The study design and key efficacy and safety end points of the two trials used in the analysis have been described in detail elsewhere (Winter et al. 2013; Mugie et al. 2014). Brief descriptions of the study designs are given below and an overview is provided in Table 1. Both studies were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996), the principles of the Declaration of Helsinki (World Medical Association, 2013), and local ethical and legal requirements. Written informed consent was obtained and signed by each child's legal guardian and by the investigator before the initiation of any study procedures.
Children were included in the study if they were aged 4–12 years, with Tanner stage I–II physical development (Marshall and Tanner 1969, 1970) and functional constipation (defined as a history of fecal impaction occurring periodically in the past 2 months in addition to fewer than three bowel movements per week and/or a history of fecal incontinence). They received a single dose of prucalopride 0.03 mg kg−1 in oral solution (0.2 mg mL−1) taken with 30-mL water. Two hours after dosing, children received a site-specific standardized snack of milk and cookies. Blood samples of 1 mL each were taken at the following times postdose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48, and 72 h. Urine was collected before prucalopride administration and for 0–6 h, 6–12 h, and 12–24 h periods postdose. Prucalopride concentration was determined in plasma using a validated radioimmunoassay technique described previously (Winter et al. 2013), which is linear over the range 0.1–55.0 ng mL−1 and has a lower limit of quantification (LLOQ) of 0.1 ng mL−1. Accuracy and precision were measured for the quality control samples (0.17–10.1 ng mL−1): the mean accuracy ranged from 90.8% to 97.7% and overall precision from 5.0% to 13.4%.
Children aged from 6 months to 18 years with functional constipation were treated with prucalopride or placebo in an 8-week double-blind phase, and were then entered into a 16-week open-label, active comparator phase (PEG 4000). Although the inclusion criteria specified an age of 6 months or older, in practice, no patients younger than 1 year were recruited. Patients were defined as having functional constipation if they had two or fewer spontaneous bowel movements per week with at least one of the following during the month (or 2 months for those aged ≥4 years) before inclusion in the study: at least one episode of fecal incontinence per week (after acquisition of toileting skills); history of retentive posturing or excessive volitional stool retention; history of painful or difficult bowel movements; presence of a large fecal mass in the rectum; or history of large-diameter stools.
Patients were randomized to receive once-daily doses of placebo or prucalopride 0.04 mg kg−1 up to a maximum dose of 2 mg. After 4 weeks of treatment, the dose could be adjusted for each patient (maximum total dose of 2 mg once daily). A dose increase to 0.06 mg kg−1 had to occur if there were no safety concerns and there was an insufficient response to treatment, and a dose decrease to 0.02 mg kg−1 had to occur if there were safety/tolerability concerns that were likely to be related to treatment and there was a sufficient response to treatment.
Sparse PK blood sampling was conducted: one sample was collected at the start of treatment on day 1 (1–3 h postdose, close to maximum plasma concentration [Cmax]) and two samples were collected at steady state, after 8 and 24 weeks of treatment (at 14–26 h postdose, close to expected minimum drug concentration [Cmin]).
Prucalopride concentrations were determined from blood samples using a validated high-performance liquid chromatography–tandem mass spectrometry method. The LC/MS/MS system was comprised of the following devices (Shimazdu Corporation, Columbia, MD): SIL-30ACMP autosampler set to 4°C; CBM-20A controller; CTO-20AC column oven set to 25°C; and LC-30AD pumps. Mobile phase A consisted of 0.1 mol/L ammonium acetate in reverse osmosis water (pH 7.0). Mobile phase B consisted of 1 mol/L ammonium acetate in reverse osmosis water (pH 7.0): MeOH: ACN (10:45:45, v/v/v). An Xbridge C18, 4.6 × 250 mm, 5 μm analytical column was employed (Waters, Milford, MA), and flow rate was set to 0.8 mL/min. The high-performance liquid chromatography (HPLC) gradient started at 100% mobile phase A, ramped to 20% mobile phase B in 1 min; ramped from 20 to 35% mobile phase B in 9 min; ramped to 37% mobile phase B in 6 min; ramped to 100% mobile phase B in 14 min and held for 5 min, eventually returned to initial conditions in 0.1 min, and re-equilibrated for 4.9 min.
A Q Exactive™ mass spectrometer with Xcalibur 2.2 software was utilized (Thermo Fisher Scientific, Waltham, MA). The following MS conditions were employed with the heated electrospray interface (HESI): positive ion or positive/negative ion switching polarity; capillary temperature set to 300°C; sheath gas flow rate was 75 arb; auxiliary gas flow rate was 15 arb; sweep gas flow rate was 3 arb; S-lens level was 50; and heater temperature was 500°C. The survey scan event cycle range was m/z 100–1000 at resolution 70,000 full width at half-maximum (FWHM), and the data-dependent scans were at resolution 35,000 FWHM or 17,500 FWHM.
The method was linear over the range 0.2–100 ng mL−1 and had an LLOQ of 0.2 ng mL−1. Accuracy and precision were measured for the quality control samples (0.60–80 ng mL−1): the mean accuracy ranged from 99.2% to 103.2% and the overall precision from 3.9% to 4.1%.
HESI Constipation Case Study1.The RN observes Joan's abdomen is firm and distended. The RN performs and abdominal assessment. In what sequence should RN perform it? Inspection, auscultation, percussion, palpation2.Which assessment is most important for RN to perform? Auscultate bowel sounds- b/c of subjective data reported by Joan (bloat and nausea) and objectivedata (abdomen firm and distended), RN's first concern is that Joan may have decreased peristalsis.3.In assessing bowel sounds, it's important for the nurse to perform which actions? -Listen up to 5 minutes when auscultating bowel sounds. -inspect first and then auscultate for bowel sounds before percussing and palpating (RN should inspect first, and then auscultate for bowel sounds before percussing and palpating. Percussion and palpation can alter abdominal findings, so inspection and auscultation are indicated prior to percussion and palpation)4.The RN auscultates her bowel sounds and hears faint gurgling sounds after 3 min. How will nurse record finding Hypoactive bowel sounds5.While the RN is completing the assessment, Joan starts crying and laments, "I just knew something would go wrong." How should RN respond? Tell me what is making you feel so upset6.Joan tells RN she hates hospitals because, she says, "nobody ever tells you what's happening, and you end up with all these things going wrong." Which response by RN will encourage continued verbalization by the client? It sounds as if you have had another experience that did not go so well7.Joan responds, "I did everything my HCP told me to do. The surgery must have failed. It was supposed to make my intestines work better!" How should RN respond? Explain to client the multiple factors that can decrease peristalsis postoperatively, even when the desired surgical outcome is achieved (constipation is not a poor surgical outcome. multiple factors surrounding abdominal surgery can lead to decreased peristalsis)8.The RN explains to Joan that she has developed constipation, probably as the result of a number of factors. Joan has not been taking oral fluids well, but she has been receiving IV fluids. Her total fluid intake for the previous 24hrs was