WO2023239684A1

WO2023239684A1 - Methodology related to dehydration treatment

Info

Publication number: WO2023239684A1
Application number: PCT/US2023/024513
Authority: WO
Inventors: Alison HUGHES; Tesado CHRISTIAN; Priti THAKOR
Original assignee: Johnson & Johnson Consumer Inc.
Priority date: 2022-06-06
Filing date: 2023-06-06
Publication date: 2023-12-14

Abstract

A method to assess the effectiveness of an oral fluid in the treatment of a subject suffering from an acute non-diarrhea illness, the method including: having the subject answer a self-rating questionnaire, where the subject selects a self-rating based on a 1 to 5 scale to create a baseline value; administering a first serving of the oral fluid to the subject; having the subject repeat the self-rating questionnaire at least one time over a 72-hour period after the first serving of the oral fluid is administered to create at least one additional value; and measuring a variation between the at least one additional value and the baseline value, where the variation indicates the effectiveness of the oral fluid in the treatment of the subject.

Description

METHODOLOGY RELATED TO DEHYDRATION TREATMENT

[0001] Body fluids are present in different body compartments and contain minerals, salts, dissolved proteins, fatty acids, glucose etc. The human body contains about 60% of water as body fluid, which is vital for life and performs or helps facilitate various functions like the transport of oxygen and nutrients in the body, temperature regulation, maintenance of internal environment, etc. Electrolytes in the body are essential minerals that carry an electrical charge. They are important constituents of human body fluids and help in regulating various physiological body functions.

[0002] Fluid and electrolyte imbalance in the body can result from decreased intake of fluids and/or increased fluid loss from the body in adverse conditions. Electrolyte imbalances may result from an increase or decrease concentration of sodium, potassium, calcium, and magnesium in the body. Some of the common causes of fluid and electrolyte imbalance in the body are viral illnesses, fever due to any cause, heat-related illnesses and gastrointestinal (GT) related conditions (nausea, vomiting, diarrhea, etc.). Thus, fluid and electrolyte replenishment is an essential component of the care for patients with such acute illnesses.

[0003] Such fluid and electrolyte imbalance in the body may lead to “dehydration,” which may be defined as a harmful reduction in the amount of water in the body. Dehydration is often due to increased output because of diarrhea and vomiting in gastroenteritis and is recognized easily and treatment provided as per guidelines. Symptoms of dehydration in an infant or young child may include dry mouth and tongue, no tears when crying, no wet diapers for three hours, sunken eyes and/or cheeks, sunken soft spot on top of skull, and listlcssncss and/or irritability. Symptoms of dehydration in an adult may include extreme thirst, less frequent urination, dark-colored urine, fatigue, dizziness and/or confusion. In severe cases, dehydration can lead to serious complications like, for example, heat injury (ranging from mild heat cramps to heatstroke), urinary and kidney problems (including urinary tract infections (UTI’s), kidney stones or kidney failure), seizures and/or low blood volume shock (hypovolemic shock).

[0004] While severe cases of dehydration are generally easy to detect, dehydration in acute common non- diarrheal illnesses often remains unnoticed or undiagnosed. These patients may present to their clinicians with a common complaint of general weakness, which may, in fact, be due to reduced intake and / or increased losses of water (e.g., likely due to decrease in appetite or increased insensible losses). [0005] The only effective treatment for dehydration is to replace lost fluids and electrolytes. Water, over- the-counter oral rehydration solutions, sports drinks containing electrolytes, carbohydrate solutions, and intravenous saline solutions are examples of available treatments. There is, however, little clarity on how the management of oral fluid and electrolytes imbalance along with appropriate energy intake (i.e., caloric supply) impacts patient outcome primarily on speed of recovery from acute common non- diarrheal illnesses, for e.g., patients with fever, general weakness, nausea vomiting and conditions like viral illnesses, heat related illness, upper respiratory tract infection (URTI) etc.

[0006] An objective of the present invention is to provide a method to evaluate the effectiveness of oral fluid for the restoration of hydration and energy level over time. Another objective of the present invention is to provide a method to evaluate the effectiveness of oral fluid for the restoration of hydration or energy level over time.

[0007] A further objective of the present invention is to provide a method to evaluate the effectiveness of oral fluid along with a standard of care medication treatment to help restore body fluid (hydration) and/or energy in subjects with acute common non-diarrheal illnesses with fever and/or general weakness, e.g., such as upper respiratory tract infection.

[0008] An objective of the present invention is to provide a method to evaluate the effectiveness of oral fluid in a naturalistic environment, for example at home, i.e. that does not need to be in a medical environment. Another objective of the present invention is to provide a method to evaluate the effectiveness of oral fluid without having to screen the subjects for mental or physical conditions.

[0009] Another objective of the present invention is to provide a method to evaluate the effectiveness of oral fluid in addition to standard care. An objective is to provide a method to evaluate the effectiveness of oral fluid without having to change the subject’s diet and fluid intake.

