Efficacy and Safety of Thirst-Quenching Lozenges for Xerostomia in Patients Undergoing Hemodialysis: A Prospective, Single-Arm, Open-Label Study

Citation: Sahay M, Almeida A, Naqvi SMH, Venugopal H, Kale RM, et al. (2020) Efficacy and Safety of Thirst-Quenching Lozenges for Xerostomia in Patients Undergoing Hemodialysis: A Prospective, Single-Arm, Open-Label Study. J Clin Nephrol Ren Care 6:056. doi.org/10.23937/2572-3286/1510056 Accepted: August 24, 2020: Published: August 26, 2020 Copyright: © 2020 Sahay M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Open Access ISSN: 2572-3286


Introduction
Xerostomia is a subjective complaint of dryness of oral cavity and is frequently reported (28% to 67%) in patients with end-stage kidney disease (ESKD); including those on chronic hemodialysis [1]. Xerostomia may be attributed to the reduced salivary flow as a result of atrophy and fibrosis of salivary glands as well as certain medications, which are commonly used in patients on hemodialysis [2][3][4]. Further, xerostomia and hyposalivation together augment the sensation of thirst in patients on hemodialysis. In these patients, xerostomia is associated with clinical consequences like, increased risk of oral infections and diseases, difficulty Committee at each study center. A written informed consent was obtained from all the patients prior to the study initiation after explaining to them the study protocol in the language that they understood. The study was conducted in accordance with the International Council for Harmonization good clinical practice guidelines and ethical principles of the Declaration of Helsinki.

Study population
Adult (aged ≥ 18 years) patients with ESKD undergoing hemodialysis thrice a week for at least 3 months with daily urine output of < 200 mL were included in the study. Key exclusion criteria were patients who were scheduled for kidney transplantation or immune suppressant therapy, those who exceeded average weekly IDWG of ~2.5 kg, those admitted for fluid overload in last 3 months prior to screening, or those who had heart failure (New York Heart Association class IV). Other exclusion criteria included patients with active systemic infections, autoimmune conditions causing dryness of mouth like Sjogren's syndrome, uncontrolled diabetes, hypertension, and drugs causing dry mouth. Patients receiving drugs (sympathomimetic, antihypertensive, cytotoxic, anti-HIV drugs, opioids, benzodiazepines, and anti-migraine agents) which cause xerostomia was excluded.

Study endpoints and assessments
Baseline demographics (age, sex and body mass index) and clinical characteristics (medical history and comorbidities) were recorded. The primary efficacy endpoints included pre and post changes in xerostomia inventory (XI) and dialysis thirst inventory (DTI) scores from baseline to the end of study (EOS; i.e. 2 weeks). The XI and DTI are the standard validated questionnaires for xerostomia and thirst, respectively, and were assessed at screening, baseline, and at the EOS (week 2). These included several questions to evaluate XI (Supplementary Table 1) and DTI (Supplementary Table 2) with the scale of 'never/ almost never', 'occasionally', 'fairly often/very often'.
Secondary efficacy endpoint included the proportion of patients satisfied with TQL in reducing dry mouth and thirst. The thirst severity was recorded by patients on a visual analogue score scale of 0-10 thrice a day (morning, afternoon and night). Safety was evaluated by observing adverse events (AEs), recorded as per Common Terminology Criteria for AEs (CTCAE; version 4.0), physical examination, vital signs and clinical laboratory investigations. Both patient-reported and investigator-observed AEs were recorded at all visits. Clinical laboratory investigations included blood urea, serum creatinine, blood glucose, serum uric acid, hemoglobin, glycated hemoglobin, and serum albumin at baseline and at the EOS. Patients were provided with diaries to record their fluid intake throughout the day and data were collected during each visit. in chewing, swallowing, speaking, and may contribute to increased interdialytic weight gain (IDWG), which may reduce the overall quality of life (QoL) [1,5]. The oral diseases related to xerostomia include mucosal, gingival and tongue lesions, candidiasis, dental caries, periodontal disease, oral fungal and bacterial infections [6]. Furthermore, patients on chronic hemodialysis most often receive multiple drugs concomitantly and xerostomia is exacerbated by such polypharmacy [7]. Drugs causing xerostomia often are those with anticholinergic activity or those acting through mechanisms on brain centers to reduce fluid secretion [8].
Current treatment strategies for xerostomia generally target stimulation of the salivary glands either mechanically (e.g., sugar-free chewing gums, mouthwash, or acupressure) or pharmacologically (e.g., pilocarpine and cevimeline) [1]. Irrespective of mechanical and/ or pharmacological actions, saliva substitutes are recommended for these patients with insufficient salivary secretion. These substitutes are available as different formulations containing either mucin, xanthan gum, carboxymethyl cellulose, hydroxyethyl cellulose or polyethylene glycol and have shown limited success [9][10][11]. Hence, novel strategies, which stimulate salivary secretions addressing xerostomia in patients with ESKD undergoing hemodialysis are warranted [1].
Most patients on hemodialysis need to maintain a fluid-restricted diet to prevent a high IDWG [12]. The prevalence of xerostomia is higher in these patients than in controls thus necessitating an alternative treatment that can stimulate salivary secretions and keep the oral mucosa moist. To address this unmet need in patients with chronic kidney disease suffering from dry mouth and thirst, a sugar-free xylitol based thirst-quenching lozenge (TQL) with unique release profile, proprietary patented technology, has been developed by Dr. Reddy's Laboratories. Xylitol is a natural sweetener and was proven to be effective in relieving symptoms of drug-induced xerostomia [13]. This study evaluated the efficacy and safety of TQL in reducing dryness of mouth and thirst in patients with chronic kidney disease stage 5 undergoing hemodialysis. Moreover, patient satisfaction with the use of TQL in reducing thirst was determined.

