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Keywords:

  • diabetic gastroparesis;
  • diabetes type 1;
  • diabetes type 2;
  • gastroparesis;
  • oral ghrelin receptor agonist

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

Background  Gastroparesis causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis.

Methods  A total of 92 outpatients were randomized to once-daily administrations of 10-mg (= 22), 20-mg (= 21), 40-mg (= 23) TZP-102 or placebo (= 26). The primary endpoint was the change from baseline in gastric half-emptying time (T½) utilizing 13C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE).

Key Results  Gastric T½ changes were not statistically significant between TZP-102 and placebo after 28 days of treatment at any dose. Clinical improvements (−1.0 to −1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes.

Conclusions & Inferences  TZP-102 for 28 days, at doses of 10–40 mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

Gastroparesis is a chronic disorder of abnormal gastric motility often occurring in patients with long-standing type 1 or type 2 diabetes producing nausea, early satiety, postprandial fullness, bloating, and upper abdominal pain.1 Disease burden for gastroparesis is considerable, and outcomes data compared with age- and gender-matched healthy control populations show a substantial amount of morbidity.1–5

Treatment options for gastroparesis include lifestyle and dietary modifications, and prokinetic and antiemetic therapy, although data from adequately powered clinical trials in patients with gastroparesis are few in number.6 Currently available prokinetic options are inadequate mainly due to adverse event profile as well as poor efficacy, thus limiting use of these therapies. Given the poor correlation between the degree of delay in gastric emptying and the severity of the symptoms of gastroparesis,7,8 treatment goals have focused on symptom relief and restoration of nutritional status. There is an unmet need for better treatment options for gastroparesis.9

Ghrelin, the natural ligand for the growth hormone (GH) secretagogue (hGHS-R1a) receptor, is produced primarily in the gastric mucosa in association with eating and coordinates gastric motility.10,11 Pharmacologic doses of exogenous ghrelin produce gastrokinetic effects in patients with idiopathic, surgery-induced, and diabetes-associated gastroparesis,12–14 although the short half-life limits therapeutic potential.15 Oral TZP-102, a low molecular weight synthetic macrocyclic compound, has a substantially longer half-life thereby allowing more sustained action as a potent ghrelin receptor agonist, in a manner analogous to parenteral ghrelin agonist activity.16 The promotility activity of TZP-102 has been demonstrated in a rat model of gastric emptying in which TZP-102 produced dose-dependent increases in gastric emptying of up to 51% (when compared to vehicle), comparable to the 35–57% increased gastric emptying seen in rats with 30 mg kg−1 oral metoclopramide. The objective of this clinical study was to evaluate safety and efficacy of TZP-102 for 28 days in patients with gastroparesis due to diabetes.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

This multicenter, randomized, double-blind, placebo-controlled, outpatient study was conducted from April 2009 to May 2010 at 18 centers: eight United States, four Denmark, three Poland, and one site each in Norway, Sweden, and the United Kingdom (Clinical Trial Registry# NCT00889486; protocol TZP-102-CL-G002). All participants gave written informed consent and all sites had Institutional Review Boards/Ethics Committees study approval; this study was performed in accordance with the Declaration of Helsinki.

Study patients and eligibility

Eligible adults (18–80 years) had type 1 or 2 diabetes, BMI <35, glycosylated hemoglobin (HbA1c) level ≤10.0%, documentation of delayed gastric emptying, and a history of gastroparesis symptoms for at ≥3 months in the absence of gastrointestinal obstruction. Baseline gastric emptying was assessed by breath test (GMBT; Metabolic Solutions, Inc., Nashua, NH, USA). A gastric half-emptying time ≥150 min was required for eligibility. The Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) Questionnaire, in which the first 9 of 20 symptom-specific questions comprise the Gastroparesis Cardinal Symptom Index (GCSI),17 was completed to assess gastrointestinal symptoms during the previous 2 weeks using a 6-point likert scale ranging from none to very severe. A GCSI Total Score of ≥2.66 at Screening and ≥1.90 at Day 1 were required for eligibility.

Patients with prior gastrectomy, gastric bypass, vertical banding gastroplasty, lap band, fundoplication, or vagotomy/pyloroplasty, or who had bowel obstruction within 12 months were excluded as were those with severe cardiovascular, pulmonary, hepatic, renal disease or eating disorders, active gastric electric stimulators, or a history of hepatitis B, C or HIV. Daily use of narcotics for abdominal pain or use CYP3A4 substrates with known QT risk was prohibited. Contraception was prerequisite for fertile women. Stable dosage of all concomitant medications was required for at least 3 weeks prior to study drug dosing (14 days prior to the GMBT visit) and the same regimens maintained until study completion. Use of domperidone, cisapride, erythromycin, and ondansetron were prohibited; patients with persistent symptoms for 3 months on a stable metoclopramide dosage were allowed.

