title: Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043).
abstract: Red blood cell (RBC) hydration is regulated in part by the Ca(2+) -activated K(+) efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo-controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty-five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups.
authors.affiliation: University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Ataga
authors.forename: Marvin
authors.initials: M
authors.lastname: Reid
authors.forename: Samir K
authors.initials: SK
authors.lastname: Ballas
authors.forename: Zahida
authors.initials: Z
authors.lastname: Yasin
authors.forename: Carolyn
authors.initials: C
authors.lastname: Bigelow
authors.forename: Luther St
authors.initials: LS
authors.lastname: James
authors.forename: Wally R
authors.initials: WR
authors.lastname: Smith
authors.forename: Frederic
authors.initials: F
authors.lastname: Galacteros
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: James H
authors.initials: JH
authors.lastname: Hull
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Stocker
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D000986:Antisickling Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004905:Erythrocyte Aging / Q000187:drug effects*; D005260:Female; D006400:Hematocrit; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D016896:Treatment Outcome; D014320:Triphenylmethyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000081:Acetamides; D000986:Antisickling Agents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D014320:Triphenylmethyl Compounds; C472774:senicapoc