertrophy, more severe apnea was observed in preschool children than in school-age children.13 A modest association between adenotonsillar size and the apnea-hypopnea index has been reported in normal-weight children, but not in obese children.15

Gender differences exist in adolescents with males having a higher incidence than females. In pre-pubertal children, there is no significant gender difference.16  Although SDB can occur at any age, it seems to present most commonly in 2 to 5-year-olds.15-17 There appears to be some heritability as OSA runs in families. Whether this is due to genetic factors or environmental factors is unclear, but both are likely contributors. Medical conditions which increase the risk of developing SDB compared to the general population include overweight (including Prader-Willi syndrome), syndromes with midface hypoplasia (e.g., Pierre Robin sequence, Treacher Collins, Crouzon syndrome), large tongue (e.g., Trisomy 21, Beckwith Wiedeman syndrome) and neuromuscular disorders (e.g., cerebral palsy and myotonic dystrophy).18 Children with gastroesophageal reflux (GER) are also at increased risk of developing SDB due to airway edema causing narrowing. Vice versa, SDB can precipitate or worsen GER due to increased negative intrathoracic pressures.

Common treatments of SDB include adenotonsillectomy for enlarged tonsils/adenoids, CPAP therapy for moderate to severe OSA, and mandibular advancement devices or oral appliances for mild OSA or CPAP-intolerant cases. Additional interventions like weight management, nasal corticosteroids, and orthodontic treatments may also be utilized. However, these treatments come with potential complications such as pain, bleeding, skin irritation, dental changes, and growth suppression with corticosteroids.19

In many countries, Polysomnography (PSG) availability is limited and not used for the majority of children undergoing adenotonsillectomy (T&A);20,21 the decision to proceed with surgery is made on history and examination alone in 90% of children.22  Additionally, T&A is painful, costly, and carries a risk of mortality and postoperative morbidity (hemorrhage and respiratory compromise).23 Given the high numbers of children with SDB and the uncertainty of benefit from T&A for those who do not have OSA, alternatives to surgery are needed.

Sleep-disordered breathing (SDB) in children, including conditions like obstructive sleep apnea (OSA), can significantly impact their health and quality of life. Traditional treatments often involve surgery or continuous positive airway pressure (CPAP) therapy, which may not always be feasible or suitable.  Shirishavaleha and Intranasal Shadbindu Taila, an Ayurvedic formulation, has been proposed as a potential alternative treatment for SDB in children. ICD-11 Code: 7A4Z Sleep-related breathing disorders, unspecified.

NEED OF THE STUDY: To find safe and effective treatment for Sleep-Disordered Breathing in children, especially those caused by adenoid hypertrophy. SDB can lead to various health conditions, including poor sleep quality, mental and behavioral problems, and even cardiovascular problems. Adenoid hypertrophy is a common cause of SDB in children, and surgical treatments like adenoidectomy (surgical removal of adenoids) may not always be preferred due to concerns about potential risk and side effects. Therefore, exploring alternative treatments, such as herbal formulations like Shirishavaleha and intranasal oils like Shadbindu Taila, can provide non-invasive options that may help to manage the symptoms of SDB effectively.

The trial drug is based on Shirisharishta of Bhaishajya Ratnavali.25 Taking the difficult palatability of Shirisharishta into consideration formulation to be converted into Shirishavaleha.26The trial drug Shirishavleha is selected to provide an effective form of therapy with a good palatability and acceptability by children of every age group. Shirish (Albezzia lebbeck Benth.) is principal ingredient of the formulation which is described as-“Vish-ghan” i.e. removes toxins. According to Ayurveda, the poisonous substances interfere with our immune system and27Albizzia species is known to have diverse pharmaceutical action including anti-inflammatory, and analgesic activity.28 REVIEW OF LITERATURE**:**

The term breathing-related sleep disorder refers to a spectrum of breathing anomalies ranging from chronic or habitual snoring to upper airway resistance syndrome (UARS) to frank obstructive sleep apnea (OSA) or, in some cases, obesity hypoventilation syndrome (OHS). The American Academy of Sleep Medicine (AASM) identifies several types and subtypes of sleep-related breathing disorders.29 Primary snoring:   Known as simple snoring, this is the mildest form of SDB. Although known as habitual, it is defined as snoring more than 3 nights per week without evidence of hypoxia, hypercarbia or arousability.30-31 Upper airway respiratory resistance syndrome:      Defined as snoring with increased effort needed to breathe during sleep and frequent arousals, without encountered obstructive events nor abnormal change in blood gas. Obstructive hypoventilation (HV):   Defined as snoring plus elevated end-expiratory carbon dioxide partial pressure in the absence of recognizable obstructive events.30-31 Obstructive sleep apnea syndrome:  Defined as a disorder of breathing during sleep characterized by intermittent complete obstructive or prolonged partial upper airway obstruction and/or apnea that distort ventilation while in a sleep further disturb normal sleep patterns. Classification based on PSG results as proposed by Dayyat et al7 stated that it is essential to differentiate OSA from other disorders as the treatment and complications are different.