The severity of peripheral neuropathy was assessed using the Michigan Neuropathy Screening Instrument18 and cardiovascular autonomic neuropathy measurements included beat-to-beat heart rate variation (abnormal = a difference ≤10 beats min−1 in a supine patient breathing 6 times min−1) and orthostatic hypotension evaluation (abnormal = systolic blood pressure decrease ≥20 mmHg or diastolic blood pressure ≥10 mmHg within 3 min after standing). Screening assessments included hematology, clinical chemistry and 12-lead ECGs.

Treatment groups and dosing

In the precedent study in healthy volunteers the maximum total TZP-102 plasma concentration (Cmax) appeared to plateau at the 40-mg dose level while reaching an unbound Cmax (free TZP-102) in the range expected for potential activity at this and lower dose levels administered once daily. Hence, in the current study, patients were randomized to oral TZP-102 (10 , 20 , or 40 mg) capsules or matching placebo capsules for 28 days, which was taken once daily at least 30 min before breakfast. Randomization was by site with a block size of four; given slow enrollment and the participation of many sites, measures were implemented to maintain overall balance across treatment arms for the entire study, and for this purpose a blocked, adaptive randomization scheme was employed via a third party unblinded biostatistics group. Study personnel, the sponsor, and patients were blinded to treatment assignments for the duration of the study.

Study visits occurred on days 1 (first day of dosing), 8, 15, and 28 (last day of dosing) with follow-up on days 42 and 58.

Study endpoints

The study was powered on the change from baseline (CFB) in gastric half-emptying time (T½), which was the primary efficacy endpoint. Each study site used the GMBT to determine gastric emptying using a muffin meal labeled with 13C-octanoate (350 kcal; 7 g fat; 64 g carbohydrate; 9 g protein) during the Baseline GMBT Visit (day −16 to −7) and day 28. Breath samples were obtained 26 times for analysis, twice prior to the labeled meal then every 15 min for 6 h after ingestion. The patient’s blood glucose was measured with a glucometer prior to the GMBT test meal (−60, −15, −∼5 min) and during the GMBT (1 and 2 h postmeal). If the initial glucose was ≥250 mg dL−1, GMBT was delayed 60 min. Few patients had hyperglycemia exceeding this threshold prior to GMBT test meal at either Baseline (= 1) or Day 28 (= 4) exclusively, while six patients (1 or 2 per treatment arm), had this level of hyperglycemia at both Baseline and Day 28 GMBT evaluations (i.e., testing performed in same glycemic context), although variability in blood glucose is acknowledged as a potential confounder for gastric emptying measurement. Delayed gastric emptying with the 6-hour GMBT was defined as a T½≥150 min based on proprietary validation in 100 individuals, and comparison to scintigraphy, technical variations, and pharmacological modulation in nearly 100 additional persons (Metabolic Solutions, Inc. Validation of Breath 13CO2 by Isotope Ratio Mass Spectrometry). The study eligibility threshold for the Baseline Visit GMBT half-emptying time of ≥150 min represented the mean plus approximately 1 standard deviation (SD) for T½ measured in healthy subjects.

Secondary endpoints explored the effect of TZP-102 on improvement in gastroparesis symptoms at Day 28 for each dose using validated indexes and questionnaires, but the study was not specifically powered for these endpoints, and for these analyses P-values should be considered descriptive and not inferential.

Overall treatment evaluations (OTE), a validated instrument that measures symptom improvement,19 were completed by patients and clinicians at the Day 15 and Day 28 to rate gastroparesis-related symptoms as improved, unchanged, or worsened since the start of study treatment and impact on daily activities. Evaluations were scored on a 15-point scale from −7 (Symptoms Worse and Change Extremely Important) to 7 (Symptoms Better and Change Extremely Important); 0 = unchanged.

The PAGI-SYM Questionnaire (inclusive of the GCSI portion) was completed by patients on Day 1, Day 8, Day 15, and Day 28, and at follow-up visits on Day 42 and Day 58, and CFB evaluated. In addition, a subset of four main symptoms was analyzed as a four-symptom composite, namely nausea, upper abdominal pain, early satiety, and bloating as an unplanned exploratory analysis for future deployment as a daily diary application in light of regulatory and cognitive debrief context, as well as prevalent symptomatology, and is used as primary endpoint in ongoing large phase 2b studies.

An exploratory responder analysis was undertaken wherein a responder was defined as a patient with ≥50% decrease from baseline in GCSI Total score at the last two on-treatment visits (both Day 15 and Day 28). This analysis, planned prospectively in terms of the 50% threshold, was developed in a similar manner to the FDA guidance for industry on patient-reported outcome endpoint selection for irritable bowel syndrome.20

Safety

Safety was evaluated by adverse events, clinical and laboratory evaluations, physical examination, vital signs, and 12-lead ECGs at each visit. Fasting and 1 and 2 h postprandial blood glucose concentrations were measured using a glucometer before and during the GMBTs. The safety population consisted of all randomized and treated patients.

