Nutrition 65 (2019) 167À172 Contents lists available at ScienceDirect Nutrition journal homepage: www.nutritionjrnl.com Applied nutritional investigation Time to treatment response of a magnesium- and sulphate-rich natural mineral water in functional constipation Christophe Dupont M.D., Ph.D. a,*, Florence Constant M.D., Ph.D. b, Aurelie Imbert M.Sc. b, Guillaume Hebert Ph.D., M.B.A. c, Othar Zourabichvili M.D., Ph.D. d, Nathalie Kapel Pharm.D., Ph.D. e a Service d'Explorations Fonctionnelles Digestives Pediatriques, AP-HP, Hopital^ Necker Enfant Malade, Universite Paris Descartes, Paris, France b Nestle Waters M.T., Issy-les-Moulineaux, France c SC Partners, Paris, France d Quanta Medical, Rueil-Malmaison, France e Laboratoire de Coprologie Fonctionnelle, Hopitaux^ Universitaires Pitie Salp^etriere - Charles Foix, APHP, Paris, France ARTICLE INFO ABSTRACT Article History: Objectives: First-line recommendations for the management of functional constipation include nutritional- Received 11 June 2018 hygienic measures. We previously showed that a natural mineral water rich in sulphates and magnesium Received in revised form 22 February 2019 (Hepar) is efficient in the treatment of functional constipation. The aim of this study was to consolidate those Accepted 24 February 2019 first results and determine a precise time to respond to Hepar. Keywords: Methods: This multicenter, randomized, double-blind, controlled study of the effect of Hepar on stool consis- Bowel movement tency and frequency in functional constipation included 226 outpatients. After washout, patients used 1.5 L Functional constipation of water daily, including 1 L of Hepar or of low-mineral water, during 14 d. In addition to a daily reporting of Clinical trial stool consistency by the patient, an expert investigator blindly analyzed stool consistency (Bristol stool scale) Natural mineral water based on photographs taken by the patient. Treatment Results: The primary endpoint was met. Treatment response was more frequent in the Hepar arm than in the control group at day 14 (50% versus 29%, respectively; P = 0.001). Mean time to treatment response was shorter in the Hepar group (6.4 d) than in the control arm (7.3 d; P = 0.013). Concomitant stool scoring was available for 60% of the patients. Scores given to 79% of the stools were similar between the patient and the expert (differences 1). Safety analyses showed excellent results. Conclusion: This study confirms the efficacy and safety of Hepar in the treatment of functional constipation and shows that it is associated with a response within 7 d. Hepar could be a safe response to the current absence of first-line medication in the treatment of functional constipation. © 2019 Published by Elsevier Inc. Introduction performed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the magnesium- and sul- Chronic constipation has an estimated prevalence of 14% phate-rich natural mineral water Hepar in women outpatients (around 20% in France) and is twice as more frequent in women with functional constipation according to the Rome criteria III [7]. than in men [1À3]. It is associated with a major effect on patients’ No significant effect was observed at week 1 (primary criterion) quality of life and high health care and other indirect costs [4,5]. but constipation was significantly reduced after 2 wk of 1 L/d First-line recommendations are lifestyle changes, therapeutic Hepar. The 1 L Hepar group also showed very good safety, a education, and nutritional-hygienic measures including 15 to decreased number of hard or lumpy stools (Bristol stool scale, 40 g/d fiber and sufficient water intake [2,6]. In 2013, we P =0.030 versus baseline), and a substantial decrease in the use of rescue medication (P = 0.034 versus controls). Patient response This study was funded by Nestle Waters France. FC and AI participated in the correlated with magnesium and sulphate concentrations. How- study design; collection, analysis, and interpretation of the data, writing of the ever, that 4-wk study could not allow determining the precise report; and in the decision to submit the article for publication. CD, GH, NK, and OZ delay until response to the treatment (between 1 and 2 wk). Addi- ’ received honoraria for their participation in the study. FC and AI are Nestle Waters tionally, stool consistency was estimated using the Bristol stool employees. * Corresponding author: Tel.: +33 (0)1 44 49 25 60; Fax: +1 44 49 25 96. scale, based on the sole patient declaration, which could question E-mail address: [email protected] (C. Dupont). validity of this measurement. https://doi.org/10.1016/j.nut.2019.02.018 0899-9007/© 2019 Published by Elsevier Inc. 168 C. Dupont et al. / Nutrition 65 (2019) 167À172 The present study aimed to determine the precise delay until If abdominal pain became greater than 70 on a 100-mm visual analog scale response to 1 L/d of Hepar and confirm