CLASSICAL REVIEW:

Shadbindu Taila:

एरण्डमूलं तगरं शताह्वाजीवन्ति रास्ना सह सैन्धवञ्च ।

भृङ्गविडङ्गमधुयष्टिका च विश्वौषधं कृष्णतिलस्य तैलम् ॥

आजं पयस्तैलविमिश्रितञ्च चतुर्गुणे भृङ्गरसे विपक्वम्।

षडबिन्दवो नासिकयोर्निधेया निहन्ति शीघ्रं शिरसो विकारान् ॥

च्युतांश्च केशांश्चलितांश्च दन्तान् दुर्बद्धमूलांश्च दृढीकरोति ।

सुवर्णदृष्टिप्रतिमञ्च चक्षुर्बाह्वोर्बलञ्चाप्यधिकं ददाति ॥ (भैषज्यरत्नावली, शिरोगाधिकार, ६५/८१-८३)33

 Shadbindu Taila is a herbo-mineral formulation described in Shiro Roga Chikitsa Prakaranam 65/81-83 of Bhaishajya Ratnavali and indicated in various clinical conditions, especially in Urdhvajatrugata Vikara i.e. supraclavicular disease condition, it is directed to be used as Nasya.32

The majority of ingredients of Shadbindu Taila possess Vatahara and Vedanasthapaka Karma. Shadbindu Taila containing Ajadugda, Bhringaraja, and Tila Taila is a classical recipe mentioned for Nasya in all Shirorogas. Kshira (Milk) possesses good Rasayana and Vatashamak action Bhringaraja is VataKaphashamaka, Vedana Sthapaka, and Vatahara. Most of the Kalka dravyas in the formulation exhibit Vatahara and Vedanasthapaka action.33 In Agraya Sangraha, Taila is mentioned as best Vatahara.Presence of Saindhava makes itTeekshna as well and probably due to above mentioned Vatakapha Shamaka properties and Teekshna Guna, the dose of Shadbindu Taila is mentioned only 6 bindu as per classics, and hence the name Shadbindu Taila.33

SHIRISHAVALEHA :

Acharya Charaka has mentioned Shirish in Charaka Samhita Sutrasthana 25th chapter as a Vishaghna Dravya in Agreya prakaran. In Shusrut samhita Acharya has been described Shirish in Salsaradi gana. Shirish (Albizzia lebbeck Benth) has found its place in all the important Nighantuswith a variety of synonyms and Guna-karmas. The present review on Shirish of different Nighantus can be useful to know about the different formulations of Shirish in which different parts of this plant are used. Most of the Nighantus have mentioned Shirish has good Vishaghna, Kushthagna, Pramehaghna Kasahara, Svasaharaproperties. A detailed clinical study is required to understand the mode of action of these drugs and their  efficacy. Shirisharishta is a well-known ayurvedic fermented formulation of Albizzia lebbeck Benth. It is described in Bhaishjaya ratnavali (72/72-74)34. Shirisharishta has few disadvantages, such as complicated and time consuming preparation procedure, poor palatability and acceptability at all age group. So the Avaleha form of the same using the bark will be prepared. The useful part advocated for Shirisha in classics is Sara (heartwood). One has to destruct the whole plant to collect required amount of Sara. Previous study suggested that Shirishavaleha prepared either with bark or heartwood                            can be used in the therapeutic management which is safe and free from adverse drug reactions so the part bark will be taken in this study35. These were evaluated for their anti-inflammatory activities.

AIM(S) OF RESEARCH STUDY:

To compare the efficacy of Shirishavaleha and intranasal administration of Shadbindu Taila versus Shirishavaleha and intranasal administration of Normal Saline in the management of Sleep-Disordered Breathing (SDB) due to adenoid hypertrophy in children of age group 3-12 years.OBJECTIVES OF THE RESEARCH PROJECT: PRIMARY OBJECTIVE:

 1. To determine the efficacy of 6 weeks of Shirishavalehaand intranasal administration of Shadbindu Taila versus Shirishavaleha and intranasal administration of Normal Saline in improving sleep quality in children with Sleep-Disordered Breathing (SDB) due to Adenoid Hypertrophy by using Pediatric Sleep Questionnaire- SDB Subscale. [ANNEXURE 1]

SECONDARY OBJECTIVE:

1. To determine the efficacy of 6 weeks of Shirishavaleha and intranasal administration of Shadbindu Taila versus Shirishavaleha and intranasal administration of Normal Saline in reduction of ANR (Adenoidal nasopharyngeal ratio) in children with Sleep-Disordered Breathing (SDB) due to Adenoid Hypertrophy by using Radiological Evidences. [ANNEXURE 3]

2. To assess the effect of Shirishavaleha and intranasal administration of Shadbindu Taila versus Shirishavaleha and intranasal administration of Normal Saline on the Quality of life, of the child (at 6 weeks) by using OSA-18 Quality of Life survey. [ANNEXURE 5]

 MATERIAL AND METHODS

SETTING AND LOCATION**:**The study will be run in the Outpatient Setting at the Department of Kaumarabhritya, All India Institute of Ayurveda, New Delhi.