Pharmacodynamic and pharmacokinetic assessments

Serum GH and IGF-1 concentrations were assessed before and hourly for 4 h after the first and last administrations of study drug at the Day 1 and Day 28 visits. TZP-102 plasma concentrations were evaluated before and through 6 hours after administration of the first and last doses of study drug at the Day 1 and Day 28 visits. Trough TZP-102 plasma concentrations were performed Day 8 and Day 15 and posttreatment measurements were obtained at the Day 42 and Day 58 visits. Serum GH and IGF-I concentrations were measured at the Medical Research Laboratory, Aarhus University Hospital, Aarhus, Denmark (immunofluorometric assay; AutoDELFIA® platform for GH, PerkinElmer Life and Analytical Sciences, Turku, Finland). TZP-102 concentrations in plasma were measured by a validated high performance liquid chromatographic method using mass spectrometric detection (LC-MS/MS) (lower limit of quantification of 0.5 ng mL−1; working range 5.0–5000 ng mL−1; Charles River Laboratories, Montreal, Quebec).

Statistical analyses

Fifteen patients in each treatment group provided 85% power to detect a mean decrease from baseline in T½ of at least 20% in each TZP-102 treatment group, based on a two-sided t-test with alpha = 0.05. The efficacy population consisted of all randomized patients with at least one postdose efficacy evaluation. Data are expressed as mean ± SD.

A repeated measures analysis of covariance (ancova) controlling for the baseline value and the premeal glucose concentration was used to evaluate the CFB on Day 1(after a single dose of treatment) and Day 28 in gastric half-emptying time (T½) and time to maximum rate of gastric emptying or lag time (Tlag) measured by the 13C-octanoate GMBT.

ancova in the intent-to-treat (ITT) population was used to analyze the CFB for each dose level compared with placebo for symptom-related efficacy endpoints at each assessment time point (Day 8, Day 15, and Day 28), controlling for the baseline value for each parameter. When data were missing, a last observation carried forward (LOCF) imputation was used through Day 28, although not thereafter. No adjustments to the alpha were made for multiplicity of endpoints or multiple comparisons between active treatment groups and placebo as this is an exploratory phase 2a study. Exploratory analyses of all combined active doses vs placebo were also conducted to assess symptom improvement.

The GCSI Total Score responder analysis utilized a two-sided Fisher exact test for the comparison of all TZP-102 doses (combined) to placebo. The Patient and Physician OTE evaluations on Day 15 and Day 28 were analyzed using a Wilcoxon rank-sum test to compare each active TZP-102 group with the placebo group.

Pharmacokinetic parameters included the Cmax (ng mL−1), and corresponding Tmax, and the area under the total TZP-102 plasma concentration vs time curve (AUC ng h mL−1) from hour 0 to hour 6 after dosing, calculated using the linear trapezoidal rule (AUC0–6).

Serial GH and IGF-1 concentrations from Day 1 and Day 28 were used to calculate the area under the serum concentration vs time curve (ng h mL−1) from hour 0 to hour 4 (GH AUC0–4 and IGF-1 AUC0–4,) using the linear trapezoidal rule. Changes in GH AUC0–4 and IGF-1 AUC0–4, from Day 1 to Day 28 were evaluated.

Linear correlation analyses on variable pairs (including gastric emptying vs symptom severity, and TZP-102 Cmaxvs changes in GH, IGF-1, glucose, body weight, and HbA1c levels) were conducted and the degree of correlation [correlation coefficient (r)] between the two variables summarized.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

Overall 177 patients were screened, and 85 patients were not randomized due to screening criteria failures as summarized in Fig. 1 (CONSORT diagram). Ninety-two patients were randomized to receive once-daily administrations of 10 mg (= 22), 20 mg (= 21), 40 mg (= 23) of TZP-102 or placebo (= 26) for 28 days. Sixty-three patients randomized in the TZP-102 groups and 22 patients randomized to placebo completed the study through the follow-up assessment; the single patient on TZP-102 who discontinued study drug due to an adverse event (AE) of chest pain (serious, not related) completed all study visits.

image

Figure 1.  CONSORT flow diagram.

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Demographic and baseline characteristics are shown in Table 1 and were similar across dose groups. Patient age for all patients was 49.9 ± 11.9, 65% were women (= 60) and 91% were white (= 84). The duration of diabetes was 19 ± 14 years and 3.1 ± 4.0 years for gastroparesis symptoms (72 of 92 patients had a gastroparesis diagnosis antedating study and 14 had previously received prokinetic drugs); 60% (= 55) of patients had type 1 diabetes. The Michigan Neuropathy Screening Instrument score indicated mild neuropathy with a score of 4.9 ± 2.9/13; 51% of patients (= 47) had evidence of autonomic neuropathy based on heart rate variability. Baseline HbA1c was 8.3 ± 1.5%. The Baseline GCSI Total Score was 3.3 ± 0.8, indicating moderate-to-severe gastroparesis symptoms. Vomiting and retching were milder than other symptoms at entry, with group-mean scores ranging from 0.9–1.9 and 2.3–2.5, respectively. The overall prevalence of persistent individual GCSI/PAGI-SYM symptoms for all patients demonstrated a predominance of nausea, upper abdominal pain, and symptoms reflective of early satiety and bloating present at both Screening and Baseline. Vomiting and retching were less frequently reported. Specifically, across all treatment groups (= 92), pretreatment symptoms included nausea 86 (93.5%), retching 68 (73.9%), vomiting 37 (40.2%), upper abdominal pain 81 (88.0%), early satiety 84 (91.3%), loss of appetite 84 (91.3%), and all patients had fullness and bloating including larger belly in 87 (94.6%).

