title: Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis.
abstract: BACKGROUND
  TZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a.
  
  
  METHODS
  Patients with type 1 or 2 diabetes, delayed gastric half-emptying (T(1/2)), and ≥3 months gastroparesis symptoms randomized 1 : 1 : 1 to double-blind placebo, 10-mg, or 20-mg TZP-102 once daily for 12 weeks (Study TZP-102-CL-G003). Study TZP-102-CL-G004 patients randomized 1 : 1 to 10-mg TZP-102:placebo three-times-daily. Primary endpoint was change-from-baseline through Weeks 11-12 in Daily Diary of Gastroparesis Symptoms Questionnaire (GSDD) via electronic Patient Recorded Outcome device: worst severity of nausea, early satiety, bloating, and upper abdominal pain in 24 h (0 = none-to-5 = very severe). GSDD Composite Score for eligibility was ≥2.5 (Day-14-to-baseline). Patient Overall Treatment Evaluation (OTE) provided an anchor-based minimal clinically important difference (MCID) for GSDD Composite Score.
  
  
  RESULTS
  Study TZP-102-CL-G003 enrolled 201 outpatients: females 72%; Caucasians 87%; type 2 diabetes 61%; insulin-dependent 65%; age mean ± SD 53 ± 11.3 years; HbA1c 7.8 ± 1.5%; GCSI 3.4 ± 0.7; GSDD Composite 3.6 ± 0.6; gastric T1/2 131 ± 32 min; n = 69 (10-mg), n = 66 (20-mg), n = 66 (placebo). Primary endpoint (GSDD): significant improvement in all arms, although not for TZP-102 vs placebo: mean change-from-baseline -1.7, -1.4, -1.5 (10-mg, 20-mg, placebo); Gastroparesis Cardinal Symptom Index -1.8, -1.6, -1.5, respectively. The OTE (all patients) at Week-12 was: Patient 3.7 ± 3.2 and Physician 3.6 ± 3.0 with median score for both of 5.0 = important on scale of improvement; individual MCID was 1.61 and 0.94 for group analyses, greater than expected. Study TZP-102-CL-G004 with similar demographic/disease characteristics was prematurely terminated for efficacy futility (n = 64 with Week-4 assessments).
  
  
  CONCLUSIONS
  Efficacy of TZP-102 was not demonstrated compared with placebo in diabetic gastroparesis; however, there was substantial symptom improvement in all arms (ClinicalTrials.gov NCT01452815/NCT01664637).
authors.affiliation: Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: McCallum
authors.forename: A
authors.initials: A
authors.lastname: Lembo
authors.forename: T
authors.initials: T
authors.lastname: Esfandyari
authors.forename: B R
authors.initials: BR
authors.lastname: Bhandari
authors.forename: N
authors.initials: N
authors.lastname: Ejskjaer
authors.forename: C
authors.initials: C
authors.lastname: Cosentino
authors.forename: N
authors.initials: N
authors.lastname: Helton
authors.forename: E
authors.initials: E
authors.lastname: Mondou
authors.forename: J
authors.initials: J
authors.lastname: Quinn
authors.forename: F
authors.initials: F
authors.lastname: Rousseau
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004311:Double-Blind Method; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D018589:Gastroparesis / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D047028:Macrocyclic Compounds / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D054440:Receptors, Ghrelin / Q000819:agonists*
chemical_list: D047028:Macrocyclic Compounds; D054440:Receptors, Ghrelin
keywords: diabetes type 1; diabetes type 2; diabetic gastroparesis; oral ghrelin receptor agonist