METHOD OF DATA COLLECTION:

• The data of the selected participants (those who comply with the inclusion criteria and willing to take part in the study) will be collected.

• The selected participants will undergo the series of events which include informed

consent about the study, their demographic details and a detailed history will be taken as per

the requirements of the study.

 STUDY DESIGN: This is a Randomized, two-arm, clinical trial, examining the effectiveness of Shirishavaleha and Intranasal administration of Shadbindu Taila  There will be two treatment groups with 6 weeks of treatment.

 Table 2: STUDY DESIGN

Study Type

 Randomized Two-Arm Clinical Trial

|Purpose

 Treatment and analysis

|Masking

 Open label

|Timing

 Prospective

|End Point

 Effectiveness

|No. of groups

 Two

  |Randomization

Computer-generated randomization

|Sample size

60 (30 in each group)

|Control

Controlled

 METHODS FOR STATISTICAL ANALYSIS:

 Ã˜  The data would be presented in the form of Descriptive Statistics such as Mean ± SD, SEM or Range etc., whichever is applicable. The data would be depicted in the form of Tables, Charts, Graphs, Diagrams etc., wherever it is applicable.  Data related to all the intend to treat participants would be considered for safety related assessments and those completing the course of treatment (Per protocol) would be considered for efficacy assessment.

Ø  The data generated is subjected to normality test with Shapiro- Wilk test. If normality test is passed, parametric test would be employed otherwise non parametric test is employed.

Ø  For objective data, paired ‘t’ test will be employed to assess before and after treatment differences within the groups and unpaired ‘t’ test will be employed for assessing the differences within the groups.

Ø  For subjective data, Wilcoxon signed rank test will be employed to assess before and after treatment differences within the groups.

Ø  Mann- Whitney U test will be employed for assessing the difference between the trial and control groups.

Ø  For multiple comparisons of more than 2 sets within the same group – repeated period of ANOVA for parametric data and Friedman’s test for non-parametric data would be used.

Ø  P valve ≤ 0.05 will be considered as statistically significant.

Ø  IBM SPSS Statistics application for Windows, version 26 will be used for analysis.

Ø  Clinical effect size would also be determined using design appropriate methods.

 SAMPLE SIZE AND CALCULATION:

Ø  Group 1 Shadbindu Taila and Group 2 Normal saline and additional drug Shirishavaleha along with Shadbindu Taila that efficacy assumed to be 70%, assuming the power of the test as 80% and level of significance as 5%, two-sided test calculated sample size is 67. Assuming a 10% dropout the study should include 60 cases per group.

 Ã˜  The study initially aimed for a sample size of 67 participants in each group, but due to limitations in time and resources, only 30 patients will be included in each group.

Formula

H0 : P1 = P2 Ha : P1 ≠ P2

N = Z1-α/2 {

+Z1-β

}2

(P1-P2)2

 Where,

P = P1+P2

2

P1 : Proportion in the first group

P2 : Proportion in the second group

Α  : Significance level

1-β : Power

RANDOMIZATIONPatients satisfying eligibility criteria would be randomly assigned in a 1:1 ratio to receive either Shirishavaleha and Intranasal administration of  Shadbindu Taila or Shirishavaleha and intranasal administration of Normal Saline. Computer-generated randomization will be used for the allocation of participants in either of the two groups.

ELIGIBILITY CRITERIA Patients will be assigned to a randomized study treatment only if they meet all of the inclusion criteria and none of the exclusion criteria.

Inclusion criteria:  Each patient must meet all of the following criteria to be enrolled in this study:  1.   Children between the ages of 3 and 12 years.   2.   Has symptoms of SDB as determined by a Brouillette score ≥ -1 on screening.  3.   Radiological Evidence of Adenoidal nasopharyngeal ratio between 0.60 to 0.79 (mild to moderate).

4.   Parents/Caretaker providing consent on the participant’s behalf. Exclusion criteria:

 1.   Adenoidal Nasopharyngeal Ratio(ANR) >0.79 (severe).

2.   History of tonsillectomy and/or adenoidectomy.

3.   Prior diagnosis of craniofacial, neuromuscular, syndromic, or defined genetic disorders.

4.   History of hemorrhagic diathesis or recurrent (daily) or severe epistaxis.

5.   History of nasal surgery or trauma that has not fully healed.

6.   Active tonsillitis or nasal infection.

7.   BMI over the 97th percentile for age and gender.

8.   Snoring while awake at rest.

9.    Known hypersensitivity to the study drug or its formulation.

10.     Has used oral, intravenous or intranasal steroids, or oral montelukast in the past 6 weeks.

11.     Is known to require systemic steroids prior to the completion of the study treatment period.

12.     Had treatment with any other investigational drug within 6 months prior to randomization.

13.     Children who are unable to comply with study procedures or follow-up visits, or whose guardians are unable to provide informed consent or comply with study requirements, may be excluded.

WITHDRAWAL CRITERIA: 1.   Children/Guardian unable to continue treatment.