Table 1.   Summary demographics and baseline characteristics
ParameterTZP-102 dose
10 mg = 2220 mg = 2140 mg = 23Placebo = 26
  1. *GCSI component of PAGI-SYM symptoms graded: 0 = none; 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very severe.

  2. PAGI-SYM symptom of upper abdominal pain (above the navel) graded: 0 = none; 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very severe.

Age (years)
 Mean (SD)50.0 (11.37)49.8 (12.33)49.7 (12.60)50.2 (12.12)
 Min, max31, 6621, 6420, 7027, 70
Gender, n (%)
 Male6 (27.3)7 (33.3)9 (39.1)10 (38.5)
 Female16 (72.7)14 (66.7)14 (60.9)16 (61.5)
Race, n (%)
 Asian1 (4.5)000
 Black2 (9.1)3 (14.3)02 (7.7)
 White19 (86.4)18 (85.7)23 (100.0)24 (92.3)
Baseline body mass index (kg m−2)
 Mean (SD)28.3 (4.85)29.8 (5.13)28.7 (5.83)28.6 (4.64)
 Min–max19.8, 39.318.4, 40.719.6, 37.518.7, 35.5
Duration of diabetes (years)
 Mean (SD)19.6 (10.92)17.0 (15.23)24.2 (14.58)16.7 (12.37)
Type of diabetes, n (%)
 Type 112 (54.5)10 (47.6)18 (78.3)15 (57.7)
 Type 210 (45.5)11 (52.4)5 (21.7)11 (42.3)
Insulin use, n (%)16 (72.7)14 (66.7)19 (82.6)19 (73.1)
Baseline HbA1c (%)
 Mean (SD)8.2 (1.30)7.9 (1.53)8.7 (1.49)8.3 (1.57)
Duration of gastroparesis (year)
 Mean (SD)3.2 (5.47)3.7 (4.39)3.1 (3.68)2.5 (2.31)
Baseline GMBT T½ (min)
 Mean (SD)191.6 (59.35)192.1 (52.99)190.0 (38.33)195.9 (54.67)
 Min, max146.8, 360.0138.8, 360.0150.5, 294.9147.1, 360.0
Baseline GMBT Tlag (min)
 Mean (SD)116.1 (57.32)123.9 (65.06)118.0 (33.68)113.3 (32.23)
 Min, max36.7, 311.359.2, 360.079.0, 202.964.9, 218.5
Baseline GCSI total score
 Mean (SD)3.5 (0.60)3.2 (0.77)3.1 (0.80)3.4 (0.78)
 Min, max2.0, 4.41.8, 4.80.8, 4.52.1, 4.9
Baseline nausea*
 Mean (SD)3.6 (1.10)3.2 (1.21)3.1 (1.35)3.1 (1.03)
 Min, max1.0, 5.00.0, 5.00.0, 5.00.0, 5.0
Baseline retching*
 Mean (SD)2.5 (1.63)2.3 (1.77)2.3 (1.36)2.4 (1.55)
 Min, max0.0, 5.00.0, 5.00.0, 4.00.0, 5.0
Baseline vomiting*
 Mean (SD)1.9 (1.67)0.9 (1.48)1.4 (1.90)1.2 (1.54)
 Min, max0.0, 5.00.0, 4.00.0, 5.00.0, 4.0
Baseline upper abdominal pain
 Mean (SD)3.3 (1.08)2.7 (1.62)3.0 (1.46)3.1 (1.24)
 Min, max1.0, 5.00.0, 5.00.0, 5.00.0, 5.0
Baseline early satiety*
 Mean (SD)3.6 (1.33)3.1 (1.53)2.9 (1.42)3.5 (1.45)
 Min, max0.0, 5.00.0, 5.00.0, 5.00.0, 5.0
Baseline bloating (loosen clothing)*
 Mean (SD)4.3 (0.70)4.0 (0.92)3.7 (1.25)4.3 (0.87)
 Min, max3.0, 5.02.0, 5.01.0, 5.02.0, 5.0
Baseline stomach visibly larger*
 Mean (SD)4.0 (1.46)3.7 (1.15)3.4 (1.56)4.0 (1.17)
 Min, max0.0, 5.01.0, 5.00.0, 5.00.0, 5.0
Baseline postprandial fullness*
 Mean (SD)4.0 (0.90)4.0 (0.92)3.7 (0.92)4.2 (0.82)
 Min, max2.0, 5.02.0, 5.01.0, 5.02.0, 5.0
Baseline stomach fullness*
 Mean (SD)4.1 (0.94)3.9 (0.77)3.7 (1.02)4.0 (1.08)
 Min, max1.0, 5.02.0, 5.01.0, 5.01.0, 5.0
Baseline loss of appetite*
 Mean (SD)3.5 (1.44)2.9 (1.35)3.0 (1.38)3.4 (1.21)
 Min, max0.0, 5.00.0, 5.00.0, 5.00.0, 5.0

