Following informed consent, 54 patients were screened and 49 (25 males and 24 females) were enrolled. Patients were excluded for a normal biopsy at baseline that ruled out proctitis (n = 1), disease extending beyond the rectum, to the 20-cm biopsy (n = 2), and biopsy confirming Crohn’s disease (n = 2). The study population was male (51%) and primarily Caucasian (87.8%) with a mean age of 12.5 ± 3.51 (SD) years (). Forty-one (83.7%) subjects had a history of ulcerative proctitis, with a mean time since onset of 1.7 ± 1.82 years. Only 36.7% of recruited patients were already taking a stable dose of 5-ASA or sulfasalazine (average dose 2.0 g/day) at dosages compliant with the protocol.
Demographic and Baseline Characteristics (N = 49)
Of the 49 enrolled patients, 45 patients (91.8%) remained on the 500 mg dosage for the entire duration of their involvement in the trial. Only four patients (8.2%) had their dose increased from 500 mg to 1000 mg (500 mg twice daily) at the first follow-up visit. The dose increase was due to worsening or no change in the patient’s condition, as evaluated by the PGA despite a DAI close to 4 in three of these four patients.
Thirty-seven patients (75.5%) completed the trial. Nearly 25% (n = 12) of patients terminated early due to treatment-emergent adverse event (n = 1), biopsy reading not confirming ulcerative proctitis diagnosis (n = 7), treatment failure (n = 2), C. difficile in stools (n = 1), or poor protocol compliance (n = 1). Of note is that patients could be enrolled in the study pending biopsy and stool culture results. If proctitis was not confirmed in these patients they were withdrawn from the study but included in the safety analysis. Among the 37 patients who completed the 6-week trial, 29 (78.4%) underwent all study procedures, while eight patients (21.6%) did not (most missed follow-up stool culture).
Treatment compliance, assessed by suppository returns, was 97.9% ± 5.8% from baseline to week 3 and 96.7% ± 9.1% from week 3 to week 6.
The ITT population (n = 49) had DAI mean scores at baseline of 5.5 ± 1.4 (range 4–11) (, ). Significant reductions from baseline were observed in mean DAI scores at week 3 (1.6 ± 2.0; P < 0.0001) and at week 6 (1.5 ± 1.9; P < 0.0001) (). The primary efficacy endpoint was the change in DAI score from baseline to week 6. At week 6 the mean DAI score had decreased by −4.0 ± 2.1 (P < 0.0001 versus baseline) (). No differences were observed in the change in DAI score between weeks 3 and 6.
Disease Activity Index (DAI) Score (Intent-To-Treat-Population; N=49)
Individual DAI Components and PGA After Mesalamine Treatment (500 mg HS or BID) in the ITT Population, N = 49
DAI scores throughout study visits. DAI, Disease Activity Index; ***highly significant from baseline. For week 6 DAI scores the LOCF method was used for missing data.
Significant differences were observed for all individual DAI components between baseline and week 3 and baseline and week 6 (), although no statistical differences were observed in individual DAI components between week 3 and week 6.
Data were available from 45 patients who could be analyzed for response and remission status. Response was achieved in the vast majority of patients (n = 42; 93.3%) at week 3 and at week 6 (n = 44; 91.7%). Similarly, the majority of patients met criteria for remission at week 3 (n = 37; 82.2%) and at week 6 (n = 39; 81.3%).
At baseline the majority of subjects were negative for pANCA (n = 35; 72.9%) and ASCA (n = 46; 95.8%). Patient response to treatment did not correlate with either pANCA or ASCA in this study population.
Descriptive statistics for the ITT population are presented for PGA scores obtained at week 3 and week 6 (see ). At week 3 physicians assessed 85.4% of patients (n = 41) as “minimally improved” (n = 6) or “much improved” (n = 35). Similarly, in the PGA scores at week 6 the physicians assessed 81.25% of patients (n = 39) as “minimally improved” (n = 5) or “much improved” (n = 34). By weeks 3 and 6, very few patients were assessed as “no change” (week 3: n = 4; (8.3%); week 6 n = 2; (4.2%), “worse” (week 3: n = 3 (6.3%); week 6 n = 7; (14.6%) or “much worse” (week 3: n = 0; 0%; week 6 n = 0; 0%).
All 49 patients included in the safety population received at least one dose of study drug. The total extent of exposure to study treatment was 41.0 ± 9.3 days. A total of 41 patients out of 49 (83.7%) reported at least one treatment-emergent adverse event (TEAE) and a total of 169 TEAEs. The majority of TEAEs (69.2%) were mild and were considered not related to study therapy. The most common TEAEs judged to possibly be related to study drug were in the category of gastrointestinal disorders and nervous system disorders, the most frequent in each respective category being abdominal pain (16.4%) and headache (8.2%). Three serious TEAEs were reported by two patients: one case of anemia requiring a blood transfusion (considered two events) and one case of emotional disorder. None were considered to be related to study therapy. Gastrointestinal disorders (mostly abdominal pain, diarrhea, or vomiting) represented the TEAEs reported by the highest number of patients (n = 30, 61.2%). Other TEAEs included: 1) burning/heat sensation at suppository administration site (n = 9, 18.4%); 2) headache (n = 13, 26.5%); and 3) retrosternal pain/heartburn (n = 6, 12.2%). Hematology, serum chemistry, and urinalysis laboratory values remained within normal ranges and/or the observed changes were deemed not clinically significant.