2.   Whenever the investigator decides it is in the subject’s best interest to be withdrawn.

3.   Noncompliance

4.   Loss of follow-up

INVESTIGATIONSRoutine examinations like CBC, ESR, and Thyroid Profile will be done before treatment to rule out any other system pathologies.

DIAGNOSTIC CRITERIA1.   Physical examination

2.   Based on Signs and Symptoms of SDB5

a.    Snoring

b.    Breathing pauses

c.    Restlessness

d.    Mouth breathing

e.    Daytime sleepiness

f.     Adenoid facies

g.    Has difficulty concentrating

h.    Behavioral problems

 3.       Brouillette score:

Symptoms of Sleep-Disordered Breathing in the preceding 02 weeks based on the Parent

I.Does your Child Snore {S}?  Brouillette et.al.46

a.            Never =0

b.            Sometimes (1-2 nights/week) = 1

c.            Often (3-5 nights/week) = 2

d.            Always (6-7 nights/week) = 3

II.Does your child have difficulty during Sleep {D}?

a.        Never =0

b.        Sometimes (1-2 nights/week) = 1

c.        Often (3-5 nights/week) = 2

d.        Always (6-7 nights/week) = 3

III.Have you seen your child stop breathing while asleep? {A}

a.        Yes = 1

b.        No = 0

Summary Score would be obtained using the Original Equation from

Summary Score = 1.42D + 1.41A + 0.71S - 3.83

Where-

D is difficulty breathing during sleep,

A is apnea observed during sleep, and S is snoring.

Values assigned to D and S were 0, never; 1, occasionally; 2, frequently; and 3, always.

Values assigned to A were 0, no; and 1, yes.

Score less than -1 demonstrates absence of Significant SDB symptoms

Score Greater than or equal to -1 will be considered for inclusion in the study.

 4.   Radiological evidence [ANNEXURE 3]

PARAMETER FOR ASSESSMENT OF STUDY OUTCOMES :

 OBJECTIVE PARAMETERS :

 1.      Pediatric Sleep Questionnaire – SDB subscale [ANNEXURE 1]

2.      GLASGOW CHILDREN’S BENEFIT INVENTORY [ANNEXURE 2]

3.      Radiological evidence [ANNEXURE 3]

4.      Actigraphy [ANNEXURE 4]

5.      OSA-18 Quality of Life Survey [ANNEXURE 5]

PLAN OF TREATMENT:

Table 4: GROUPINGPatients will be randomly allocated using computer-generated randomization into 2 groups.

Groups

Intervention

Dose

And Anupana

Route

Frequency and Aushadhasevanakaala

Duration

Post Treatment Follow-up

|A**.**

             Shirishavaleha

 As per age group

With lukewarm water

Oral

Two times/day

Pragabhakta

(Before meal)

      6 weeks

          4 weeks

|Shadbindu Taila

 As per age group

 Nasal

 Once a day

  |      B.

             Shirishavaleha

As per age group with lukewarm water

Oral

Two times/day

Pragabhakta

(Before meal)

           6 weeks

| Normal saline

 As per age group

 Nasal

 Once a day

**DRUGS AND DOSES:Interventional Drug Name: Shirishavaleha

Dose – The dose will be fixed according to Young’s formula keeping in mind the adult dose of Avaleha is 20gm which is taken from a previous study47.

Young’s formula

• adult dose X {age / (age + 12)}

 

Age (Yrs)

Avaleha average doses

|3-5

5g in two divided doses

|6-8

7.36~7g in two divided doses

|9-12

9.09~9g in two divided doses

Interventional Drug Name: Shadbindu Taila**

Age (Yrs)

Intranasal doses

|3-6

1 drop in each nostril once a day

|7-12

2 drops in each nostril once a day

Interventional Drug Name: NormalSaline**

Age (Yrs)

Intranasal doses

|3-6

1 drop in each nostril once a day

|7-12

2 drops in each nostril once a day

Shadbindu Taila is an adult formulation, justification for the usage of this in the pediatric population**:**According to classical texts, there are no contraindications for the use of Intranasal administration Shadbindu Taila in the Pediatric population.33 The dosage and frequency are adjusted according to age, ensuring it is suitable for a child’s physiology. This often involves using significantly lower doses compared to adults.

Table: 5    STUDY PROCESS

Baseline

(0 day)

1st visit

(2 weeks)

2nd visit

(4 weeks)

3rd visit

(6 weeks)

Post-treatment     follow up

After 4 Weeks

|Consent/assent

✔️

     |Physical examination

✔️

✔️

✔️

✔️

✔️

|Investigations

✔️

     |Clinical features of SDB

✔️

✔️

✔️

✔️

✔️

|Radiological evidence

✔️

  âœ”️

✔️

|OSA-18 Quality of life survey

✔️

✔️

✔️

✔️

✔️

|Glasgow children’s benefit inventory

✔️

✔️

✔️

✔️

✔️

|Actigraphy

 âœ”️

✔️

✔️

✔️

|PSQ

✔️

✔️

✔️

✔️

✔️

WASHOUT PERIOD**:**

In the case where a potential participant has had oral or IV steroids, Leukotrine inhibitors, Antihistamines prior to study, a 6 week wait will be required before enrolment in the trial (giving a 6 week washout period).