Summary of the Invention

[0010] A first embodiment of the invention relates to method to assess an effectiveness of an oral fluid in a treatment of a subject suffering from an acute non-diarrhea illness, the method including: a) having the subject answer a self-rating questionnaire comprising a module related to hydration level, where the subject selects a self-rating based on a 1 to 5 scale to create a baseline value; b) administering a first serving of the oral fluid to the subject; c) having the subject repeat the self-rating questionnaire at least one time over a 72-hour period after the first serving of the oral fluid is administered to create at least one additional value; and d) measuring a variation between the at least one additional value collected in step c) and the baseline value collected in step a), where the variation indicates the effectiveness of the oral fluid in the treatment of the subject.

[0011] A second embodiment of the invention relates to a method to assess an effectiveness of an oral fluid in a treatment of a subject suffering from an acute non-diarrhea illness, the method including: a) having the subject answer a self-rating questionnaire comprising a first module and a second module, where the first module relates to energy level and the second module relates to hydration level, and where the subject selects a self-rating on a 1 to 5 scale to create a baseline value for each of the first module and the second module; b) administering a first serving of the oral fluid to the subject; c) having the subject repeat the self-rating questionnaire at least one time over a 72-hour period after the first serving of the oral fluid is administered to create at least one additional value for each of the first module and the second module; and d) measuring a variation between the at least one additional value collected in step c) and the baseline value collected in step a) for each of the first module and the second module, wherein the variation indicates the effectiveness of the oral fluid in the treatment of the subject.

[0012] According to an embodiment, the subject may repeat the self-rating questionnaire at least one time during the first 24 hours after the first serving of the oral fluid is administered. According to another embodiment, the subject may repeat the self-rating questionnaire at least one time during a period between 1 hour and 72 hours after the first serving of the oral fluid is administered. According to a further embodiment, the subject may repeat the self-rating questionnaire at least one time during the first 24 hours after the first serving of the oral fluid is administered, and may repeat the self-rating questionnaire at least one additional time during a period between 1 hour and 72 hours after the first serving of the oral fluid is administered.

[0013] According to an embodiment, the method may further include an additional step of determining from the variation whether the subject experienced an improvement in the module (as described in the first embodiment), or in the first module and/or the second module (as described in the second embodiment).

[0014] According to an embodiment, the oral fluid may be a ready to drink electrolyte solution. According to another embodiment, the subject does not need to be in a medical environment, such as a hospital, when the method is performed. According to further embodiment, the subject has no limitation on diet during the method, particularly, no limitation on fluid intake after the first serving of the oral fluid is administered.

[0015] According to an embodiment, the first module may comprise a question asking the subject to rate his/her level of energy and may further comprise examples of normal physical activities such as dressing, toileting, eating, bathing, that the subject should be able to perform when adequately energized.

[0016] According to another embodiment, the module (as described in the first embodiment) and/or the second module (as described in the second embodiment) may comprise a question asking the patient to rate his/her level of hydration and may further comprise examples such as having moist tongue/mouth, being able to make saliva or spit, being able to sweat, not feeling thirsty, that the patient should be able to experience when adequately hydrated.

[0017] According to an embodiment, the 1 to 5 scale further may include a description of physical symptoms associated with each value of the 1 to 5 scale.

[0018] According to a further embodiment, the method may be implemented by a software on a mobile device such as a smartphone. For example, the software may use the baseline value collected to recommend a type or amount of oral fluid to be administered to the subject. The software may further enable the purchase of the type of oral fluid to be administered to the subject. Additionally, the software may use the variation measured to determine whether the subject experienced an improvement in the module or whether additional treatment may be necessary. Further, the software may be used by the subject or a medical professional.

[0019] According to another embodiment, the method may be adapted to assess an effectiveness of an oral fluid in the treatment of multiple subjects suffering from the same or various acute non-diarrhea illnesses.

Detailed Description

[0020] One embodiment of the invention relates to an assessment method of the effectiveness of oral fluid in speed of recovery from acute non-diarrhea illnesses of a subject, the method including: a) submitting a subject to a self-rating questionnaire having at least one module, to create a baseline value; where the module is rated on a 1 to 5 scale and refers to hydration level; b) administering a first serving of an oral fluid to the subject; c) repeating the self-rating questionnaire at least 1 time over a 72 hour period after the first serving of the oral fluid is administered; and d) measuring variation in selfrating collected over the c) step period in comparison to the baseline collected in step a).

[0021] Another embodiment of the invention relates to an assessment method of the effectiveness of oral fluid in speed of recovery from acute non-diarrhea illnesses of a subject, the method including: a) submitting the subject to a self-rating questionnaire having at least one module, to create a baseline value; where the module is rated on a 1 to 5 scale and refers to energy level; b) administering a first serving of an oral fluid to the subject; c) repeating the self-rating questionnaire at least 1 time over a 72 hour period after the first serving of the oral fluid is administered; and d) measuring variation in selfrating collected over the c) step period in comparison to the baseline collected in step a).

