Phase 2b, randomized, double‐blind 12‐week studies of TZP ‐102, a ghrelin receptor agonist for diabetic gastroparesis

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. Key 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 T 1/2 131 ± 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 & Inferences 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).