STANDARDIZATION OF DRUGS·  Authentication of raw drugs will be done taking help from Dept. of Dravyaguna, AIIA

·  Preparation of the study drugs will be done taking help from Dept. of Rasashastra & Bhaishajyakalpana as per feasibility and as per AIIA guidelines.

QUALITY CONTROL PARAMETERS OF SHADBINDU TAILA:

Ø Preliminary phytochemical tests for major secondary metabolites.48

Ø Physicochemical characterization: Refractive index, specific gravity, saponification value, Iodine value, Acid value.49

Ø Extraction of phytochemical constituents from Shadbindu Taila.

Ø TLC profile

QUALITY CONTROL PARAMETERS OF SHIRISHAVALEHA**:**

 Ã˜ Organoleptic characteristics: Colour, odour, touch and taste.

Ø Physico‑chemical analysis: Loss on drying50, pH value51, water soluble extractive52, methanol soluble extractive53, determination of sugar contents54,

Ø Qualitative test for various functional groups55,56.

Ø TLC profile

SOP for Shadbindu taila**:**

 The SOP for the preparation of Shadbindu taila involved the following steps:

Ø The preparation of Murchhit Krishna Tila taila: will follow the reference from the Ayurvedic Formulary of India57 for Murcchana of Krishna Tila Taila (KTT). The ingredients and parts used will be mentioned in Table 6.

Ø The preparation of Bhringa Rasa:  will consider fresh juice obtained from the macerated whole plant of E. alba as Bhringa Rasa.

Ø The preparation of Kalka: will involve taking each Kalka Dravya (1/64 part powder) in a vessel and mixing it, followed by adding a sufficient amount of water until a uniform paste is obtained.

Ø The preparation of Shadbindu Taila:  will involve indirectly heating Murcchana of Krishna Tila Taila (MKTT) (1 part) on a mild flame (by placing a pan between the burner and vessel to avoid direct heating) with Bhringa Rasa (4 part), Saindhava Lavana (1 part powder), and Kalka obtained from Kalka Dravya. The mixture will be stirred intermittently until it becomes slimy. The heating will be stopped, and Aja Paya (4 part) will be added. The mixture will be kept standing overnight. The next day, the heating will be continued until the mixture attains Sneha Siddhi Lakshana (completion test for chief desired characteristics) like Gandha‑Varna‑Rasotpatti (desired smell, color, and taste), Shabdahinata (no cracking sound), Phenodgama (appearance of froth), and Vartivat Kalka (rolling of paste of herbal drugs between fingers). Finally, the mixture will be filtered when hot through muslin cloth and stored in an amber-colored bottle until use.

Table 6: List of ingredients for the Murchana of Krishna Tila Taila

 

Sanskrit name

Description

Part used

Quantity

|Jala

Water

‑

10 part

|Manjishtha

Rubia cordifolia L.

Root

1/16 part

|Haritaki

Terminalia chebula Retz.

Pericarp

1/64 part

|Bibhitaki

Terminalia bellerica Roxb.

Pericarp

1/64 part

|Amalaki

Emblica officinalis Gaertn.

Pericarp

1/64 part

|Bala

Coleus vettiveroides K. C. Jacob.

Root

1/64 part

|Haridra

Curcuma longa L.

Rhizome

1/64 part

|Jaladhara     (Mushtha)

Cyperus rotundus L.

Rhizome

1/64 part

|Lodhra

Symplocos racemosa Roxb.

Stem bark

1/64 part

|Suchipushpa (Ketaki)

Pandanus odoratissimus L.

Root

1/64 part

|Vatankura (Nyagrodha)

Ficus benghalensis L.

Leaf bud

1/64 part

Table 7:   Ingredients of Shadbindu Taila:

S.No.

Plant

Botanical name

Part used

Quantity

|1.

KrishnaTila Taila

Sesamum indicum Linn.

Seed oil

1 part

|2.

Bhringaraja

Eclipta alba Hassk.

Whole plant

4 part

|3.

Aja Dugdha

Goats milk

Dugdha

1 part

|4.

Eranda

Ricinus comunis Linn.

Root

1/8 part

|5.

Tagar

Valeriana wallichi DC.

Rhizome

1/8 part

|6.

Shatava

Anethum sowa Roxb.

Fruit

1/8 part

|7.

Rasna

Alpinia galanga Swartz.

Root

1/8 part

|8.

Jivanti

Leptadenia reticulata W&A

Root

1/8 part

|9.

Saindhava

Rock salt

1/8 part

|10.

Vidanga

Embelia ribes Burm.f.

Fruit

1/8 part

|11.

Yashtimadhu

Glycyrrhiza glabra Linn.

Root

1/8 part

|12.

Shunthi

Zingiber officinalis Roscoe.

Rhizome

1/8 part

|13.

Tejpatra

Cinnamomum zeylanicum

Bark

1/8 part

SOP for Shirishavaleha:

It involves the manufacturing of Kwatha and Avaleha.