previous results [7]. In addi- (VAS), rescue medication (i.e., two sachets of 10 g macrogol 4000/d) was autho- tion, this study included a parallel stool ranking (Bristol stool scale) rized until return to the basal abdominal pain level. by an expert physician using photographs taken by the patient. Measurements During the screening visit (V0), the physician collected sociodemographic Methods characteristics, previous medical history and history of the constipation episode (Rome III criteria), onset of symptoms, abdominal pain on a 100-mm VAS, dietary Study design habits, physical activities, and previous and current treatments. The patient was provided with a self-evaluation via an e-diary to collect the following information: This was a multicenter, comparative, randomized, double-blind, placebo-con- trolled study to confirm efficacy of the daily consumption of 1 L/d of Hepar for 14 d in constipated outpatients. the number and type of stools (Bristol stool scale) [9]; Secondary objectives were to assess the mean time to response to the daily abdominal pain rating during the previous 24 h; consumption of 1 L of Hepar, and the effect of 1 L Hepar on stool frequency and physical activity; and consistency, abdominal pain, and Rome III criteria. drug, water, beverage, and food consumption during washout. Participants At inclusion (V1), the physician collected information on the following: Healthy patients meeting all of the following criteria were included in the the weekly number and type of stools; study: Rome III criteria; patient's ability to complete the e-diary; Female outpatients ages 18 to 60 y; patient compliance with the washout treatment (count of unused bottles); and Having diagnosis of functional constipation according to the Rome III criteria [8]; patient's use of rescue medication over the previous week. Not using any laxative drug for 3 d before screening; Having easy access to toilet; fi During the nal visit (V2), the physician collected information on the Regularly eating vegetables and fruits; following: Participating in physical activity, reasonable walking periods, or exercise twice or three times a week; and the weekly number and type of stools; Drinking 1. 5 § 0.5 L/d of water. Rome III criteria; adverse events (AEs); Patients who presented any of the following criteria were excluded from the study: patient compliance with the treatment (count of unused bottles); and patient's use of rescue medication over the previous 2 wk. Known dissatisfaction with Hepar; For the washout and the treatment periods, the type of stool was assessed Treatment or disease (current or past) likely to interfere with evaluation of the directly by the patient on the e-diary (Bristol stool scale) [9] and also was analyzed study parameters; and blindly by an expert investigator (Bristol stool scale). The expert performed a blind Documented pregnancy. review of stool consistency based on photographs taken by patients of each of their stools. These photographs were made accessible through an online database. Both The study was conducted by 28 city-based general practitioners located evaluations from the patient and the expert were performed according to the Bris- throughout France. tol stool scale, which classifies stools in seven types, with type 1 and 2 indicating marked constipation; types 3, 4, and 5 indicating normal stool form; and types 6 and 7 indicating diarrhea. Pictures not clear enough to allow analyze were not con- Interventions sidered by the expert. After a screening visit, patients followed a washout period during 7 to 9 d before Outcomes study inclusion. Patients had to stop any drug treatment that would interfere with transit and drink 1.5 L/d of a low-mineral spring water (Nestle Purelife, Nestle The primary endpoint was the response to a 2-wk 1 L/d Hepar water consump- Waters, France). At the inclusion visit, patients were randomized to the control or tion. It was evaluated using a composite variable based on two separate compo- Hepar group according to the chronological order of inclusion and to a predeter- nents of the Rome III criteria: mined randomization list in balanced blocks of four treatment units (SAS software; SAS Institute, Cary, NC, USA). The randomization list was prepared in advance by the statistician from the society in charge of the logistic of bottles and secured in an elec- 4 stools per week or an increase of 2 stools as compared with baseline and tronic file with restricted access. Two sets of sealed envelopes kept by the investiga- <25% of lumpy or hard stools, as reported by the patient. tor and the study manager in a secure and locked place were generated to contain the patient's randomization number and allocated group. The investigator could Both of these criteria were required to consider a patient had responded to break the blinding in case of absolute emergency and in accordance with the spon- treatment.