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CLP-1001 failed to improve symptoms, exercise performance in patients with HF
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LAS VEGAS — Treatment with a cross-linked polyelectrolyte polymer yielded similar results to placebo for the improvement of symptoms of fluid overload and exercise performance in patients with HF, according to data from the STEPWISE trial presented at the Heart Failure Society of America Annual Scientific Meeting.
The double blind, multicenter trial assessed CLP-1001 (Sorbent Therapeutics), a nonabsorbed, superabsorbent cross-linked polyelectrolyte polymer. The polymer, which absorbs water and attracts sodium and potassium cations in the gastrointestinal tract, is intended for the prevention and treatment of hyperkalemia, as well as management of congestion.
STEPWISE followed a phase 2a study that assessed the effect of CLP-1001 vs. placebo on serum potassium levels. Data from 111 patients with HF and chronic kidney disease indicated no significant effect on serum potassium, but a trend toward improvement in 6-minute walk test, body weight, Kansas City Cardiomyopathy Questionnaire (KCCQ) score and NYHA class.
The primary endpoint for STEPWISE was a composite of changes in 6-minute walk test, body weight, KCCQ quality-of-life score and NT-proBNP, as well as time to HF, renal failure or death. Participants were randomly assigned to CLP-1001 (n=135) or placebo (n=139) for 8 weeks. The starting dose was 7.5 g mixed with food every other day, with gradual increases to 7.5 g daily, 7.5 g daily with an additional 7.5 every other day, and finally 7.5 g twice daily, in the absence of contraindications or a need for dose reduction. Patients also underwent an additional 4 weeks of follow-up via telephone after completing the regimen.
All participants had been hospitalized for HF or underwent unscheduled outpatient treatment due to congestion in the previous 2 to 8 months, with incidences of HF including pulmonary congestion as indicated by chest X-ray, peripheral edema or ascites, or both. Patients had serum potassium levels of 4 mEq/L or higher and an estimated glomerular filtration rate of 25 mL/min/1.73 m2 to 80 mL/min/1.73 m2.
The study was terminated early by the sponsor, without informing the steering committee, due to a withdrawal of funding. Upon termination, 94% of the placebo group and 90% of the CLP-1001 group had completed the 8-week regimen, and 86% and 82%, respectively, had also completed the 4-week post-treatment follow-up period.
The two groups did not differ significantly with regard to the primary outcome (P=.3241). For individual components of the endpoint, results slightly favored the placebo group with regard to changes in 6-minute walk test and NT-proBNP, as well as time to HF/renal failure/mortality. The researchers noted that the largest differences in z scores occurred for body weight and KCCQ score, both of which favored CLP-1001. Sustained, significant differences in serum potassium levels occurred in the CLP-1001 group at 4 weeks (–0.4 mmol/L; P<.0001) and 8 weeks (–0.3 mmol/L; P=.0172). Significant transient reductions in serum magnesium (–0.1 mmol/L; P<.0001) and serum creatinine levels (–0.08 mg/dL; P=.013) were also observed.
“[CLP-1001], as administered in this study, did not improve symptoms or exercise performance, and was neutral in its primary endpoint,” John G.F. Cleland, MD, of Imperial College London, said during his presentation. “In contrast to the phase 2a study, serum potassium fell, so we have achieved the primary endpoint of the wrong study.”
Cleland added that some remaining issues warranting assessment include whether the results were related to dose issues, as the phase 2a study incorporated a larger dose than those in STEPWISE, and the degree of adherence to the intervention. – by Adam Taliercio
For more information:
Cleland JGF. Late-Breaking Clinical Trials. Presented at: the Heart Failure Society of American Annual Scientific Meeting; Sept. 14-17, 2014; Las Vegas.
Disclosure: Cleland reports serving as an adviser to Sorbent Therapeutics.
Perspective
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Javed Butler, MD, MPH
Patients with HF are known to have residual congestion, despite therapy, that may be subclinical and not evident on routine examination. Persistent congestion, either on examination or as assessed with invasively measured pulmonary capillary wedge pressure or natriuretic peptide levels, correlates with worse prognosis. However, diuretic therapy is associated with worsening renal function, and therefore may not be used aggressively. Thus, alternate means of decongesting patients are needed. Similarly, the risks of hyperkalemia with drugs that modulate the renin-angiotensin-aldosterone system, especially the mineralocorticoid receptor antagonists, limit either initiation or up-titration of these medications to recommended doses. This is particularly a concern among patients with renal insufficiency, which is common in HF.
The STEPWISE trial assessed a cross-linked polyelectrolyte (CLP) polymer that absorbs water in the gastrointestinal tract. Also, the molecule’s high density of negative charges attracts cations like Na+ in the small bowel and K+ in the colon. Thus, this orally administered agent has the potential to treat both congestion and hyperkalemia — and, in turn, help optimize HF therapies.
In this trial, 274 patients were randomly assigned CLP-1001 vs. placebo and followed for 8 to 12 weeks. There was no difference in adverse outcomes between the two groups. The primary endpoint was a composite of changes in 6-minute walk test, body weight, quality-of-life scores, natriuretic peptide levels and clinical events. The primary endpoint was not significantly different between the two groups. Serum potassium concentration was lowered by the polymer, and the reduction in weight was similar to that observed in an earlier phase 2a study with this agent, but there was no difference in exercise performance or natriuretic peptide levels.
These results are difficult to clinically reconcile, and highlight an issue related to the use of highly sophisticated composite endpoints. For example, clinically, one would expect reduction in weight as a sign of effective decongestion, which should lead to a reduction in natriuretic peptide levels, as well as improvement in exercise tolerance. Thus, it is difficult to interpret the results of this study. Moreover, the sponsor terminated the study before complete follow-up, which adds to the complexity.
Overall, the study did not reach its primary endpoint, and had mixed results that neither confirm nor reject the benefits of this therapy. However, considering that this polymer addresses two unmet needs in patients with HF, and appears to be safe, these mixed results necessitate further research with this or similar drugs, in order to assess the potential explanation for these results, including the right patient population, doses, duration of therapy and endpoint ascertainment.
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