[0022] A further embodiment of the invention relates to an assessment method of the effectiveness of oral fluid in speed of recovery from acute non-diarrhea illnesses of a subject, the method including: a) submitting the subject to a self-rating questionnaire having at least 2 modules, to create a baseline value, where each module is rated on a 1 to 5 scale and includes a module referring to energy level and a module referring to hydration level; b) administering a first serving of an oral fluid to the subject; c) repeating self-rating questionnaire at least 1 time over a 72-hour period after the first serving of the oral fluid is administered; and d) measuring variation in self rating collected over the c) step period in comparison to the baseline collected in step a).

[0023] By “module” it is meant one or more questions having a particular aspect of the subject physical condition in common. The number of questions in a module is not limited and a module may include one question or more, for example two questions, three questions, four questions; preferably each module includes one question.

[0024] By “oral fluid” it is meant any aqueous solution comprising electrolytes and carbohydrates that may be orally ingested by or administered to a subject, such as ready to drink electrolyte solutions. Electrolytes maybe selected from sodium, potassium, chlorine, citrates, carbonates, bicarbonates, and combinations thereof. Carbohydrates may be glucose or other mono or disaccharides. Electrolytes are beneficial for hydration and carbohydrates are beneficial for energy restoration. The oral fluid may contain other elements such as magnesium, calcium; or molecules such as taurine or vitamin, for example vitamin C.

[0025] In a preferred embodiment the said oral fluid is a ready to drink electrolyte solutions. In a further preferred embodiment, the said oral fluid is a fruit-based drink with electrolytes.

[0026] The oral fluid may be administered to a subject in need thereof several times a day, for example 1 to 8 times per day, for example 1 to 6 times per day, for example 1 to 4 times per day, for example 2 to 6 times per day, for example 2 to 4 times per day, for example 3 to 6 times per day, for example 3 to 4 times per day; over a period of 24 hours or 48 hours or 72 hours, or over a period as per medical requirement or as medically prescribed. The appropriate number of servings of oral fluid per day, as well as the period over which the servings of the oral fluid should be administrated, to a particular subject is dependent on and defined by the subject’s specific need, based, for example, on medical advice.

[0027] By “serving” of an oral fluid it is meant the volume of oral fluid to be administered to a subject. This volume is subject dependent and is defined as per subject need, based on a medical advice or prescription, given the concentration in electrolytes and carbohydrates of said oral fluid.

[0028] It may be preferable to repeat the self-rating questionnaire several times over the 72 hour period after the first serving of the oral fluid is administered, preferably at least one time, or two times, or even three times during the first 24 hours after the first serving of the oral fluid is administered, for example at 20 minutes, 40 minutes, 60 minutes; and preferably at least one time, or two times, or even three times during the first hour to 72 hour period after the first serving of the oral fluid is administered, for example at 6 hours, 24 hours and 48 hours. Other hour combinations are also possible, including, for example, any combination of 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 56 and 72 hours after the first serving of the oral fluid has been administered.

[0029] Assessments made within the first hour after the first serving of the oral fluid is administered provide information about the onset of response to treatment with the oral fluid, for example the instant energy recovery or the hydration recovery. Assessments made between the first hour and 72 hours after the first serving of the oral fluid first serving administration provide information about the long-lasting response to treatment with the oral fluid, for example the energy recovery or the hydration recovery.

[0030] Examples of “acute non-diarrhea illnesses” may include for example subjects with symptoms such as fever, general weakness, nausea, vomiting; and subjects with conditions like viral illnesses, heat related illness, upper respiratory tract infection (URTI) and urinary tract infections (UTI).

[0031] According to an embodiment, the assessment method may comprise an additional step e) after step d) where step e) is: determining from the measure of step d) the percentage of subject experiencing improvement in one of the energy level module or the hydration level module. By experience an “improvement” in a module it is meant at least a 1 -point increase in rating, compared to the baseline obtained in step a). [0032] According to a further embodiment, the assessment method may comprise an alternative additional step e’) after step d) where step e’) is: determining from the measure of step d) the percentage of subject experiencing improvement in both the energy level module and the hydration level module.

[0033] It may be beneficial to assess both the hydration and energy levels during recovery at the same time since these two benefits may not be related to the same component of the oral fluid, for example the water and electrolytes component will provide hydration and the carbohydrate component will provide energy. An oral fluid with an insufficient amount of carbohydrate may provide hydration but not sufficient energy recovery.

[0034] According to an embodiment, the assessment method may comprise an alternative additional step e”) after step d) where step e”) is: determining from the measure of step d) the percentage of subject experiencing improvement in the hydration level module.

[0035] The assessment method may exclude questions related to mental health when screening the subject. Eliminating the need to screen subjects for mental health allows the methodology to be simplified for home environment use or any other use that does not require medical supervision. Mental health screening questions, for example those related to depression, are routinely included in medical patient health screening questionnaires.

