Society: AGA

Introduction: Chronic nausea and abdominal pain are debilitating symptoms that often co-exist in children with functional abdominal pain disorders (FAPD). Standard medical therapy (SMT) includes the off-label medications, cyproheptadine and amitriptyline. While several pediatric studies have demonstrated the benefits of percutaneous electrical nerve field stimulation (PENFS) in children with FAPD, no study has compared outcomes of PENFS to SMT. We aimed to compare improvements in abdominal pain, nausea and disability using validated measures between these treatments.
Methods: The electronic medical records (demographic data and medical history) of patients aged 11-21 years who met the Rome 4 criteria for a FAPD and had been treated with 4 weeks of PENFS, cyproheptadine or amitriptyline were reviewed. Outcomes were evaluated using validated questionnaires collected as part of clinical care at baseline and follow-up within 3 months (FU) and included: Abdominal Pain Index (API), Nausea Severity Scale (NSS), and the Functional Disability Inventory (FDI).
Results: Of the 101 patients, 35% had functional dyspepsia and had IBS each while 30% had functional abdominal pain. Of these, 49 (48%) were treated with PENFS, 31 (31%) with cyproheptadine and 21 (21%) with amitriptyline and median ages in these groups were 17 (15-19), 16 (15-18) and 15 (11-16) years respectively. In all three groups, majority were females (75%, 90% and 52% respectively).
In the PENFS group, API (p=0.001), NSS (0.05) and FDI (p=0.04) were lower at FU compared with baseline. All scores decreased but were not significant in the cyproheptadine group. API scores decreased at FU in the amitriptyline group (p=0.03). Examining each outcome longitudinally, the API and NSS scores were lowest in the PENFS group. The FDI scores however, were lowest in the amitriptyline group.
Comparing outcomes between groups, API scores were significantly lower in PENFS versus cyproheptadine (p=0.04) but not between PENFS and amitriptyline (p=0.64, figure 1). The NSS scores were significantly lower in PENFS vs. cyproheptadine (p<0.001), between PENFS vs. amitriptyline (p<0.001) and in amitriptyline vs. cyproheptadine (p=0.04). The FDI scores were only lower in the amitriptyline vs. cyproheptadine group (p=0.03).
Conclusion: In children with FAPD, PENFS showed improvements in abdominal pain, nausea and disability while amitriptyline showed improvements in abdominal pain within 3 months of treatment. PENFS was more effective than SMT in reducing nausea scores within 3-month follow-up. PENFS was also more effective than cyproheptadine in improving abdominal pain scores but did not differ from amitriptyline. Amitriptyline improved disability scores more than cyproheptadine.

<b>Figure 1. Outcomes between PENFS and SMT</b><br /> Pairwise comparison of outcomes between PENFS and SMT examined using linear mixed modeling; data presented as Least Square (LS) Means and 95% Confidence Interval (CI) and p-value indicate pairwise group difference; PENFS: Percutaneous Electrical Nerve Field Stimulation, SMT: Standard Medical Therapy, API: Abdominal Pain Index, NSS: Nausea Severity Scale, FDI: Functional Disability Inventory, <i>n=101 patients</i>

Figure 1. Outcomes between PENFS and SMT
Pairwise comparison of outcomes between PENFS and SMT examined using linear mixed modeling; data presented as Least Square (LS) Means and 95% Confidence Interval (CI) and p-value indicate pairwise group difference; PENFS: Percutaneous Electrical Nerve Field Stimulation, SMT: Standard Medical Therapy, API: Abdominal Pain Index, NSS: Nausea Severity Scale, FDI: Functional Disability Inventory, n=101 patients

Introduction: Functional constipation (FC) is prevalent in childhood and can severely impact quality of life, but no prescription treatments are US Food and Drug Administration (FDA)-approved for pediatric use. In adults, linaclotide (LIN), a guanylate cyclase-C agonist, is FDA-approved to treat chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. This phase 3 trial assessed the efficacy and safety of LIN vs placebo (PBO) in pediatric patients aged 6 to 17 years with FC.

Methods: This phase 3, randomized, double-blind, PBO-controlled study (NCT04026113) enrolled patients aged 6–17 years who met modified Rome III criteria for FC. Participants were randomized 1:1, stratified by age group (6–11 and 12–17 years), to receive LIN 72 μg or PBO once daily for 12 weeks. The primary efficacy endpoint was change from baseline in 12-week spontaneous bowel movement (SBM) frequency rate (SBMs/week). The key secondary efficacy endpoint was change from baseline in 12-week stool consistency based on the Bristol Stool Form Scale. Comparisons between LIN and PBO for efficacy endpoints were conducted using an analysis of covariance (ANCOVA) model with study intervention, with age group as fixed factors and baseline value as a covariate. Adverse events (AEs), laboratory values, vital signs, and electrocardiograms were monitored.