Few patients had Baseline gastric half-emptying <150 min (1 or 2/group); mean values for all patients were 193 min (T½) and 117 min (Tlag), and were similar across groups. The majority of patients had a longstanding diagnosis of gastroparesis for a duration of 1 year or more at the time of study entry and/or had formal prior scintigraphy with retention in excess of the consensus thresholds or prior historical (non-study) breath tests with T½ above normal limit: 22/26 (85%) placebo; 15/22 (68%) 10 mg TZP-102; 17/21 (81%) 20 mg TZP-102; 19/23 (83%) 40 mg TZP-102. Thus, in the majority of cases (79% overall) diabetic gastroparesis was previously documented/established. While eligibility criteria required GMBT T½≥150 min, the following proportions of patients also had delayed gastric emptying at a threshold 2 SD above the mean for healthy subjects, i.e., ≥168 min: 15 (58%) placebo; 13/22 (59%) 10 mg TZP-102; 13 (62%) 20 mg TZP-102; 15 (65%) 40 mg TZP-102.

Primary endpoint: gastric emptying analyses

There were no statistically significant differences between any TZP-102 group and placebo in CFB in GMBT T½ or Tlag. Day 28 CFB for GMBT T½ showed salutary decrease in all groups: −6.0 ± 54.0, −18.8 ± 41.7, −26.4 ± 35.1, and −24.8 ± 46.0 min in the 10-, 20-, and 40-mg TZP-102 groups and placebo, respectively; these results did not materially differ with no significant difference vs placebo when: (i) analysis was limited to patients with GMBT-associated preprandial glucose <250 mg dL−1 (pretreatment); or (ii) analysis was undertaken of the subset with pretreatment GMBT T1/2  168 min. Change from baseline in GMBT lag times numerically improved in all groups (−11.7 ± 46.7, −18.9 ± 59.8, −20.6 ± 35.0, and −7.3 ± 35.2 min for the 10-, 20-, and 40-mg TZP-102 groups and placebo, respectively). Linear correlation analyses showed no correlations between T½ and symptom severity (GCSI Total Score) at baseline (r = 0.116, = 0.273) or at the end of the 28-day treatment period (r = 0.049, = 0.641), or between the CFB in T½ and symptom improvement after 28 days of treatment (r = 0.057, = 0.600). Further details of the gastric emptying evaluations and concomitant postprandial glucose measurements following consumption of the test meal are provided in Table 2 and data are depicted for the subset with pretreatment GMBT T1/2  168 min in Table 3. The pattern of postprandial glucose elevation following test meal ingestion was similar during Baseline and Day 28 GMBT. There was no apparent correlation between pre-GMBT-meal blood glucose levels and gastric T1/2 (Fig. S1), although as expected individual patients with shorter gastric T1/2 tended to have higher delta postprandial glucose values; ancova with postprandial glucose as covariate failed to show any statistically significant difference vs placebo in CFB for gastric T1/2 for any individual TZP-102 dose or all TZP-102 doses combined.

Table 2.   Gastric motility breath test half-emptying time and concomitant postprandial glucose results
 10 mg TZP-10220 mg TZP-10240 mg TZP-102All TZP-102PlaceboPlacebo vs 10, 20, 40 mg, & all TZP-102
Day 28CFBDay 28CFBDay 28CFBDay 28CFBDay 28CFB P-value
  1. *patients with a Day −16 to Day −7 (Baseline) half-emptying time <150 min were excluded from analysis.

  2. Patients with a Day −16 to Day −7 (Baseline) half-emptying time <168 min were excluded from analysis (T1/2 168 min is the mean plus 2 standard deviations for T1/2 in healthy subjects).