Process validation of Kwatha preparation:

The kwatha of Twak will be prepared individually, transferring 1 part of Shirisha yavakuta added into a stainless steel container with a 15 l capacity. 10 part of potable water will be added58 allowed to soak overnight. The next morning, the contents will be subjected to heat, and they will be continuously stirred throughout the process until the volume reduces to 1/4th, i.e., 3.12 l. The temperature will be maintained between 85-95°C throughout the procedure of kwathana (boiling), and it will approximately take 6.40 h to complete the process of kwatha.

 Process validation of Avaleha preparation:

Shirisha Kwatha (1 part) will be shifted into a stainless steel vessel and will be added with 4 part of Guda. The contents will be subjected to mild heat over an LPG stove until the Guda completely dissolves. The mixture will be filtered through a clean cotton cloth to separate any undissolvable material in Guda. The filtrate will be collected into another sterile vessel and subjected to heat until Avaleha Siddha Lakshanas appear. After observing the classical characters of Avaleha, heating will be stopped, and praksepa dravyas in the specified quantities will be added. The temperature will be maintained between 95-110°C during the procedure of Avaleha paka, and on average, it will take 6.45 h to complete the process.

Table 8: Ingredients of Shirishavaleha:

INGREDIENT

BOTANICAL NAME

PART

|Shirish

Albizzia lebbeck Benth.

Bark- 1 part

|Pippali

Piper longumLinn.

Fruit – 1/50 part

|Priyangu

Callicarpa macrophylla Vahl.

Flower – 1/50 part

|Kushtha

Saussurea lappa C.B.Clarke

Root– 1/50 part

|Ela

Elettaria cardemomum Maton.

Seeds– 1/50 part

|Nilini

Indigofera tinctoriaLinn.

Root– 1/50 part

|Haridra

Curcuma longaLinn.

Rhizome– 1/50 part

|Daruharidra

Berberis aristata DC.

Stem– 1/50 part

|Shunthi

Zingiber officinale Roscoe.

Rhizome– 1/50 part

|Nagakesara

Mesua ferra Linn.

Stamen– 1/50 part

|Guda

Jaggery

4 part

|Jala

Potable water

10 part

  Association of Sleep-Disordered Breathing and Adenoid hypertrophy and the usage of Shirishavaleha: The adenoid is a single mass of tissue located way in the back of the nose in the passage that connects the nasal cavity to the throat. This tissue like the tonsils in the throat helps filter out bacteria and viruses and produce antibodies to help the body fight off infections (’first line of defence)’. In most children, the adenoid enlarges normally during early childhood when most infections of the nose and throat are most common. They usually shrink as the child gets older and tend to disappear by puberty.59

An enlarged adenoid, or Adenotonsillar hypertrophy frequently narrows the nasopharynx and oropharynx, leading to the partial or total obstruction of the upper airways. Even if the enlarged adenoid is not substantial enough to physically block the back of the nose, it can obstruct airflow enough so that breathing through the nose requires an uncomfortable amount of work, and inhalation occurs instead through an open mouth. causing alterations to the auditory and orthognathic apparatus, and results in sleep disorders such as snoring and obstructive sleep apnoea resulting in daytime sleepiness, behavioral issues, and cognitive impairments,60,61-63 The enlarged adenoid can also obstruct the nasal airway enough to affect the voice without actually stopping nasal airflow altogether.

The trial drug Shirishavleha is selected to provide an effective form of therapy with a good palatability and acceptability by children of every age group. Shirish (Albezzia lebbeck Benth.) is principal ingredient of the formulation which is described as-“Vish-ghan” i.e. removes toxins. According to Ayurveda, the poisonous substances interfere with our immune system and27Albizzia species is known to have diverse pharmaceutical action including anti-inflammatory, and analgesic activity.28 Shirisha also possesses anti-allergic properties and a mast cell-stabilizing and immunomodulatory activity9.

 MANAGEMENT OF ADVERSE CASES**:**If there are any adverse effects, it will be reported to the Pharmacovigilance Cell of AIIA, New Delhi, and additional pharmacological drugs will be prescribed in consultation with contemporary medical practitioners, or other ayurvedic drugs will be administered in consultation with the experts in this field (Form attached in Annexure).

RESCUE MEDICATIONIf required, study participants will be allowed to take rescue medication under supervision. It will be recorded in the CRF, serious morbid conditions, patients will be withdrawn from the study.

**STUDY ENDPOINTS:****PRIMARY OUTCOME :**1.      Improvement in sleep quality by using Pediatric Sleep Questionnaire- SDB subscale [ANNEXURE 1] (Timeframe: 2nd weeks, 4th weeks, 6th weeks, and 10th weeks)

 **SECONDARY OUTCOME :**1.      Reduction of ANR (Adenoidal nasopharyngeal ratio) in children with Sleep-Disordered Breathing (SDB) due to Adenoid Hypertrophy by using Radiological evidence [ANNEXURE 3] (Timeframe: 6th weeks and 10th weeks).