Results: Among 328 patients who received at least 1 dose of study drug (LIN, n=164; PBO, n=164), 55.2% were female and 69.8% were White; mean age was 11 years. Overall, 145 (88.4%) in the PBO and 148 (90.2%) in the LIN group completed 12 weeks of study treatment. Treatment groups had similar baseline stool frequency (mean SBMs/week, [SD]; LIN, 1.16 [0.83]; PBO, 1.28 [0.87]). Compared with PBO, LIN-treated patients showed significant improvement from baseline in 12-week SBM frequency rate (least square means, standard error; LSM, [SE]; LIN 2.22 [0.19] vs PBO 1.05 [0.19] SBMs/week; P < 0.0001) and 12-week stool consistency (LSM, [SE]; LIN 1.11 [0.08] vs PBO 0.69 [0.08]); P = 0.0001). Sensitivity analyses and analyses of age subgroups (Figure 1) were consistent with primary analyses. Treatment-emergent AEs (TEAEs) reported in >2% of patients were diarrhea (LIN, 4.3%; PBO, 1.8%) and COVID-19 (LIN, 2.4%; PBO, 3.0%). Both groups had similar proportions of patients with AEs: TEAEs (LIN, 17%; PBO, 21%), serious AEs (1.2% for both), and TEAEs leading to study treatment discontinuation (LIN, 1.2%; PBO, 1.8%). One AE of special interest of diarrhea was reported in a 17-year-old but it was considered not related to study drug and resolved within a day without sequelae.

Conclusion: LIN 72 μg once daily demonstrated significant improvement in the SBM frequency rate and stool consistency in pediatric patients with FC and exhibited a favorable safety profile consistent with prior adult data and a prior pediatric phase 2 FC study.

LS mean change from baseline in weekly SBM frequency for pediatric patients (aged 6-17 years) during the 12-week treatment period

LS mean change from baseline in weekly SBM frequency for pediatric patients (aged 6-17 years) during the 12-week treatment period

To date, there are no validated measures to assess chronic abdominal pain (AP) in clinical trials (CT) of children with Disorders of Gut-Brain Interaction (DGBIs). Currently used AP measures are extrapolated from studies on adults or children with acute AP. Those may not be suited to measure chronic AP. The EMA and FDA have not issued recommendations for pediatric CT on DGBIs. Rome IV criteria only recommended the 1-10 numeric rating scale (NRS) and the 1-100 visual analogue scale (VAS). This recommendation was mostly based on expert opinion. The document stressed the great need for studies validating AP measures. Still, no studies were published. This hinders the strength of evidence of future recommendations. AIMS- Primary- Assess commonly used pain scales in children with DGBIs. Secondary- Compare specific pain measures with the overall subjective assessment of AP well-being in children. Methods- Prospective nested study from multicenter crossover RCT. Children with AP-DGBIs completed daily diaries for 7 weeks. It included 3 widely used AP scales: NRS, VAS, Faces Pain Scale Revised (FPS-R), and a global improvement question from a large multicenter pediatric RCT on AP-DGBIs. “Did your belly feel OK today?”. Scales were normalized to a 10-point measure. Strength of correlations among scales and questions was assessed with Pearson Correlation Coefficient (r). Results-30 subjects (mean [SD] age, 14.1 [3.4] years; 24 female [80.0%]; 16 [53.3%] functional AP, 14 [46.7%] IBS completed the study. Children completed 4975 of 5880 (84.6%) responses. Means and standard deviation of AP intensity: VAS 4.22 [2.43], NRS 4.25 [2.32], FPS-R 4.10 [2.20] and global question 4.80 [0.50]. VAS and NRS had strongest correlation among them, r=0.906 (p<0.001). The FPS-R also demonstrated strong correlations with VAS r=0.774 (p<0.001), NRS r=0.771 (p<0.001). The 3 scales exhibited weaker but significant correlations with the global question: VAS r=0.676 (p<0.001), NRS r=0.684 (p<0.001), FPS- 0.640 (p<0.001). Strong correlations were consistent when stratified by gender and by age groups (9-14 years and 15-21 years). Conclusion: This is the first study to assess the most commonly used AP scales in children with DGBIs. It fills a gap in the literature, on time for future Rome V recommendations. It supports the recommendations of Rome IV on using the VAS and NRS scales. It also suggests that FPS-R that was not part of Rome IV can also be used in RCTs. As expected, and congruent with the biopsychosocial model, there was a weaker correlation between AP measures and the global improvement question. This suggests that the global question measures more domains than AP alone and that global questions should also be incorporated in DGBIs RCTs in children.

Lee Ginton

Appearances