Study design
This was a prospective, open-label, single-arm study to evaluate the efficacy and safety of TQL in patients with chronic kidney disease stage 5 who were on hemodialysis at two centers in India between 2018 and 2019.

Ethics statement
The study protocol and informed consent form were reviewed and approved by an Independent Ethics from baseline, indicating improvements, when compared with those at the EOS. In context with XI questionnaires, percentage patients opted for 'fairly often' as a response for following questions (baseline vs. EOS): required sip of liquid to swallow food (39.3% vs. 6.0%), dry mouth while eating food (41.7% vs. 10 Table 3. Most patients responded as satisfied versus unsatisfied with the study treatment (91.3% vs. 8.7%; Table 4). Patients' response on overall treatment satisfaction questionnaires showed that a greater number of patients were satisfied in terms of relief in condition, relief in symptoms, side effects, timing of medication, and overall confidence on medication and

Study treatment
The study consisted of a 1-day screening phase, 1-week stabilization phase, and a 2-week treatment phase with a 1-week follow-up. Overall, patients had 8 visits: screening (Visit 1: Day 0), baseline (Visit 2: Day 7 ± 1), treatment period (Visit 3: Day 9; Visit 4: Day 11; Visit 5: Day 14; Visit 6: Day 16; Visit 7: Day 18) and end of study (Visit 8: Day 21 ± 1). Patients were administered TQL weighing 1650 mg (manufactured by Dr. Reddy's Laboratories) thrice a day for 2 weeks. Each TQL contained xylitol, lactose monohydrate, isomalt, acacia, hydroxypropyl cellulose, sucralose and magnesium stearate. There was no relation of the drug dosage to the meals and patients were advised to continue with the permitted concomitant medications.

Statistical analysis
The effect of treatment was compared with the baseline variables using the general linear model of Chi-square tests. The XI scale, DTI scale and the patient satisfaction scales were recorded on a 5 and 7 points Likert scale, respectively. The responses were cumulatively grouped as the worst response together and the best responses together and then the analysis was carried out using Chi-square for the frequency outcome comparison of before and after the intervention for the overall population.

Patients
A total of 90 patients were enrolled and received TQL, of which 89 patients completed the study and one patient withdrew consent. At the discretion of the principal investigator, 6 patients were excluded from the study due to non-compliance and final data set evaluation was done for 83 participants. The mean age of the patients was 45.3 years and the majority were men (69.0%). Half of the patients had normal body weight (Table 1).