[0036] The assessment method may also exclude the requirement of any physical test to be performed to screen the subject. Eliminating the requirement for a subject’s physical or medical testing (e.g., urine sample and/or blood work) allows the methodology to be simplified for home environment use or any other use that does not require medical supervision. Furthermore, some physical tests for subjects or patients (e.g., urine color) may be misleading and direct the wrong diagnosis. For example, urine color is darker or lighter depending on the subject and, therefore, is not a reliable indicator of dehydration.

[0037] The assessment method may not need the subject to be in a medical environment, such as a hospital, when the method is performed. It may be beneficial to be able to perform this assessment outside of a medical environment because it allows a subject to evaluate the effectiveness of the oral fluid in naturalistic condition (real life condition) when the subject is at home (in the home environment) or in a remote location. In other words, being able to perform this assessment without any medical environment enables naturalistic, or “in the home environment”, evaluation of the oral fluid without the need of any particular instrument or medical setup. It simplifies the assessment and makes it easier for the subject to comply with the assessment method.

[0038] The assessment method may not need any limitation on the subject’s diet during the method implementation, particularly, no limitation on fluid intake after the first serving of an oral fluid administration of step b). Allowing the subject to keep their regular diet and hydration pattern may be beneficial because it allows naturalistic evaluation of the effectiveness of oral fluid administered. It further provides evidence that the improvement in the subject hydration or energy, or both energy and hydration, is not related to a change in the subject’ s regular diet and hydration pattern but indeed due to the absorption of the oral fluid. Finally, it does not introduce any burden on the subject in their daily routine, such as the subject’s natural diet and hydration pattern.

[0039] The energy level module may include a question asking the subject to rate his/her level of energy and may provide examples of normal physical activities such as dressing, toileting, eating, bathing, that the subject should be able to perform. Examples like this may help the subject to understand what to focus on. The energy level module may also include other examples of normal physical activities, in addition to or instead of those listed above. Alternatively, the rating and/or question may focus on examples of abnormal physical activities such as fatigue and weakness.

[0040] The hydration level module may include a question asking the subject to rate his/her level of hydration and may provide examples such as having moist tongue/mouth, being able to make saliva or spit, being able to sweat, not feeling thirsty; that the subject should be able to experience when adequately hydrated. Examples like this may help the subject to understand what to focus on. The hydration level module may also include other examples of feeling adequately hydrated, in addition to or instead of those listed above. Alternatively, the rating and/or question may focus on examples of dehydration such as thirst and dry mouth.

[0041] The 1 to 5 scale in the module of the self-rating questionnaire may be associated with indications of which value is the worst and which is the best. For example, the scale may be similar to: 1 = best, 2 = good, 3 = average, 4 = bad, 5 = worst, or conversely 1 = worst, 2 = bad, 3 = average, 4 = good, 5 = best. This indication or a similar indication may enable the subject to avoid any mistake when assessing the effectiveness of the oral fluid. Different subjects, based on their own subjective perception, may consider either 1 or 5 as associated with the best experience. Misinterpretation of the ranking scale may result in subjects providing ranking opposite to their intent. Giving a clear indication of the ranking scale end points relative value helps to avoid any confusion.

[0042] The 1 to 5 scale in the module of the self-rating questionnaire may be associated with a description of physical symptoms for at least part of the values of the scale. For example, the hydration level module could include a scale similar to the following: 1 = not thirsty, 2 = slightly thirsty, 3 = thirsty, 4 = very thirsty and 5 = extremely thirsty. This indication or a similar indication may enable the subject to avoid any mistake when assessing the effectiveness of the oral fluid. Different subjects, based on their own subjective perception, may consider cither 1 or 5 as associated with the best experience. Misinterpretation of the ranking scale may result in subjects providing ranking opposite to their intent. Giving a clear indication of the ranking scale end points relative value helps to avoid any confusion.

[0043] According to an embodiment, the assessment method may be implemented by software or a software App on a mobile device such as a smartphone. Implementation of the assessment method on a smartphone may make it easier to use and/or more convenient for the subject and/or medical professional using the App. It would allow the assessment method to be used outside medical facilities and/or the home environment. Having data directly in a digital format also allows reduction of paperwork and potential transcription mistakes. [0044] The assessment method may be implemented by a software App on a mobile device, where the App may be programmed to make a recommendation for the purchase of oral fluid, such as a ready to drink electrolyte solutions or fruit-based drink with electrolytes. The recommendation may be made by an algorithm that evaluates the subject’s answers to the self-rating questionnaire. The recommendation could also be made by a medical professional that is affiliated with the App, for example a virtual doctor or nurse.

[0045] The software App may be further able to link a recommendation to a third-party website selling the recommended oral fluid or may have a direct-to-consumer purchase platform for the recommended oral fluid, so that the subject can immediately purchase the oral fluid for treatment. Having an automatic recommendation of an appropriate oral fluid with electrolytes and carbohydrates, such as a ready to drink electrolyte solution, may help the subject to get quick access to the relevant product to address the lack of hydration and/or energy. Or, if the App were used by a medical professional, rather than by the subject or patient, it may also help the medical staff to make recommendation of products adapted to the subject needs.