T 1/2 min Mean (SD)185.6 (53.3)−6.0 (53.95)173.3 (55.1)−18.8 (41.7)163.6 (28.1)−26.4 (35.1)174.0 (46.9)−17.2 (44.3)171.1 (47.5)−24.8 (46.0)0.319, 0.887, 0.598, 0.821
Proportion of patients with T1/2 < 150 min*6/21 (28.6%)10/19 (52.6%)8/23 (34.8%)24/63 (38.1%)9/25 (36.0%)0.754, 0.361, 1.000, 1.000
Proportion of patients with T1/2 < 168 min5/13 (38.5%)8/13 (61.5%)8/15 (53.3%)21/41 (51.2%)8/15 (53.3%)0.476, 0.718, 1.000, 1.000
Postprandial glucose mg dL−1 Mean (SD)
GMBTDay -16 to −7Day 28Day -16 to −7Day 28Day -16 to −7Day 28Day -16 to −7Day 28Day -16 to −7Day 28
Before Test meal (absolute value)172.4 (77.4)182.1 (77.8)161.6 (73.4)160.2 (65.4)172.7 (56.4)164.2 (48.8)169.1 (68.5)168.8 (64.5)176.7 (71.7)152.9 (56.8)
60 min after test meal (absolute value)227.9 (71.0)225.7 (78.3)217.7 (99.2)217.9 (77.2)239.8 (62.4)256.4 (88.7)228.6 (78.1)233.7 (82.1)239.5 (79.1)222.3 (79.5)
120 min after test meal (absolute value)230.5 (78.8)218.9 (68.4)218.3 (80.9)229.0 (94.9)271.2 (92.1)251.9 (83.7)240.3 (85.9)233.6 (82.9)259.0 (78.3)237.7 (78.0)
Change from before test meal to 60 min after test mealΔ55.4 (81.7)Δ43.1 (73.3)Δ56.1 (74.7)Δ61.1 (58.6)Δ69.5 (76.9)Δ93.6 (76.4)Δ60.5 (76.8)Δ66.4 (72)Δ62.8 (66.3)Δ69.3 (53.5)
Change from before test meal to 120 min after test mealΔ58.1 (95.5)Δ36.8 (94.8)Δ56.7 (71.8)Δ68.9 (79.7)Δ100.8 (97.5)Δ87.6 (80.5)Δ72.1 (90.3)Δ64.8 (86.5)Δ82.3 (73.0)Δ84.8 (59.2)
Table 3.   GMBT T1/2 (min) change from baseline (CFB) among patients with baseline T1/2  168 min (2 SD above mean)
 10 mg TZP-10220 mg TZP-10240 mg TZP-102All TZP-102Placebo
Baseline (Day −16 to −7)
 N1313154115
 Mean (SD)216.9 (66.7)215.6 (55.3)207.4 (36.9)213.0 (52.4)224.1 (57.4)
Day 28
 N1313154115
 Mean (SD)197.2 (54.8)186.4 (65.6)170.2 (30.5)183.9 (51.5)179.9 (55.6)
Day 28 CFB
 N1313154115
 Mean (SD)−19.7 (57.2)−29.2 (48.1)−37.2 (36.98)−29.1 (46.97)−44.2 (46.0)
P-value (vs Placebo)0.3250.6390.8640.606 

Symptom improvement analyses

There were statistically significant improvements in GCSI Total Score, and a number of the individual GCSI symptom scores across all three TZP-102 dose groups vs placebo. Fig. 2 shows the changes from baseline in GCSI Total Score for all dose groups. All doses of TZP-102 (combined) showed statistically greater decline in GCSI relative to placebo. A mean decline in GCSI Total Score of −1.0 to −1.4 was achieved across individual dose groups (compared to a mean decline of −0.6 for placebo) without a consistent dose response between 10 and 40 mg. Baseline, Day 28 and CFB results for the individual GCSI symptoms and for the PAGI-SYM symptom of upper abdominal pain are summarized in Table 4 for each TZP-102 dose group and the placebo group. The most marked improvement relative to placebo was apparent for attributes of satiety and bloating, which generally had higher scores at study entry. For all TZP-102 doses combined (= 66 patients) statistically significant impact on measures of early satiety and bloating was particularly notable, with trends toward significance for nausea and upper abdominal pain. Consistent significant activity was noted at the 20-mg dose level.

image

Figure 2.  GCSI total scores at baseline and after 28 days for the placebo and TZP-102 dose groups. Lower scores indicate milder symptoms on a scale where 0 = none, 1 = very mild, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe. Changes from baseline (CFB) are shown, and P-values for TZP-102 vs placebo are indicated above the bars.

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Table 4.   Mean (SD) scores and changes from baseline (CFB) for individual symptoms at after 28 days of once-daily treatment with TZP-102 QD vs placebo in patients with diabetic gastroparesis
 10 mg TZP-102 (= 22)20 mg TZP-102 (= 21)40 mg TZP-102 (= 23)All TZP-102 (= 66)Placebo (= 26)Placebo vs 10, 20, 40 mg, & all TZP-102
Day 28CFBDay 28CFBDay 28CFBDay 28CFBDay 28CFB P-value
  1. *GCSI component of PAGI-SYM symptoms graded: 0 = none; 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very severe.

  2. PAGI-SYM symptom of upper abdominal pain (above the navel) graded: 0 = none; 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very severe.