Efficacy
Patients displayed favourable outcomes to the TQL with a reduction in the mean (SD) XI (Baseline: 38. 2       How satisfied or dissatisfied are you with the ability of the medication to prevent or treat your condition? How convenient or inconvenient is it to take the medication as instructed? Overall, how confident are you that taking this medication is a good thing for you? QoL due to complications in chewing/swallowing and an increased risk of oral disease [1]. Treatment with sugar-free TQL showed a significant reduction in xerostomia and thirst and a decrease in consumption of fluid. Patients also showed satisfaction with TQL use in reducing dry mouth. Available treatment options have limited success in terms of alleviating thirst and associated comorbidities in these patients. A few studies, which were conducted to evaluate the efficacy of treatments with pharmacological as well mechanical actions such as pilocarpine, artificial saliva, chewing gum, and acupressure in patients with xerostomia on hemodialysis, were inconclusive and/or contradictory for xerostomia symptoms (such as salivary flow and impact on thirst) [14][15][16][17][18]. Clinical benefits have been reported with saliva substitutes in patients with radiotherapy-related xerostomia or with Sjögren syndrome [9][10][11]. A cross-sectional study in patients on hemodialysis has demonstrated that 2-week treatment with chewing gum and saliva substitute significantly reduced XI (p = 0.024) and DTI (p = 0.015) scores compared to baseline [19]. In contrast, in another study, regular use of sugarless chewing gum for 3 months did not alleviate xerostomia symptoms and thirst in a group of 38 patients on hemodialysis [15].
In a randomized study, patients on chronic hemodialysis who had received liquorice mouthwash showed significant lowering of XI scores at day 5 and day 10 compared to baseline [20]. Another study reported that xerostomia improved in terms of reduced XI score with 4 weeks of treatment with auricular acupressure [18]. Additionally, the other treatment options used for the management of dry mouth and to prevent damage of salivary glands including pilocarpine and cevimeline, reported severe AEs (sweating, vomiting, and diarrhea) [1].
Above studies on xerostomia have shown efficacy with different treatment strategies but not proven as a complete standard-of-care for xerostomia in patients with ESKD undergoing hemodialysis. The current study showed clinical benefits of the TQL for xerostomia, patients' answers to individual questions, which its form.
There was a significant reduction in the mean (SD) fluid consumption from 718.9 (178.4) mL at baseline to 568.1 mL (260.2; p = 0.001) at the EOS. Visit to visit comparison showed a reduction in fluid consumption at every visit until EOS ( Table 5).
The IDWG was monitored throughout the study. Mean (SD) weight was 62.2 kg (7.9) at the baseline and 62.4 kg (7.9) at the EOS with no significant change ( Table 6).

Safety
No serious AEs or deaths were reported in the study. One patient discontinued the study due to diarrhea; however, this resolved later. No major changes were observed in blood glucose levels. The mean (SD) fasting blood glucose was 101.1 (85.1) mg/dL at the baseline and was 90.8 (22.9) mg/dL at the EOS. The mean postprandial glucose level was 124.8 (20.8) mg/dL at baseline and 126.6 (20.8) mg/dL at the EOS.

Discussion
Xerostomia, often encountered in patients on chronic hemodialysis, negatively impacts the patients'  altogether evaluated overall XI scores, showed that at baseline, higher proportion of the patients required sip of liquid for swallowing food, felt dryness of mouth when eating a meal, frequently drank water during the night, had dryness of mouth, and difficulties in eating dry food. Reduction in all the above individual complications was reported with the lozenges and at the EOS, a high number of patients answered 'never' or 'almost never' for these questions. Similarly, in the DTI questionnaires at baseline, patients opted for 'often' or 'fairly often' in response to the following questions-thirst was a problem, thirsty during the day, thirsty during the night, social life influenced by thirst, thirst before, after, and during the dialytic session. However, at EOS, a high proportion of patients treated with lozenges answered 'never' or 'almost never' for the above complications. Thirst and dry mouth impact the QoL of patients who are on hemodialysis. Thirst can be a sign of disorientation and discomfort in these patients [21]. Previously published studies reported that approximately 80% of the patients are non-adherent with restrictions on liquids, which eventually contributes to IDWG and reduced QoL [22].
Studies have reported a positive correlation among xerostomia, thirst and IDWG; in general, patients on hemodialysis with high levels of thirst and xerostomia, gain more weight between hemodialysis sessions [12,23]. The IDWG results from consumption of salt and liquids between two hemodialysis sessions [24,25]. Non-adherence to the fluid-restricted diet may result in complications, such as congestive heart failure and cardiovascular comorbidity, hypertension, and acute pulmonary edema [12,22]. In the current study, a significant reduction was reported in the mean fluid consumption from baseline to the EOS; mean body weight was consistent throughout the study and none of the patients experienced IDWG. This consistent body weight change observed during the study, despite a significant change in fluid consumption might be due to several other factors including diet which were not controlled during the study.
A strong association between xerostomia and reduced QoL has been reported earlier [26,27]. Our study reported enhanced QoL with the TQL. Overall, a significant difference was observed in the patients who were satisfied with the study treatment versus those who were not satisfied; patient's satisfaction was in terms of relief in condition, relief in symptoms, side effects, timing of medication, and overall confidence on medication and its form. The study is limited by the inherent limitation of being an open-label, single-arm study, with short duration and small sample size. Further long-term head-to-head studies with large sample size are warranted to corroborate the results in this study.