Table 2.

The outcomes of randomised clinical trials investigating traditional and novel medications for the treatment of diabetic gastroparesis21,25–45,59,66

Author and year of study	Study groups and INT	Efficacy on gastroparesis symptoms	Efficacy on GE	Safety
Dopamine D2 receptor antagonist
Snape et al.34 (1982)	Metoclopramide (10 mg orally, four times per day) Placebo (two 3-week treatment INT with a 1-week washout period before cross-over)	No significant changes observed in abdominal pain or bloating	Using GES, a 24% increase in GE rate (P <0.01) was reported 3 weeks after treatment versus 5% increase in placebo	N/A
McCallum et al.35 (1983)	Metoclopramide (10 mg orally, four times per day) Placebo (for 3 weeks)	A significant improvement of fullness and nausea (P <0.05) in the INT versus placebo (assessed using grading diary sheets)	GE improved in the INT group compared to baseline values (P <0.05, assessed by GES scintigraphy) but not to placebo	Restlessness, amenorrhea, headache, constipation and leg cramps were noted in the metoclopramide group
Ricci et al.36 (1985)	Metoclopramide (10 mg orally, four times per day) Placebo	Significant improvement of fullness, bloating, nausea and anorexia when compared to placebo (P <0.05) No significant correlation between changes in symptoms and GE improvement	GE improved significantly (isotope retention was 91% at baseline and 78.6% after metoclopramide administration)	Mild symptoms ignore, such as sedation, headache and mild hand tremors were noted in metoclopramide-receiving patients
Parkman et al.33 (2014)	Metoclopramide (10 mg orally, four times per day; n = 18) Metoclopramide (10 mg nasal spray, four times per day; n = 35) Metoclopramide (20 mg nasal spray, four times per day; n = 36)	Using TSS scores, CFB was significantly improved in the 20 mg nasal spray group compared to the oral group (P = 0.026)	N/A	Three subjects discontinued the study due to severe restlessness, severe drowsiness and mild headache. Nausea was more frequently reported in the oral group
Parkman et al.44 (2015)	Metoclopramide (10 mg nasal spray, four times per day; n = 95) Metoclopramide (14 mg nasal spray, four times per day; n = 95) Placebo (n = 95)	GSDD scores did not improve significantly in the INT groups as compared to placebo Severity scores improved significantly only in women for both INT groups as compared to placebo (P = 0.02 each)	N/A	AEs were mild to moderate. They were more frequent in the 14 mg (8.4%, including headache, dizziness, diarrhoea, cholelithiasis, vomiting and nausea) rather than the 10 mg group (nausea, myoclonus, and memory impairment)
Patterson et al.37 (1999)	The following regimens were given for 4 weeks: Metoclopramide (one 10 mg tablet plus one placebo tablet were taken four times per day) Domperidone (two 10 mg tablets were taken four times per day)	No significant differences between groups in improving symptoms (improved by 41.1% with domperidone and 38.9% with metoclopramide)	N/A	Somnolence, anxiety, akathisia and depression were significantly more severe in the metoclopramide group after 2 and 4 weeks of treatment (P <0.001) Severe CNS events accounted for treatment discontinuation in four patients and one patient in the metoclopramide and domperidone groups, respectively
Silvers et al.45 (1998)	Domperidone 20 mg (four times per day; n = 105) Placebo (n = 103)	Significant improvements were noted in the domperidone group for total symptoms (P = 0.011), nausea (P = 0.024) and early satiety (P = 0.004) compared to placebo	N/A	No significant differences between both groups in the tolerability profile Headache, diarrhoea, abdominal pain, rhinitis and sinusitis were most commonly reported among patients
Franzese et al.25 (2002)	Domperidone (0.9 mg/kg three times per day; n = 14) Cisapride (0.8 mg/kg three times per day; n = 14)	Significant improvements in the TSS in both groups (P <0.001 each) compared to baseline	Ultrasonography revealed significant shortening of GE time in the domperidone group compared to baseline (P <0.01). No remarkable differences were noted in the cisapride group	N/A