Examples

[0046] Study Design: To study the effect of oral fluid in dehydration and energy recovery in subjects, using the above referenced assessment methodology the following prospective, interventional, open-label, multicenter, naturalistic study involving subjects was conducted. Subjects were supplied with an oral fluid, in particular with one of the ORSL® variants (ORSL® Apple Drink or ORSL® PLUS Orange Drink), as an adjuvant along with standard of care medication treatment, as per physician’ s discretion in subjects experiencing acute common non-diarrheal illnesses with fever and/or general weakness, e.g. upper respiratory tract infection (URTI). Hydration and energy levels were evaluated following consumption of ORSL® variant through an assessment methodology, referred to as the “Aided Recovery Scale Questionnaire” (collected by patient-reported outcome (PRO)) followed by telephone interview or online review with the physician. The data were recorded in this study both by subjects via a “Aided Recovery Scale” and a “Subject Experience Questionnaire” and by physicians via a “Physician Recommendation Experience questionnaire”. The study was conducted over a period of 72 hours (and up to 78 hours in case follow-up of an adverse event [AE] was required). The term “patient” in this example of study is equivalent to the term “subject” in the rest of the specification.

[0047] Subjects who presented to a hospital, out-patients department (OPD) or clinic with fever and/or general weakness due to an acute non-diarrheal illness such as URTI were examined by a physician. When the clinical decision was taken to recommend ORSL® variants as an adjuvant to a subject, the physician considered enrolling the subject into this study. During the in-clinic visit, after signing the informed consent form (ICF) and enrollment into the study, subjects were trained and instructed on the use of diary cards. The subjects were also trained on using Subject Experience questionnaire which were completed after telephone interview or online. The subjects were provided with ORSL® variant packs as recommended by the physician sufficient for the duration of the study. The subject left the site/study center, and ORSL® variant packs consumption and all assessments were conducted at the subject’s home.

[0048] The subjects recorded their experiences in their energy and hydration level using the “Aided Recovery Scale” starting from baseline (prior to consumption of ORSL® variant) and at 20, 40 and 60 minutes, 6, 24 and 48 hours after consumption. On completion, the Aided Recovery Scale Questionnaire from each patient was securely transferred to sponsor. Each subject visited the study site on one occasion for inclusion into the study. A follow-up call by the Investigator to the subject took place after 72 hours. No further in-clinic visits were in the scope of this study, unless deemed necessary by the Investigator.

[0049] Study Population: Patient inclusion criteria included subjects greater or equal to 18 years of age, who:

• were able to comprehend and willing to sign an Informed consent form (ICF) and to comply with all aspects of the Study;

• were willing and able to respond to subjective questions;

• had a score of 3 or greater in both energy and hydration on the “Aided Recovery Scale” at the time of the screening (baseline) visit; and

• were diagnosed in the preceding two weeks with acute febrile illness (e.g. URTI, viral illness) and/or generalized weakness/fatigue due to acute non-diarrheal illness.

[0050] Exclusion Criteria: Patients were excluded for the following reasons:

• Subjects needing in-patient hospitalization

• Subjects who had undergone any GI surgeries, which are known to affect absorption anytime in the past

• Women who had a positive pregnancy test at screening

• Subjects with pre-existing medical conditions that may have impacted study measurements or ability to comply with study procedures, including but not limited to malabsorption syndrome, congestive heart failure, cirrhosis, hepatic failure, malignancy, sepsis, chronic infections like Tuberculosis, Chronic obstructive pulmonary disease, Syndrome of inappropriate antidiuretic hormone secretion, renal failure, etc.

• Participation in any clinical trials in the last 3 months

• Use of any other oral rehydration solution and/or any other ready to drink solution in the last 48 hours.

• Use of any medications which might have interacted with oral rehydration solution as per physician discretion • Subjects with nausea, vomiting, diarrhea, suspected or confirmed malaria, dengue or typhoid confirmed by culture positive test, active CO VID- 19 disease, subjects in convalescence post COVID-19 <3 weeks and off steroids <2 weeks

• Subjects presenting with a urinary tract infection (UTI)

• Subjects who, in the Investigator’s opinion, were not suitable to take part in the study

• Subjects who were related to those persons involved directly or indirectly with the conduct of this study (i.e., Principal Investigator, sub-investigators, study coordinators, other site personnel, employees of the applicant company, contractors of the applicant company, and the families of each)

[0051] Discontinuation Criteria: Subjects who developed diarrhea, or were diagnosed with malaria, culturepositive typhoid, dengue, CO VID-19 (newly diagnosed), etc. or required hospitalisation for any cause were discontinued from the study. However, data collected for such subjects were retained for the purpose of analysis and no further efforts were made to obtain or record additional information regarding the subject from the point of discontinuation.

