Primary and secondary endpoint analysis of N08C9 (Alliance): A phase III randomized study of sulfasalazine versus placebo in the prevention of acute radiation enteritis.

Abstract

562 Background: An interim futility analysis at ASTRO 2013 led to early closure of N08C9 (Alliance), a randomized controlled trial (RCT) comparing sulfasalazine (SSZ) versus placebo (PBO) in the prevention of radiation enteritis during pelvic RT. This is the full analysis of the primary endpoint (PE) and secondary endpoints (SEs) of the trial. Methods: A multi-institutional RCT conducted by the Alliance for Clinical Trials in Oncology assessed the effect of 1000 mg SSZ b.i.d. versus PBO b.i.d. in the treatment of pelvic RT related enteritis. Study participants (SPs) received the study agents during RT and for 4 weeks afterwards. The PEwas the maximal severity of diarrhea toxicity (CTCAE version 4.0) during and up to 6 weeks after RT. SEs, including the maximum severity of diarrhea (MSD) and the duration of MSD, rectal bleeding, abdominal cramping, tenesmus, and constipation, were graded weekly during RT by a health care provider. Bowel function was assessed using a self-administered bowel function questionnaire weekly during RT, afterwards at 6 weeks, and at 12 and 24 months. A two-sided 0.05-level Wilcoxon rank-sum test was used to test the equality of the distributions of MSD grades. The planned study size was 128 SPs. Results: 87 SPs were enrolled in the study between 4/29/2011 and 5/13/2013, with evenly distributed baseline factors. Toxicity data were available in 84 SPs during RT and in 54 SPs in the 6 weeks following RT. There was no significant difference in the distribution of MSD grades between the SSZ and PBO arms (p=0.41 regardless of attribution; p=0.09 at least possibly attributed to the study agent). No significant differences were observed in SEs during RT and after RT, except the abdominal pain occurring after completion of RT was higher in SPs receiving SSZ (p=0.02). More SPs required antidiarrheal agents on the SSZ arm (49% vs. 29%, p=0.06). Conclusions: Despite prior single institution RCT’s suggesting a benefit for SSZ (Kilic 2001; Pal 2013) in this clinical context, the results of this large, multi-institutional trial demonstrate that SSZ does not reduce the risk of enteritis and may worsen acute GI toxicity during pelvic RT. Clinical trial information: NCT01198145.