A randomised controlled trial of Absorbatox™ C35 in Irritable Bowel Syndrome: A pilot study JR KLOPPERS A randomised controlled trial of Absorbatox™ C35 in Irritable Bowel Syndrome: A pilot study Jean Rial Kloppers 12795836 Dissertation submitted in partial fulfilment of the requirements for the degree Magister Pharmaciae in Clinical Pharmacy at the Potchefstroom campus of the North-West University Supervisor: Dr JC Lamprecht Co-supervisors: Mr GK John and Prof JR Snyman November 2008 (])etficatetf to qerartf (}Qa{ 'l(foppers, my Fiero, mentor and' 6e!Dvetffatlier. SO£I <JY.EO (i£0<RJ}f ! ABSTRACT Background: Irritable Bowel Syndrome (IBS) is one of the most common gastrointestinal disorders managed by primary care physicians and gastroenterologists. It is a recurrent and chronic disorder characterised by abdominal discomfort, bloating and altered defecation patterns. IBS casts significant burdens on patients' quality of life and has an enormous economic impact through direct costs in health care utilization and indirect costs through absenteeism from work. Many IBS sufferers have resorted to complimentary and alternative medicine (CAM) mainly because of the ineffective cure rate with conventional western treatment. It is estimated that 40% of IBS sufferers seek symptomatic relief from CAM. A lack of understanding of the pathophysiology mechanism has been labelled as the main cause for poor IBS management. Nevertheless, several hypotheses have been proposed, including abnormal motility, visceral hypersensitivity, inflammation and infection, neurotransmitter imbalance, and psychological factors. In addition, IBS patients are considered to be visceral hypersensitive to luminal factors and intestinal gas. Aim: To assess the efficacy of Absorbatox™ C35, a natural, non-toxic zeolite, with enhanced ion exchange capacity, as well as water and gas adsorbing properties, in the treatment of IBS in a 6-week randomised , double-blind, placebo-controlled trial with parallel group assignment. Methods: Ethical approval for the study was received (Ethical approval number NWU-0001- 008-S5) and the necessary consent from trial candidates were received as per international guidelines. Sixty-seven (67) IBS candidates were recruited for participation. Only th irty-three (33) patients met the trial entry criteria. IBS candidates were diagnosed using the Rome Ill diagnostic criteria. Organic diseases were first excluded by a full blood count and a physical examination. Any alarming symptoms, that could be indicative of diseases other than IBS, were also excluded during the preliminary examination. A 2-week run-in phase evaluated baseline symptoms. Patients were randomly assigned using a simple computer generated random codes system. Patients received 750 mg Absorbatox™ C35 three times daily or Placebo for 4 consecutive weeks. Symptoms were evaluated using validated questionnaires. The primary outcome was assessed using a global symptom endpoint, "adequate relief' questionnaire. Patients were characterised as overall responders if they reported "adequate relief' in 50% of treatment weeks. Secondary outcomes included a 50-point reduction in total severity score according to the IBS Severity Scoring System (!BS-SSS). The !BS-SSS was used to assess separate symptom ratings, such as abdominal pain, bloating , "bowel habit satisfaction" and disease "interference with life in general". Stool parameters, including consistency, frequency and urgency were also ass'essed. Statistical analysis was primarily based on intention-to-treat analysis. Secondary outcomes were analysed through descriptive statistics. Statistical significance level was pre-set at 0.05, which means that whenever p < 0.05, the null-hypothesis was rejected . Results: Seventeen (17) patients received Absorbatox™ C35 and sixteen (16) received Placebo. Two patients from the Absorbatox™ C35 group did not return after randomisation, hence only 31 patients were included in the intention to treat analysis. A total of twenty-nine (29) patients completed the entire study. A dropout rate of 12.12% (4/33) was encountered. At the end of treatment (12/15) 80% and 50% (8/16) of patients were classified as overall responders in the Absorbatox™ C35 and Placebo groups respectively (p = 0.085). After three and four weeks of treatment the number of weekly responders was significantly higher in the Absorbatox™ C35 group compared to the Placebo group (p = 0.02 and p = 0.016 for week 3 and 4, respectively). Moreover, both Absorbatox™ C35 and the Placebo groups were associated with significant decreases in the total severity score (p < 0.001 and p = 0.005, respectively). Likewise, both groups were associated with significant decreases in clinical parameters like pain, distension, bowel habit