title: Modified release terbutaline (SKP1052) for hypoglycaemia prevention: a proof-of-concept study in people with type 1 diabetes mellitus.
abstract: OBJECTIVE
  In this randomized, single blind, cross-over study 2.5 mg and 5 mg of the modified-release terbutaline formulation (SKP-1052) were compared with conventional immediate-release terbutaline (IRT, 5 mg) and placebo on overnight blood glucose (BG) and hypoglycaemia in 30 subjects with type 1 diabetes mellitus.
  
  
  METHODS
  Subjects received subcutaneous injections of insulin glargine (individualized doses) before dinner. SKP-1052, IRT or placebo was administered around 21:00 hours. BG and terbutaline concentrations were monitored overnight for 10 h post-dosing. Endpoints comprised of the nadir BG (BGn 0-10 h, primary endpoint), mean overnight BG (BGmean), morning BG (BGmorning) and hypoglycaemia rates as well as pharmacokinetic (PK) endpoints.
  
  
  RESULTS
  SKP-1052 delayed release of terbutaline by 2 h [PK-tmax (mean ± SD) 5.0 ± 2.1 h (2.5 mg) and 4.7 ± 1.7 h (5 mg) vs. 2.6 ± 1.3 h with IRT, p < 0.01, respectively]. Compared with placebo, no significant differences were observed for BGn 0-10 h across treatments, but both 5 mg formulations showed less hypoglycaemic events [10 (IRT), 16 (SKP-1052) vs. 33], higher BGmean (120, 114 and 95 mg/dl) and BGmorning (126, 126 and 101 mg/dl, all comparisons p < 0.05 vs. placebo). Numerically higher BG-levels between 3 and 8 h post-dosing were observed with 2.5 mg SKP-1052 vs. placebo.
  
  
  CONCLUSIONS
  Compared with IRT SKP-1052 delays release of terbutaline. 2.5 mg SKP-1052 led to numerically higher BG 3 to 8 h post-dose without fasting hyperglycaemia while 5 mg SKP-1052 resulted in fasting hyperglycaemia vs. placebo. Future studies will investigate optimized doses of SKP-1052 for nocturnal hypoglycaemia prevention.
authors.affiliation: Profil, Neuss, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Nosek
authors.forename: J-M
authors.initials: JM
authors.lastname: Cardot
authors.forename: D R
authors.initials: DR
authors.lastname: Owens
authors.forename: P
authors.initials: P
authors.lastname: Ibarra
authors.forename: K
authors.initials: K
authors.lastname: Bagate
authors.forename: G
authors.initials: G
authors.lastname: Vergnault
authors.forename: K
authors.initials: K
authors.lastname: Kaiser
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: T
authors.initials: T
authors.lastname: Heise
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005215:Fasting; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000378:metabolism*; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D013726:Terbutaline / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D013726:Terbutaline