Nausea*2.5 (1.54)−1.1 (1.51)1.7 (1.65)−1.5 (1.69)2.0 (1.69)−1.0 (1.58)2.1 (1.63)−1.2 (1.58)2.6 (1.47)−0.5 (1.36)0.372, 0.029, 0.184, 0.067
Retching*1.7 (1.58)−0.8 (1.15)1.1 (1.56)−1.2 (1.60)1.4 (1.53)−0.9 (1.42)1.4 (1.55)−0.9 (1.39)1.7 (1.55)−0.8 (1.53)0.936, 0.222, 0.642, 0.509
Vomiting*1.3 (1.67)−0.5 (1.53)0.6 (1.20)−0.3 (1.27)1.2 (1.87)−0.2 (1.76)1.0 (1.62)−0.3 (1.52)1.1 (1.45)0.0 (1.11)0.577, 0.342, 0.828, 0.47
Upper abdominal pain2.2 (1.38)−1.0 (1.50)1.6 (1.80)−1.1 (1.37)2.3 (1.50)−0.7 (1.36)2.1 (1.57)−0.9 (1.40)2.7 (1.64)−0.4 (1.70)0.172, 0.043, 0.448, 0.086
Early satiety*2.5 (1.41)−1.1 (1.52)1.7 (1.45)−1.4 (1.57)2.3 (1.46)−0.6 (1.75)2.2 (1.45)−1.0 (1.64)3.1 (1.29)−0.4 (1.13)0.068, 0.001, 0.161, 0.009
Bloating (loosen clothes)*2.5 (1.53)−1.7 (1.64)2.4 (1.63)−1.5 (1.57)2.6 (1.56)−1.2 (1.50)2.5 (1.55)−1.5 (1.56)3.3 (1.67)−1.0 (1.46)0.082, 0.125, 0.342, 0.075
Stomach visibly larger*2.6 (1.40)−1.3 (1.62)2.2 (1.55)−1.5 (1.47)2.3 (1.57)−1.2 (1.90)2.4 (1.50)−1.3 (1.66)3.4 (1.68)−0.6 (1.30)0.082, 0.018, 0.042, 0.011
Postprandial Fullness*2.6 (1.53)−1.3 (1.86)2.3 (1.62)−1.8 (1.37)2.2 (1.57)−1.5 (1.59)2.4 (1.56)−1.5 (1.61)3.4 (1.30)−0.8 (1.26)0.143, 0.0195, 0.028, 0.013
Stomach fullness*2.5 (1.26)−1.6 (1.65)2.3 (1.45)−1.6 (1.50)2.5 (1.31)−1.2 (1.17)2.4 (1.33)−1.5 (1.44)3.5 (1.10)−0.5 (1.27) 0.009, 0.002, 0.0143, 0.001
Loss of appetite*2.1 (1.51)−1.4 (1.40)1.2 (1.29)−1.7 (1.43)1.8 (1.41)−1.2 (1.68)1.7 (1.44)−1.4 (1.50)2.3 (1.64)−1.2 (1.59)0.625, 0.044, 0.452, 0.186

Onset of symptom score improvements was evident after 1 week of TZP-102 treatment. Changes over time in the subset of four main symptoms analyzed as a composite (nausea, upper abdominal pain, early satiety, and bloating) for each TZP-102 dose and placebo are illustrated in Fig. 3. Overall combined active doses showed an increased trajectory of decline and a statistically significant difference from placebo at Day 28, signaling symptom improvement.

image

Figure 3.  Changes in total gastroparesis four-symptom composite score during and after treatment (mean of PAGI-SYM nausea, not able to finish meal, upper abdominal pain and bloating; P-values versus placebo).

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A significantly greater proportion of patients given TZP-102 (all doses relative to placebo) were GCSI Total Score responders meaning that they achieved a ≥ 50% decrease in GCSI from baseline at the last two on-treatment evaluations (both Day 15 and Day 28). Specifically, 19/66 patients treated with TZP-102 (28.8%) reduced their Baseline GCSI Total Score by at least half vs 2/26 (7.7%) of patients given placebo (= 0.0308). While a dose response was not evident, all active groups had a higher percentage of responders compared with placebo: 6 (27.3%), 7 (33.3%), 6 (26.1%) given 10, 20, or 40 mg of TZP-102, respectively, vs 2 (7.7%) in the placebo arm.

More favorable, positive, mean scores for the Patient OTE (3.8 ± 3.5, = 0.005) and physician OTE (3.7 ± 3.4, = 0.011) compared with placebo (1.2 and 1.5, respectively) were reported on Day 28 for the 20-mg TZP-102 group. Mean scores for 10- and 40-mg TZP-102 groups, 1.8 and 2.1 for Patient OTE, respectively, and 2.0 (physician OTE for both doses) were not statistically significant vs placebo at Day 28, although a statistical trend was present for all TZP-102 doses combined for the patient assessment (Patient OTE 2.6 ± 3.6, = 0.052; physician OTE 2.5 ± 3.1, = 0.137). Correlations between Day 28 Patient OTE scores and GCSI scores (Total Score, all three subscale scores and all individual GCSI symptom scores, except for vomiting) and between Day 28 physician OTE scores and GCSI scores were highly significant (P ≤ 0.007).

