Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of ...action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis.
This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4.
Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl,
<0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively.
A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone.
AMPLIFY, NCT03824587.
Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular ...phosphate transport.
In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg the latter down-titrated, if needed) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group.
Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg down-titrated dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action.
Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.
Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of ...tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C).
In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period.
Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45 years, 81.4% women), a significantly greater proportion of patients treated with tenapanor met the primary endpoint than patients treated with placebo (27.0% vs 18.7%, P = 0.020). Abdominal symptoms and global symptoms of IBS also improved with tenapanor (P < 0.05 vs placebo). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in 6.5% and 0.7% of patients receiving tenapanor and placebo, respectively, during the 12-week treatment period.
Tenapanor 50 mg b.i.d. improved IBS-C symptoms and was generally well tolerated, offering a potential new treatment option for patients with IBS-C.
How do people determine the relative difficulty of mental tasks and physical tasks, and how do they determine the preferred order of such tasks? Is it harder to make such decisions if 1 task is ...mainly mental and the other is mainly physical than if both tasks are the same kind? To address these questions, we conducted 3 experiments. In experiment 1 we asked participants to judge the relative difficulty and preferred ordering of mental tasks (math problems). In experiment 2 we asked participants to judge the relative difficulty and preferred ordering of physical tasks (moving a bucket back and forth). In experiment 3 we asked participants to judge the relative difficulty and preferred ordering of the same mental and physical tasks as in the first 2 experiments but with 1 of the tasks being mental and the other being physical. We reasoned that if mental task difficulty and physical task difficulty share a common code and if task ordering is systematically related to task difficulty, then judgments in experiment 3 should be as systematic as judgments in Experiments 1 and 2. The results confirmed the prediction and helped extend the notion of common codes for perception and performance to the evaluation of task difficulty and task ordering. A surprising finding was that mental difficulty was implicitly judged to be more important than physical difficulty for the tasks and population studied here.
Public Significance Statement
It is vital for safety and efficiency for people to make wise decisions about which activities do when. This study showed that activities judged to be easy are generally chosen before activities judged to be hard. In addition, and addressing 1 of the biggest obstacles to a full understanding of how such decisions are made, the present research shows that activities of different kinds (mental tasks and physical tasks) are likely compared and ordered with respect to an underlying abstract code for difficulty. Another finding was that mental difficulty appeared to dominate physical difficulty.
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Returning home from the grocery store with a car full of groceries requires decisions about how many bags to carry when. If the decisions exemplify
procrastination
, people should carry more bags per ...trip in late trips than in early trips (putting the hard work off until later), but if the decisions exemplify the recently discovered phenomenon of
pre-crastination
(Rosenbaum et al. in Psychol Sci 25: 1487–1496, 2014), people should carry more bags per trip in early trips than in late trips (doing the hard work early). To distinguish between these possibilities, we asked university students to carry 5 or 11 dodgeballs from one bin to another 4, 8, 12, or 16 feet away in as many trips as they wished. A random half of the subjects did the tasks with an additional requirement to memorize and then recall 7 digits after carrying all the balls from the home to the target bin. Consistent with pre-crastination, participants carried the most balls per trip in early trips, and consistent with the hypothesis that pre-crastination relates to memory load, the number of balls carried per trip was affected by the presence of a memory load. The results add to the growing evidence for the generality of pre-crastination.
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CEKLJ, DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this article, we describe a phenomenon we discovered while conducting experiments on walking and reaching. We asked university students to pick up either of two buckets, one to the left of an ...alley and one to the right, and to carry the selected bucket to the alley's end. In most trials, one of the buckets was closer to the end point. We emphasized choosing the easier task, expecting participants to prefer the bucket that would be carried a shorter distance. Contrary to our expectation, participants chose the bucket that was closer to the start position, carrying it farther than the other bucket. On the basis of results from nine experiments and participants' reports, we concluded that this seemingly irrational choice reflected a tendency to pre-crastinate, a term we introduce to refer to the hastening of subgoal completion, even at the expense of extra physical effort. Other tasks also reveal this preference, which we ascribe to the desire to reduce working memory loads.
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The ultimate tool, it could be said, is the brain and body. Therefore, a way to understand tool use is to study the brain's control of the body. A more manageable aim is to use the tools of cognitive ...science to explore the planning of physical actions. Here, I focus on two kinds of physical acts which directly or indirectly involve tool use: producing finger‐press sequences, and walking and reaching for objects. The main question is how people make choices between finger‐press sequences, and how people make choices between walk‐and‐reach sequences. Are the choices made with reference to motor imagery, in which case the longer the sequences are the longer it takes to choose between them, or are shortcuts taken which rely on distinctive features of the alternatives? The reviewed experiments favor the latter alternative. The general view of action planning emerging from this work is one in which action features are highlighted and held in memory, not just to choose between potential actions but also to control the unfolding of long actions over time. Speculations are offered about tool use.
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Tenapanor is a first-in-class, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3. This study assessed the efficacy and safety of tenapanor in patients with ...constipation-predominant irritable bowel syndrome (IBS-C).
In this phase 2, double-blind study, patients with IBS-C (Rome III criteria) were randomized (1:1:1:1) to receive tenapanor 5 mg, 20 mg, or 50 mg b.i.d., or placebo b.i.d. for 12 weeks. The primary end point was the complete spontaneous bowel movement (CSBM) responder rate, defined as the proportion of patients reporting an increase from baseline of ≥1 CSBM/week for ≥6/12 treatment weeks. Secondary end points included abdominal symptom responder rates (≥30% score improvement from baseline for ≥6/12 weeks) and a composite responder rate (CSBM and abdominal pain response in the same week for ≥6/12 weeks).
Overall, 356 patients were randomized (mean age: 45.7 years; 86.8% women) and 304 completed the study. The CSBM responder rate was significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (60.7 vs. 33.7%; P<0.001), as was the composite responder rate (50.0 vs. 23.6%; P<0.001). Responder rates for abdominal symptoms (pain, discomfort, bloating, cramping, and fullness) were significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (all P<0.05). Diarrhea was the most frequent adverse event (tenapanor b.i.d.: 20 mg, 12.4%; 50 mg, 11.2%).
Tenapanor 50 mg b.i.d. significantly increased stool frequency and reduced abdominal symptoms in patients with IBS-C. Further research into tenapanor as a potential treatment for these patients is justified.
People judge the relative difficulty of different kinds of tasks all the time, yet little is known about how they do so. We asked university students to choose between tasks that taxed ...perceptual-motor control and memorization to different degrees. Our participants decided whether to carry a box through a wide (81 cm) or narrow (36 cm) gap after memorizing six, seven, or eight digits. The model that maximized the likelihood of observing the choice data treated the extra physical demand of passing through the narrow gap as functionally equivalent to memorizing an extra .55 digits. Substantively, the model suggested that participants judged the difficulty of the compound tasks in terms of separate resources. The approach introduced here may help interrelate different kinds of task difficulty.
Public Significance Statement
If a doctor must take a long walk to get easy-to-understand information about a patient or a short walk to get hard-to-understand information, how should the doctor decide? Little is known about people's judgments concerning the difficulty of different kinds of tasks. This article introduces a method for addressing this question. It offers a way of expressing the difficulty of one kind of task in terms of another, and provides a way of determining whether the resources for the two kinds of task are treated as independent or dependent.
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