2.      Improvement in the quality of life of the child by using OSA-18 Quality of Life Survey [ANNEXURE 5] (Timeframe: 2nd weeks, 4th weeks, 6th weeks, and 10th weeks)

STUDY FLOW CHART-

Screening of the patients will be done from AIIA KB
OPD AND IPD

 

 

Assessment will be done for the
eligibility as per inclusion criteria

  

Randomization (Computer-generated) of patients will be done into 2 groups

   

Group A

Group B

 

Shirishavaleha dose as per age
group and intranasal administration of Shadbindu Taila dose as per age group for 6 weeks once
a day.

Shirishavaleha dose as per age
group and intranasal administration of normal saline a dose as per age groupfor 6
weeks once a day.

     

Baseline evaluation & treatment (at 0 day)

  

Interventions for 6 weeks

   

After treatment (AT) evaluation (at 6 weeks)

   

Follow-up (4 weeks)

          

Data Analysis and Interpretation

    INTRANASAL ADMINISTRATION OF DRUG:

The trial drug is to be administered at home by parent/guardian, or under their supervision if patient is able to self-administer.  The first dose of medicine will be given under study doctor’s supervision to ensure the correct technique.  An instructional video showing the right procedure of the Nasal Administration of the drug will be demonstrated to them as well as will be sent by email or whatsapp. Following instruction will be intimated to Parents on first visit regarding right procedure of administration of drug:-

·        Before Nasya, mild massage (Abhyanga) should be done on scalp, forehead, face and neck for 3 to 5 minutes with Tila Taila. Mild fomentation (Svedana) given by means of rubbing of palms (Hasta Sveda on Shira, Mukha, Nasya, Manya, Griva and Kantha region excluding Netra (Eyes).64

·        Position: Patient should lie down in supine position on the table. Head (Shira) should be ‘Pralambita’ i.e. extension of the neck (head tilted little backwards). Head should not be excessively extended.

·        The nostrils should be cleaned by gentle blowing of the nose.

·        Procedure: The parent/guardian should stretch the tip of the patient’s nose with his left thumb to facilitate the administration of the Nasya medicine and with the right hand the lukewarm medicine should be administered drop by drop in both nostrils alternately, in the prescribed dose.

·        The child will then gently sniff to keep the medication in the nose, but will not sniff hard as the medicine will then be swallowed.

·        If the child sneezes straight after administration, a second dose should be given.

·        After administration of Nasya patient is again subjected to gentle and mild fomentation by means of rubbing hands on Shira, Mukha, Lalat, Nasa, Manya, Griva, and Kantha region.65 Nasal secretion with residual medicine from the nose and pharynx should expel out. The patient should remain relaxed while taking Nasya. He should avoid speech, anger, sneezing, laughing and movements of head during Nasya procedure.

·        Immediate Post-Nasya Measures (Tatkaline Paschat Karma): After administration of medication through nasal route patient should lie supine for about 2-minute time interval (asking the patient to count numbers up to 100). Swallowing of Nasya medicine should be avoided. Patient should spit out the excessive medicine which has come into the oro-pharynx.

·        Patient should stay in a closed place away from wind and cold.Laghu Ahara and lukewarm water is allowed. One should avoid dust, smoke, sunshine, hot bath, riding, anger, excess fat and liquid diet. Day sleep should be avoided. Use of cold water for any purpose like drinking and bathing should be avoided.

SELECTION OF COMPARATOR:

The trial drug is based on Shirisharishta of Bhaishajya Ratnavali.25 Taking the difficult palatability of Shirisharishta into consideration formulation to be converted into Shirishavaleha.26The trial drug Shirishavleha is selected to provide an effective form of therapy with a good palatability and acceptability by children of every age group. Shirish (Albezzia lebbeck Benth.) is principal ingredient of the formulation which is described as-“Vish-ghan” i.e. removes toxins. According to Ayurveda, poisonous substances interfere with our immune system and27Albizzia species is known to have diverse pharmaceutical action including anti-inflammatory, and analgesic activity.28Shirisha also possesses anti-allergic properties and a mast cell-stabilizing and immunomodulatory activity9. Also, previous studies showed that Shirishavleha is effective in the management of allergic rhinitis.67

A previous research study showed that the effect of Intranasal saline for 6 weeks in patients with Sleep-disordered Breathing resulted in the resolution of symptoms in approximately 40% of the participants.36

Shirishavaleha is generally well-tolerated when used in recommended doses. Traditional usage and some studies suggest it is safe for long-term use under professional supervision. Regarding the safety aspect of Intranasal Normal saline, it can cause itching and irritation as per the data collected from previous studies.36

Top of Form

TRIAL DRUG DISPENSING AND ACCOUNTABILITY

Accurate records of the receipt, dispensing, and returns of all study medication will be maintained with the Department of Kaumarabhritya. At the end of the study, there will be a final reconciliation of all study medications. Any discrepancies will be investigated, resolved and documented by the study team. Unused investigational products will be recorded in compliance with applicable regulations of AIIA, New Delhi.

DRUG COMPLIANCE RECORD

Parents/legal guardians will be asked to return all empty, partially used, and unused bottles of study medications. Compliance will be assessed by measuring the amount remaining in the bottles returned, by weight. Parent(s)/legal guardian will be asked to record the missed doses in the diary provided.  Participants will be defined as “significantly non-compliant” when they have been assessed to have missed >20% of doses.  Compliance will be recorded in the CRF.