[0052] Data Collection/Data Sources: The data for the study was collected at relevant data timepoints as presented in the data collection schedule. At baseline, the treating physician carried out a physical examination and recorded demographics, medical history, details of primary ailment) s) and the standard of care medication treatment and their concomitant medications (including nutritional supplements). The data for effectiveness evaluation was recorded by subjects on PRO questionnaires in the home environment. Physicians recorded the 72-hour evaluation on the Physician Recommendation experience questionnaire. For safety evaluation, adverse event (AEs) and serious adverse events (SAEs) were recorded starting from the time of signing of the ICF. The staff from individual sites entered the study data in the electronic case report forms (eCRFs) of the Electronic data capture (EDC) system.

[0053] Data Management and Quality Assurance: The CRFs included programming checks to obtain immediate feedback if data were missing, out of range, illogical or potentially erroneous. Concurrent manual data review was performed based on parameters dictated by the data management plan.

[0054] Effectiveness: The effectiveness of the study was evaluated by comparison of:

• Patient reported outcome - Aided Recovery Scale questionnaire and Subject Experience Questionnaire; and

• Physician reported outcome: Physician Recommendation Experience Questionnaire [0055] Statistical Considerations: Regarding sample size, a sufficient number of subjects (617) who met the required inclusion/exclusion criteria were enrolled to ensure that 524 subjects completed the study, considering a drop-out rate of approximately 15%.

[0056] Final Analyses: Summary statistics were presented overall and by variant at baseline and post-baseline visits. Baseline and demographic characteristics were presented overall and by variant. Statistical tests for primary and secondary endpoints were based on hypothesis. A one sample binomial test with normal approximation was used to test whether the proportion improved significantly differs from 50%.

[0057] Thinking of the potential ability to pass along unused alpha to secondary endpoints, and the uncertainty of timely sequential performance, the truncated Holm multiple comparison procedure was applied in order to strongly control the family wise Type I error rate at 0.025, one-sided, for the different timepoints involved in each kind of primary endpoints and secondary effectiveness endpoints.

[0058] The truncated Holm multiple comparison procedure (a hybrid of its conventional form and the Bonferroni method) with a truncation fraction, 1/2, was applied. The three primary endpoints (at 6 hours, 24 hours and 48 hours) were categorized into the primary family, and the other 3 timepoints (at 20 mins, 40 mins and 60 mins) were categorized into the secondary family.

[0059] The number and percentage of subjects experiencing adverse events, treatment-emergent and treatment- related AEs during the clinical study were presented by Medical Dictionary for Regulatory Activities, System Organ Class preferred term and variant.

[0060] Exposure Definition and Measures: This was a naturalistic interventional study reflecting current clinical practice. This study evaluated effectiveness, and physician and subjects’ responses to investigational product (IP) measured in the post-marketing setting. No restrictions on concomitant treatments were associated with the study and all concomitant treatments were carefully recorded in order to evaluate their potential influence on the outcomes of interest.

[0061] End of Study Definition: The study was conducted over a period of 72 hours for each subject (and up to 78 hours in case follow-up of an AE was required).

[0062] Provision of Investigational Product: The Sponsor, Johnson & Johnson, Consumer Healthcare supplied the Investigational Products (ORSL® variant packs) and the subjects received these packs required for 72 hours from the study sites.

• ORSL® Apple Drink is a fruit juice -based drink with electrolytes (sodium, potassium and chloride), vitamin C and carbohydrates in a 200 mL pack. It is presented in a tetrabrik aseptic package. • ORSL® PLUS Orange Drink is a fruit juice-based drink with electrolytes (sodium, potassium and chloride), vitamin C and carbohydrates in a 200 mL pack. It is presented in a tetrabrik aseptic package.

[0063] ORSL® Apple Drink and ORSL® PLUS Orange Drink are Food products classified as “Electrolyte Drink”, not ORS, under applicable regulations laid down by Food Standard and Safety Authority of India. Exemplary ingredient and nutritional information of the ORSL® Apple Drink and ORSL® PLUS Orange Drink are provided below:

[0064] ORSL® Apple Drink (Figure 1):

Net Quantity: 200ml (1 serve of 200ml)

Ingredients:

Purified Water, Sugar, Dextrose, Apple Juice (reconstituted) 10%, Acidity Regulator (INS330), Sodium Citrate, Potassium chloride, Sodium chloride, Vitamin C (Ascorbic acid), Added Flavours (Nature Identical Flavoring Substances & Artificial Flavouring Substances [Apple]).

Contains permitted natural food colour (INS150a).

* Basis RDA for Adult Sedentary male, ICMR, 2020

[0065] ORSL® PLUS Orange Drink (Figure 2):

Net Quantity: 200ml (1 serve of 200ml)

Ingredients:

Water, Sugar, Dextrose, Orange Juice (reconstituted) 10%, Sodium Citrate, Acidity Regulator (INS330), Potassium chloride, Sodium chloride, Vitamin C (Ascorbic acid), Taurine, Magnesium sulphate, Calcium lactate, Added Flavours (Nature Identical Substances [Orange], Antioxidant (INS 320)).

Contains permitted synthetic food colour (INS110).