Erbas et al.26 (1993)	The following regimens were given for 3 weeks, then 3 weeks washout and 3 weeks cross-over: Metoclopramide (10 mg orally, three times per day) Erythromycin (250 mg orally, three times per day)	The total score of gastrointestinal symptoms significantly improved after erythromycin (0–5) compared to post-metoclopramide therapy (0–11; P <0.05)	Gastric T½ improved significantly in both INT groups at 60 and 90 min after meal	Two patients reported sedation, leg cramps and weakness, while one patient reported drowsiness and palpitation with use of metoclopramide
Ghrelin receptor agonist
Murray et al.27 (2005)	The patients received either ghrelin (5 pmol/kg/min) or saline on two different occasions	No significant differences between ghrelin and saline in the incidence of bloating, nausea and hunger during infusion as assessed by VAS	Significant improvement of GE (from 30% to 43%) as assessed by ultrasound	N/A
Ejskjaer et al.28 (2009)	A cross-over administration of different doses of TZP-101 infusions (80, 160, 320, or 600 g/kg) Placebo	No significant differences between the INT and placebo groups in the intensity of post-meal symptoms and postprandial fullness	Gastric T½ (20%; P = 0.043) and latency times were significantly reduced compared to placebo	No differences in AEs between TZP-101 and placebo group
Ejskjaer et al.29 (2010)	A 4-day consecutive regimen of intravenous infusion of ulimorelin at a dosage of: 20μg/kg (n = 8); 40μg/kg (n = 17); 80μg/kg (n = 13); 160μg/kg (n = 6); 320μg/kg (n = 6); 600μg/kg (n = 7); Placebo (n = 19)	In the group receiving ulimorelin 80 μg/kg, the severity of GCSI loss of appetite and vomiting scores was significantly improved (P = 0.034 and 0.006, respectively) The post-prandial fullness domain of the GSA score was significantly improved compared to placebo	No difference in gastric T½ among groups	The frequency and severity of AEs were comparable between the INT and placebo group
Ejskjaer et al.32 (2013)	The following regimens were given once daily (oral capsules before breakfast) for 28 days: TZP-102 10 mg (n = 22); TZP-102 20 mg (n = 21); TZP-102 40 mg (n = 23); placebo (n = 26)	All doses (combined) caused a significant decline of the GSCI total score compared to placebo	No significant differences in GMBT T½ between INT groups and the placebo group No correlation between GMBT T½ and the GSCI score at baseline or at 28 days	No differences in AEs between the TZP-102 and placebo groups
McCallum et al.43 (2013)	The following regimens were given once per day (oral capsules) for 12 weeks: TZP-102 10 mg (n = 69); TZP-102 20 mg (n = 66); Placebo (n = 66)	GSDD improved significantly in all groups, but no difference was reported versus placebo (CFB: −1.1 versus 0.98 for INT groups and placebo groups)	No statistical difference in CFB of GEBT among all groups	AEs occurred in 57%, 58% and 67% in the 10 mg, 20 mg and placebo groups, respectively without remarkable differences
Shin et al.38 (2013)	Relamorelin 100 μg SC once per day (n = 5) Patients crossed over with a 7-day washout period Placebo (n = 5)	Relamorelin significantly reduced GCSI-DD (P = 0.041) and NVFP (P = 0.041) scores compared to placebo	GE was significantly accelerated in eight patients relative to the placebo (P = 0.005)	No serious AEs were reported Only hunger was almost significant with relamorelin use (P = 0.063)
Shin et al.40 (2013)	A single dose of relamorelin 100 μg SC (n = 5) Patients crossed-over with a 7-day washout period Placebo (n = 5)	Since it was a single-dose study, it was not powered to investigate DG GCSI scores were similar in both groups.	Gastric T½ of solids, but not liquids, reduced by relamorelin versus placebo (P = 0.011) Significant effects were noted also in GE at 2 and 4 hours (with percent differences of 48% and 19%, respectively)	Relamorelin led to a large GE acceleration
Lembo et al.41 (2016)	Relamorelin 10 μg once per day (n = 67) Relamorelin 10 μg twice per day (n = 68) Placebo (n = 69)	The twice-daily regimen reduced vomiting severity and frequency by 60% compared to placebo, while it had no effects on abdominal pain and satiety	Significant improvement of GE (P <0.03) with twice-daily regimen	In the INT group ≥5% of patients experienced headache and worsening of glycaemic control