COMPLIANCE PROTOCOL

1.   Participants will be provided with a Compliance Chart which they will be required to fill out every day.

2.   Participants will be monitored on a regular basis through call/ WhatsApp.

3.   A minimum of 80% compliance is a must to continue the study.

CONCOMITANT MEDICATION

During the study, if concomitant oral, Intranasal, or IV steroids are required, this will result in treatment discontinuation. There are no known medications with which oral administration of Shirishavaleha and Shadbindu Taila Nasya is contraindicated.

TRANSLATIONAL VALUE

Data generated from translational research can contribute to the development of clinical guidelines for the use of Shirishavaleha and Intranasal Shadbindu Taila in the management of Sleep-Disordered Breathing in children due to adenoid hypertrophy.

 PROVISION FOR CONTINUED CARE AFTER THE STUDY PERIOD

After trial, patient will be handed over to primary consultant and regular OPD medication and assessment will be followed.

STUDY MONITORING

The study will be monitored by IRB sub-committee at Department of Kaumarabhritya, All India Institute of Ayurveda, New Delhi by Guide, Co-guides, and faculties of the department.

 ETHICAL AND REGULATORY CONSIDERATIONS:

Compliance with Good Clinical Research Practice This study will be conducted in compliance with the principles of the Declaration of Helsinki, with the current Good Clinical Practice (GCP) guidelines and with other applicable regulations. The investigator will conduct the study in compliance with this protocol. The protocol, informed consent/assent documents, recruitment advertisements and any amendments to these items will have IRB approval prior to study initiation. Voluntary informed consent/assent will be given by every study participant and the subject’s parent/guardian prior to the initiation of any study-related procedures. The rights, safety, and well-being of the study subjects are the most important considerations and prevail over the interests of science and society. It will be ensured that, all personnel involved in the conduct of this study must be qualified by education, training, and experience to perform their assigned responsibilities.

 Institutional Review Board (IRB) and Institutional Ethics Committee (IEC) Approval**:** The study will be started only after getting clearance from IRB and IEC, AIIA, New Delhi and CTRI registration. The investigator/designee will explain the study to each potential subject and the subject’s parent/guardian. The subject must indicate voluntary consent/assent by signing and dating the approved informed consent/assent form. The parent or legal guardian has to provide written informed consent for the subject. The investigator will provide the subject with a copy of the consent/assent form, in a language the subject understands. The investigator will maintain documentation that informed consent/assent was obtained prior to the initiation of any study-specific procedures.

 Protocol Compliance and Revision**:** The IRB approved protocol will be followed except in the case of a change that is intended to eliminate an immediate risk to subjects. All protocol deviations will be documented and will be submitted for approval. All protocol amendments will be submitted to IEB approval prior to implementation.

 Reports to Institutional Review Board**:** The investigator will provide the IEC with reports, updates, and other information (e.g., safety updates, protocol amendments, and administrative letters) according to regulatory requirements or Institution procedures. Record Confidentiality**:** All evaluation forms, reports, and other records will be identified in a manner designed to maintain subject confidentiality. All records will be kept in a secure storage area with limited access. Clinical information will not be released without the written permission of the subject or the subject’s parent/guardian (if appropriate), except as necessary for monitoring regulatory authority, or the IEC. The investigator and all employees and coworkers involved with this study shall not disclose or use for any purpose other than performance of the study, any data, records, or other unpublished, confidential information disclosed to those individuals for the purpose of the study. ACCESS TO DATA AND CONFIDENTIALITY:

The Research team only will have access to the participant data & final trial dataset. Data confidentiality will be maintained and Primary data will be preserved in the concerned Department for a period of 5 years.

ETHICS COMMITTEE CLEARANCE:

· The study will be started only after getting clearance from the Institutional Ethics Committee, AIIA, New Delhi.

· The present study will be carried out after taking the written consent from the Study Participants.

· The CTRI Registration will be done.

CO-OPERATION REQUIRED:

To carry out the research work collaboration with the following departments of AIIA, New Delhi

 Ã˜ Department of Rasashastra and Bhaishajyakalpana, AIIA

Ø Department of Dravyaguna, AIIA

Ø Research and Biostatistics Advisors of AIIA

Ø Collaboration outside the institute if needed

Ø  Pathology Laboratory, AIIA

Ø  Radiology Unit, AIIA

Ø  Department of Shalakya Tantra, AIIA.

Table 6: FINANCIAL SUPPORT:

S. NO.

Details

Approximate Financial Implication

|1.

Preparation of Drug

30000

|2.

Packaging, Labelling cost

5000

| Investigations cost

10000

|4.

Printing of CRF, Assent, Consent form, Participant Information Sheet

5000

|5.

Miscellaneous

30000

| TOTAL

80000

  This study will be completed within the prescribed financial limit for the work. However, if more finance is required, the request will be made for due permission and approval of the extra budget to the concerned authority AIIA, in due course of research work.

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