* Basis RDA for Adult Sedentary male, ICMR, 2020

[0066] Compliance With Investigational Product Usage: The subjects recorded the time and number of packs of their ORSL® variant consumed on diary cards.

[0067] Effectiveness Measures: Aided Recovery Scale Questionnaire consisted of 2 questions i.e., “Rate your level of energy” and “Rate your level of hydration”, which corresponded to 2 primary objectives of the study. Subjects provided their response to these questions on a scale from 1 to 5 after self-assessment of their condition of illness and how much they feel recovered after taking ORSL® variant. The responses were as follows: Strongly Disagree-1 to Strongly Agree-5. Further details on these 2 questions are provided in table below. An exemplary Aided Recovery Scale Questionnaire may be as follows:

[0068] As can be seen the Aided Recovery Scale questionnaire comprises two modules, one relating to energy: “Rate your level of energy”; and one related to hydration: “Rate your level of hydration”. Both provide examples of physical activities that the patient should be able to perform or experience when having an adequate level of energy or being adequately hydrated. These examples are provided to help the patient in the self-rating.

[0069] Screening (Baseline): Subjects were included in the study and were screened for inclusion and exclusion criteria after they or their legal representative agreed to participate in the study and signed the ICF. The subjects meeting all the eligibility criteria were enrolled in the study. The enrolled subject’s baseline data was collected by the treating physician (or designee) before administering first usage of any of the ORSL® variants.

[0070] Subjects were enrolled into the study not beyond 6:00 PM in the evening as it may have been difficult to collect data from subjects if they were enrolled after this time. The participants were provided with proper training on completing the diary cards.

[0071] Assessments (20 [± 51, 40 [± 51 and 60 [± 51 minutes): After the first consumption (after enrolment into the study) of ORSL® variants by subjects at home, subjects were responsible for recording their experience in energy levels and hydration with ORSL® variants at 20 (± 5), 40 (± 5), and 60 (± 5) minutes via “Aided Recovery Scale” questionnaire.

[0072] Assessments (6 [± 1] hours, 24 [± 4] hours, 48 [+ 4] hours and 72 [+ 4] hours): After leaving the site, the subjects consumed IPs at home, recorded the time and volume of their ORSL® variant intake (number of ORSL® variant packs used) and any AEs experienced by them on the diary cards. Subject’s experience in their energy level and hydration status at 6 (+ 1) hours, 24 (± 4) hours and 48 (± 4) hours after consumption of ORSL® variants administration were recorded by the subject themselves using “Aided Recovery Scale” questionnaire. No further site visit was required as part of this study. A telephone interview/online review by a designated study site personnel at 72 (± 4) hours was conducted for understanding the subject’s overall experience with ORSL® variant via Subject Experience questionnaire.

[0073] At 72 (± 4) hours after ORSL® variant intake, the physician contacted the subject to perform a telephone interview to assess the condition of the subject. The physician completed the assessment questionnaire. The site staff entered the data in the eCRF. At 24 (± 4) hours, 48 (± 4) hours and 72 (± 4) hours, fluids consumed in addition to ORSL® variant were also recorded to the best of subject’s memory.

[0074] Results: 617 subjects were enrolled in the study. 310 subjects received the ORSL Apple variant, and 307 subjects received the ORSL Orange Variant. All subjects completed the study, no discontinuation was observed. 62.4% of subjects were male and 37.6% of the subjects were female. The median age was 36 years (minimum 18 years, maximum 79 years). The mean age was 38.3 years with a standard deviation of 12.85. The baseline BMI (kg/m²) had a mean value of 23.85 (Std Dev 3.127), and a median value of 23.60.

[0075] Assessment based on energy or hydration: Table 1 shows the percentage of subjects feeling an improvement in either energy or hydration on “Aided Recovery Scale” after 6, 24 and 48 hours of ORSL® variants consumption. By “improvement” is meant at least 1 point improvement from baseline.

Table 1

[0076] Assessment based on energy alone: Table 2 shows the percentage of subject feeling an improvement in energy on “Aided Recovery Scale” after 6, 24 and 48hours of ORSL® variants consumption. By “improvement” is meant at least 1 point improvement from baseline. Table 2

[0077] Assessment based on hydration alone: Table 3 shows the percentage of subjects feeling an improvement in hydration on “Aided Recovery Scale” after 6, 24 and 48hours of ORSL® variants consumption. By “improvement” is meant at least 1 point improvement from baseline.

Table 3

[0078] Assessment based on energy and hydration: Table 4 shows the percentage of subject feeling an improvement in both energy and hydration on “Aided Recovery Scale” after 6, 24 and 48hours of ORSL® variants consumption. By “improvement” is meant at least 1 point improvement from baseline.

Table 4

[0079] For tables 1, 2, 3 and 4; One sided p-values:

[1] Binomial test with normal approximation was used to test whether the proportion improved was significantly greater than 50%.

[0080] Percentage improved was statistically significantly greater than 50%. The truncated Holm multiple comparison procedure was applied in order to strongly control the family wise Type I error rate at 0.025, one-sided.

