2 Minute Medicine Rewind January 25, 2016

Eluxadoline for Irritable Bowel Syndrome with Diarrhea

Current regimens for IBS, including dietary changes, anti-diarrheal agents, rifampin and alosetron, have limited efficacy. Eluxadoline is a new oral agent with mixed opioid effects that has shown promise in phase 2 trials for patients with diarrhea-prominent IBS. This phase 3 trial was a set of two randomized, double blind, placebo controlled, parallel group multicenter studies that involved 1282 patients in the first arm (IBS-3001 trial) and 1146 patients in the second arm (IBS-3002 trial). Enrolled patients were between 18 to 80 years who had IBS with diarrhea per the Rome III criteria and were assigned to either placebo, 75mg or 100mg eluxadoline. The primary end point was a composite reduction in average baseline score for abdominal pain and stool consistency. Results showed that compared with placebo, more patients in the eluxadoline groups reached the primary end point between weeks 1 and 12 of the trials. In IBS-3001, the primary end point was achieved by 23.9% of patients with the 75-mg dose and 25.1% with the 100-mg dose versus 17.1% for placebo with p=0.01 and p=0.004, respectively. Similarly, in IBS-3002, the primary end point was achieved by 28.9% and 29.6% of patients, respectively, versus 16.2% for placebo with p<0.001 for both comparisons. Similar results were found when analysis was extended to 26 weeks. The most common adverse events with eluxadoline were nausea, constipation and abdominal pain. In conclusion, this study showed the therapeutic effect of eluxadoline in reducing the symptoms of diarrhea-prominent IBS.

Laparoscopic Lavage for Perforated Diverticulitis With Purulent Peritonitis: A Randomized, Controlled Trial

Complicated diverticular perforation that results in peritonitis is treated with urgent surgical intervention, including colon resection and colostomy, which carries high risk of mortality. Recent literature suggests that such a perforation could instead be treated with laparoscopic lavage alone. This study was an open-label, randomized, controlled trial from Sweden and Denmark involving 83 patients that compared laparoscopic lavage (n=43) and the Hartmann procedure (n=40). Eligible patients had to have acute perforated diverticulitis, the presence of intra-abdominal free air or fluid on imaging, and were candidates for surgery. The primary outcome was the percent of patients having at least 1 reoperation within 12 months. Results indicated that fewer patients in the laparoscopic group (n=12, 27.9%) had reoperations compared with those in the Hartmann group (n=25, 62.5%), RR 0.41; 95% CI: 0.23 to 0.72; p = 0.004). Furthermore, total length of hospital stay was reduced in the laparoscopic group compared with that of the Hartmann group RR 0.65; 95% CI: 0.45 to 0.94; p = 0.047). Lastly, there was no statistical difference between mortality and adverse events between the two groups. The major limitation of this study was failure to enroll all patients that were eligible, likely secondary to the need to make rapid decisions in emergency situations involving patients with perforated diverticula.  In conclusion, this study showed that laparoscopic lavage was an effective method of managing diverticular perforation with peritonitis compared with the standard Hartmann’s procedure.

Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomized, phase 3, double-blind, double-dummy, non-inferiority study

Although preliminary evidence suggests the superiority of palonosetron compared to ondansetron in preventing chemotherapy induced nausea in adult patients, its safety and efficacy has not been well characterized in the pediatric population. This study was a randomized, multinational, phase 3 trial over 71 sites involving 502 patients that assigned patients to ondansetron, low dose palonosetron (10 μg/kg) or high dose palonosetron (20 μg/kg). The primary efficacy endpoint was complete response, defined as lack of vomiting or use of anti-emetic rescue medications, during the acute phase of the first chemotherapy cycle. Although inclusion criteria was extensive, in brief, the study enrolled patients from newborn to 17 years, with a bodyweight of at least 3.2kg, who had not received chemotherapy previously and who were scheduled to receive emetogenic chemotherapy. Results indicated complete response was achieved in 54% (n=90) patients in the 10 μg/kg palonosetron group, 59% (n=98) in the 20 μg/kg palonosetron group, and 59% (n=95) in the ondansetron group. The 20 μg/kg palonosetron group showed non-inferiority compared with ondansetron with weighted difference 0.36%; 97.5% CI: 11.7 to 12.4; p=0.0022). However, non-inferiority was not achieved with the 10 μg/kg palonosetron group. Lastly, the incidence of serious adverse events was lower in the high dose palonosetron group (n=43, 26%) than in the low dose palonosetron group (n=52, 31%) and the ondansetron group (n=55, 34%). In conclusion, this study corroborated the literature regarding palonosetron in the adult population and high-dose palonosetron was effective in preventing chemotherapy induced nausea in the pediatric population.

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

Currently, there is insufficient data to reliably stratify stage 1 & 2 colon cancer patients to adjuvant chemotherapy. This study relied on a new bioinformatics approach to search for biomarkers that could help with this stratification and CDX2, a transcription factor found in mature epithelial colonic tissues, was the top candidate in the study’s initial screening test.  Tissue samples were analyzed and divided into CDX2 positive and CDX2 negative groups. The primary outcome was 5 year disease free survival in patients. In the discovery data set of 466 patients, the primary outcome was lower in the CDX2 negative group (n=32, 6.9%) versus the CDX2 positive group (n=434, 93.1%), HR 3.44; 95% CI: 1.60 to 7.38; p=0.002. Similarly, in the validation set of 314 patients, the primary outcome was lower in the CDX2 negative group vs. versus the CDX2 positive group (12.1% vs. 87.9%, HR 2.42; 95% CI: 1.36 to 4.29; p = 0.003). Furthermore, the significance of the CDX2-negative status was validated clinically through analysis of 5-year survival rates after adjuvant chemotherapy, which demonstrated a higher rate of survival among the 23 CDX2 negative patients treated with adjuvant therapy versus the 25 CDX2 negative patients not treated with chemotherapy. In conclusion, this study identified CDX2 as a viable biomarker for stratify patients to receive adjuvant therapy in stage II colon cancer and showed higher rates of disease free survival in CDX2 negative patients treated with adjuvant therapies.

Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-center, randomized controlled trial

Third generation cephalosporins such as ceftriaxone are routinely used in the treatment of enteric fever, secondary to S. typhi and S. parathypi, yet are associated with slow response and a high burden of relapse. In contrast, gatifloxacin is associated with faster fever clearance and low rates of relapse. In this open, label, randomized superiority trial, 239 patients in Nepal were assigned to either gatifloxacin 10mg/kg (n= 120) or IV ceftriaxone 60mg/kg (n=119) and were evaluated for treatment failure, defined as fever clearance time of more than 7 days, need for rescue treatment, microbiological failure or disease relapse or disease complications. Eligibility criteria included children aged 2-13 years and adults aged 14-45 years with suspected enteric fevers. Results indicated treatment failure, the primary outcome, in 15% (n=18) of patient receiving gatifloxacin and 16% (n=19) in patients receiving ceftriaxone, HR 1.04; 95% CI: 0.55 to 1.98, p=0.91. In the culture confirmed population, results were less promising. 26% failed treatment in the gatifloxacin group and 7% in the ceftriaxone group (HR 0.24; 95% CI: 0.08 to 0.73; p = 0.01). Furthermore, there was a higher incidence of resistance among S. typhi in the gatifloxacin group, requiring premature termination of the trial. In conclusion, this study showed the gatifloxacin and other fluoroquinolones should not be used in treatment of enteric fever.

Image: PD

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