satisfaction and disease interference with life in general. No significant differences were observed between the Absorbatox™ C35 and Placebo groups in terms of total severity score and separate symptoms ratings. However, after 20 days of treatment the severity of distension was significantly lower in the Absorbatox™ C35 group compared to Placebo (p = 0.024). This effect was not sustainable, as the subsequent assessment (after 30 days of treatment) revealed no statistical significance between the two groups (p = 0.553). Absorbatox™ C35 was associated with a higher incidence of smooth stool (p = 0.049), but no significant difference were observed between the treatment groups in terms of stool frequency and urgency. Adverse events were of similar nature in both groups (p = 0.259). Conclusions: Although the placebo effect was largely present during the trial , Absorbatox™ C35 showed a trend towards better improvement in several endpoint measurements. The possible implications for future trials on Absorbatox™ C35 were summarised. A larger trial is recommended with adequate statistical power, which is to be conducted over an extended period of time, to obtain inter-subjectivity on the efficiency of Absorbatox™ C35 in IBS treatment. It was statistically estimated, that for the repetition of these findings under similar conditions, with an 80% and 50% response rate in Absorbatox™ C35 and Placebo respectively, 45 IBS patients would be needed in each treatment group in order to achieve statistical significance. Keywords: Irritable Bowel Syndrome, Absorbatox™ C35, zeolite, randomised controlled trial, efficacy, placebo. OPSOMMING Agtergrond: Prikkelbare dermsindroom (PDS) is een van die algemeenste gastro"lntestinale afwykings wat deur primere sorgdokters en gastroenteroloe behandel word. Dit is 'n herhalende en chroniese afwyking wat deur abdominale ongemak, opgeblasenheid en veranderde defekasiepatrone gekarakteriseer word. PDS veroorsaak dat beduidende laste op pasiente se lewenskwaliteit geplaas word en het 'n geweldige groat ekonomiese impak op direkte kostes in gesondheidsorgaanwending en indirekte kostes in die afwesigheid van werk. Baie PDS-lyers het hulle na komplimentere en alternatiewe medikasie (KAM) gewend, hoofsaakli k weens die oneffektiewe genesingspotensiaal van die konvensionele Westerse behandeling . Daar word geskat dat 40% van alle PDS-lyers simptomatiese verli gitng deur KAM soek. ' n Gebrek aan begrip vir die pato-fisiologiemeganisme word gesien as die hoofoorsaak vir die swak behandelingsuitkomste van PDS. Ten spyte daarvan, is verskeie hipoteses al voorgele, wat abnormale motiliteit, ingewandshipersensitiwiteit, inflammasie en infeksie, neuro­ oordraerwanbalans, en psigologiese faktore insluit. Daar is al voorheen aangemeld dat PDS pasiente ingewandshipersensitief is vir luminale faktore en intestinale gas. Doel: Om die effektiwitiet van Absorbatox™ C35 , 'n natuurlike, nie-giftige zeoliet, met 'n potensierende ioonruilingskapasiteit-, asook wateradsorpsie- en gasadsorpsie-eienskappe te ondersoek in die behandeling van PDS in 'n 6-weeklange ewekansige, dubbelblinde, plasebogekontroleerde proefneming met 'n parallelle groep indeling. Metodes: Etiese goedkeuring is vir die studie verkry (Etiese goedkeuringsnommer NWU-0001- 008-S5) en die benodigde toestemming , volgens internasionale riglyne, is van die proefnemingskandidate ontvang . Sewe-en-sestig (67) PDS-kandidate is vir deelname gewerf. Slegs drie-en-dertig (33) pasiente het aan die insluitingskriteria voldoen . PDS-kandidate is gediagnoseer aan die hand van die Rome Ill diagnostiese kriteria. Organiese siektes is aanvanklik deur 'n volbloedtelling en 'n fisiese ondersoek uitgesluit. Enige waarskuwingsimptome wat op ander siektes as PDS kon wys , is deur die aanvanklike ondersoek uitgeskakel. 'n 2-week ingangsfase het die basissimptome geevalueer. Pasiente is ewekansig volgens 'n eenvoudige rekenaargegenereerde ewekansige kodesisteem toegedeel. Pasiente het 750 mg Absorbatox™ C35 of Plasebo drie maal per dag vir 4 opeenvolgende weke ontvang. Simptome is aan die hand van gevalideerde vraelyste geevalueer. Die primere uitkoms is geassesseer deur van 'n globale simptoomdoel, "genoegsame verligting"-vraelys gebruik te maak. Pasiente is as algehele respondente gekarakteriseer as hulle "genoegsame verligting" in 50% van die behandelingsweke gerapporteer het. Sekondere uitkomste het 'n 50 punt vermindering in die totale felheidstelling op die PDS-Felheidstellingsisteem ('IBS-SSS') ingesluit. Die 'IBS-SSS' is gebruik om afsonderlike simptoomskattings, soos abdominale pyn, opgeblasenheid, "ontlastingsatisfaksie" en die siekte se "invloed op die lewe oar die algemeen" te assesseer. Stoelgangparameters, wat konsistensie, gereeldheid en dringendheid insluit is