[0081] From the results presented in tables 1 to 4 about assessing hydration and energy level, it can be concluded that the subjects experienced an improvement in their hydration or energy level or both hydration and energy level. This beneficial effect started to be observed within one hour of administration of the oral fluid to the subjects and was observed in 98% or more of the subjects at 48 hours. Implementation of this method in a smartphone application would show the subject that the oral fluid is working.

[0082] The assessment methodology demonstrates the ability to detect low levels of hydration and/or energy and assess improvement in hydration and energy levels in subjects over time after administration of oral fluids.

[0083] It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims.

Claims

1) A method to assess an effectiveness of an oral fluid in a treatment of a subject suffering from an acute non-diarrhca illness, the method comprising: a) having the subject answer a self-rating questionnaire comprising a module related to hydration level, wherein the subject selects a self-rating based on a 1 to 5 scale to create a baseline value; b) administering a first serving of the oral fluid to the subject; c) having the subject repeat the self-rating questionnaire at least one time over a 72-hour period after the first serving of the oral fluid is administered to create at least one additional value; and d) measuring a variation between the at least one additional value collected in step c) and the baseline value collected in step a), wherein the variation indicates the effectiveness of the oral fluid in the treatment of the subject.

2) A method to assess an effectiveness of an oral fluid in a treatment of a subject suffering from an acute non-diarrhea illness, the method comprising: a) having the subject answer a self-rating questionnaire comprising a first module and a second module, wherein the first module relates to energy level and the second module relates to hydration level, and wherein the subject selects a self-rating on a 1 to 5 scale to create a baseline value for each of the first module and the second module; b) administering a first serving of the oral fluid to the subject; c) having the subject repeat the self-rating questionnaire at least one time over a 72-hour period after the first serving of the oral fluid is administered to create at least one additional value for each of the first module and the second module; and d) measuring a variation between the at least one additional value collected in step c) and the baseline value collected in step a) for each of the first module and the second module, wherein the variation indicates the effectiveness of the oral fluid in the treatment of the subject.

3) The method according to claim 1 or 2, wherein step c) comprises having the subject repeat the selfrating questionnaire at least one time during the first 24 hours after the first serving of the oral fluid is administered.

4) The method according to claim 1 or 2, wherein step c) comprises having the subject repeat the selfrating questionnaire at least one time during a period between 1 hour and 72 hours after the first serving of the oral fluid is administered.

5) The method according to claim 1 or 2, wherein step c) comprises having the subject repeat the selfrating questionnaire at least one time during the first 24 hours after the first serving of the oral fluid is administered, and having the subject repeat the self-rating questionnaire at least one additional time during a period between 1 hour and 72 hours after the first serving of the oral fluid is administered.

6) The method according to any of claims 2 to 5, further comprising: e) determining from the variation of step d) whether the subject experienced an improvement in one of the first module or the second module.

7) The method according to any of claims 2 to 5, further comprising: e’) determining from the variation of step d) whether the subject experienced an improvement in both the first module and the second module.

8) The method according to any of claims 2 to 5, further comprising: e’ ’) determining from the variation of step d) whether the subject experienced an improvement in the second module.

9) The method of claim 1, further comprising: e) determining from the variation of step d) whether the subject experienced an improvement in the module.

10) The method according to any of the preceding claims, wherein said oral fluid is a ready to drink electrolyte solution.

11) The method according to any of the preceding claims, wherein the subject does not need to be in a medical environment, such as a hospital, when the method is performed.

12) The method according to any of the preceding claims, wherein the subject has no limitation on diet during the method, particularly, no limitation on fluid intake after the first serving of the oral fluid is administered in step b).

13) The method according to claim 2, wherein the first module comprises a question asking the subject to rate his/her level of energy and further comprises examples of normal physical activities such as dressing, toileting, eating, bathing, that the subject should be able to perform when adequately energized.

14) The method according to claim 2, wherein the second module comprises a question asking the patient to rate his/her level of hydration and further comprises examples such as having moist tongue/mouth, being able to make saliva or spit, being able to sweat, not feeling thirsty, that the patient should be able to experience when adequately hydrated. 15) The method according to any of the preceding claims, wherein the 1 to 5 scale further comprises a description of physical symptoms associated with each value of the 1 to 5 scale.

16) The method according to any of the preceding claims, wherein the method is implemented by a software on a mobile device such as a smartphone.

17) The method of claim 16, wherein the software uses the baseline value collected in step a) to recommend a type or amount of oral fluid to be administered to the subject in step b).

18) The method of claim 17, wherein the software further enables the purchase of the type of oral fluid to be administered to the subject in step b).

19) The method of claim 16, wherein the software uses the variation measured in step d) to determine whether the subject experienced an improvement in the module or whether additional treatment may be necessary.

20) The method of claim 16, wherein the software may be used by the subject or a medical professional.

21) The method according to any of the preceding claims, wherein the method is adapted to assess an effectiveness of an oral fluid in the treatment of multiple subjects suffering from the same or various acute non-diarrhea illnesses.