Camilleri et al.42 (2017)	The following SC injections were given twice per day: Relamorelin 100 μg (n = 82); Relamorelin 30 μg (n = 109); Relamorelin 10 μg (n = 98); Placebo (n = 104)	Relamorelin reduced the frequency of vomiting by 75% compared to baseline, but not compared to placebo Different doses of relamorelin decreased all composite symptoms of DG compared to placebo (P <0.05)	GE was significantly accelerated in the 10 and 30 μg groups by 12% (P <0.05) compared to placebo after 12 weeks	In the INT group, 14.5% of patients experienced dose-related deteriorations of glycaemic control; this was resolved by drug dosage adjustments
Motilin receptor agonist
Desautels et al.59 (1995)	Erythromycin base 250 mg Erythromycin base 1000 mg Placebo	N/A	Significant improvements of GE were reported between erythromycin groups and placebo (P = 0.0007) No differences were present between erythromycin 250 and 1000 mg groups	Diarrhea was reported in one patient in the erythromycin 1000 mg group
McCallum et al.21 (2007)	The following regimens were given for 12 weeks twice per day: Mitemcinal 5 mg (n = 131); Mitemcinal 10 mg (n = 130); Placebo (n = 131)	No significant effects were noted over 12 weeks among groups In a subset of the population under study (those having 75% positive weekly responses), mitemcinal 10 mg produced a significant improvement in total symptoms during the study period (P <0.05) compared to placebo	N/A	Severe AEs were reported in 18.8%, 15.9% and 20.0% of patients in the placebo, mitemcinal 5 mg, and mitemcinal 10 mg groups, respectively There were non-significant differences among groups
Barton et al.66 (2014)	The following regimens were given once per day for 4 weeks: Camicinal 10 mg (n = 18); Camicinal 50 mg (n = 18); Camicinal 125 mg (n = 22); Placebo (n = 21)	The most significant improvements occurred at 2–4 weeks for fullness and satiety for 10 mg (53%) and 50 mg (65%) groups No or little effect was reported for the highest dose	GEBT T½ decreased significantly with increasing dose (P <0.05) as assessed by swallowed wireless motility capsule	There were similar frequencies of AEs among different groups (urinary tract and gastrointestinal symptoms)
Hellström et al.39 (2016)	Each patient participated in three single oral INT (out of four INT) with a 7-day washout period in-between. The groups were: Camicinal 50 mg; Camicinal 125 mg; Placebo	No symptomatic improvement was observed	GEBT T½ decreased by 65% (P <0.05) by 125 mg camicinal compared to placebo There was a non-significant trend of reduced GEBT T½ with 25 and 50 mg doses A dose-response relationship was apparent	Headache, vomiting and decreased blood glucose were reported in a similar frequency in all groups
5-HT4 receptor agonist
Braden et al.30 (2002)	Given thrice per day: Cisapride 10 mg (n = 9); Placebo (n = 10)	N/A	GEBT T½ decreased significantly in the INT group after 12 months compared to baseline (P = 0.03); the placebo group showed no changes from baseline No effects were noted on glucose control in both groups	N/A
Lehmann et al.31 (2003)	The following treatments were given for 3 months, then 4 weeks washout and 3 months cross-over: Cisapride 20 mg twice per day; Placebo	N/A	GE improved significantly at 120 min in the INT group (P = 0.025), while gastric T½ did not differ between the INT and placebo groups (P = 0.09) No apparent improvements in glycaemic control	No serious AE Patients with prolonged QTc were excluded at the initial recruitment phase

INT = interventions; GE = gastric emptying; GES = gastric emptying scintigraphy; NA = not available; TSS = total symptom score; CFB = change from baseline; CNS = central nervous system; min = minutes; VAS = visual analogue score; AEs = adverse events; GCSI = Gastroparesis Cardinal Symptom Index; GSA = Gastroparesis Symptom Assessment; GMBT = gastric motility breath test; GSDD = gastroparesis symptom daily diary; CFB = change from baseline; GEBT = gastric emptying breath test; SC = subcutaneous; DD = daily diary; NVFP = nausea, vomiting, fullness and pain.