Pharmacodynamic and pharmacokinetic assessments

Transient increases in mean serum GH concentration were observed after dosing only with 40-mg TZP-102. The results on Day 28 did not suggest the presence of tachyphylaxis with regard to stimulation of the GH secretagogue receptor. No apparent differences between baseline and Day 28 IGF-1 serum concentration values were observed for any treatment group.

At steady-state (Day 28) a non-linear pharmacokinetic profile was evident with the 10-mg and 20-mg dose groups having comparable mean AUC0–6 and Cmax values that were slightly less than those for the 40-mg dose group. Trough TZP-102 plasma concentrations were similar across all three TZP-102 dose groups. The crude estimates for elimination half-life were ∼155–170 h.

Safety results

Safety profiles were similar in the placebo and TZP-102 groups and all TZP-102 doses appeared to be well-tolerated. Treatment-emergent AEs occurred in 50 (76%) patients receiving TZP-102 and 20 (77%) patients receiving placebo without apparent dose response: 16 (72.7%), 18 (85.7%), and 16 patients (69.6%) in the 10-, 20-, or 40-mg TZP-102 groups, respectively. The most commonly reported events are shown in Table 5. Most (84%) AEs in patients administered TZP-102 were mild (48%) or moderate (36%). AEs related to study medication were of similar frequency in the TZP-102 groups and placebo (31.8% across all TZP-102 doses and 38.5% on placebo), and only five patients had related AEs ongoing at end of study (2 placebo, 3 active).

Table 5.   The most commonly reported (occurring in ≥ 2 patients in any group) treatment-emergent adverse events
Adverse event*TZP-102
10 mg (= 22)20 mg (= 21)40 mg (= 23)Placebo (= 26)
  1. *Tabulation of spontaneously reported adverse events by investigators.

Number (%) of patients
 Nausea3 (13.6)3 (14.3)3 (13.0)4 (15.4)
 Vomiting1 (4.5)2 (9.5)1 (4.3)4 (15.4)
 Constipation3 (13.6)1 (4.8)1 (4.3)3 (11.5)
 Diarrhea3 (13.6)2 (9.5)2 (8.7)0
 Dyspepsia2 (9.1)2 (9.5)1 (4.3)0
 Abdominal pain upper2 (9.1)1 (4.8)2 (8.7)0
 Abdominal pain lower1 (4.5)02 (8.7)1 (3.8)
 Abdominal discomfort1 (4.5)2 (9.5)1 (4.3)0
 Headache1 (4.5)1 (4.8)2 (8.7)2 (7.7)
 Hypoglycemia1 (4.5)1 (4.8)1 (4.3)2 (7.7)
 Hyperglycemia01 (4.8)3 (13.0)0
 Fatigue02 (9.5)01 (3.8)
 Depression0002 (7.7)
 Hypertension02 (9.5)00
 Skin ulcer2 (9.1)000
 Urinary tract infection002 (8.7)0

Seven serious adverse events that were not considered related to study treatment were reported for six patients: five patients in the 10-mg TZP-102 group with one event each (ankle infection, diabetic ketoacidosis, skin ulcer, chest pain, gastroparesis) and one patient in the 40-mg TZP-102 group with two events (atrial fibrillation and sepsis).

No clinically relevant differences between the TZP-102 treatment groups and placebo group were apparent with regard to CFB in vital signs or any 12-lead ECG parameters. The ECG analysis of CFB for PR, QRS, and QTcB did not identify dose-dependent or TZP-102 plasma concentration-dependent changes or notable differences from placebo. Clinical laboratory results revealed no apparent drug- or dose-related trends with regard to changes from baseline or the development of any clinically significant abnormalities. Postprandial changes in blood glucose concentrations during the breath tests conducted at the Day 1 and Day 28 visits were similar across placebo and all TZP-102 groups and comparable to those observed during the pretreatment breath test. There were also no changes in fasting glucose, HbA1c levels, or body weight as a function of TZP-102 plasma concentrations after 28 days of treatment. There was no increase in body weight in the TZP-102 groups over 28 days of treatment as reflected in the mean change from baseline of −0.4 ± 1.9 kg (10 mg TZP-102), 0.0 ± 1.4 kg (20 mg TZP-102), −0.2 ± 2.2 kg (40 mg TZP-102), and 0.3 ± 1.4 kg (placebo).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

Once-daily oral administrations of TZP-102 for 28 days demonstrated significant improvements in the most prevalent symptoms of gastroparesis in diabetic patients without showing a significantly different change in gastric emptying. The average improvement in GCSI Total Score of 1.0–1.4 points across TZP-102 dose groups was greater than the placebo response of 0.6 points. The clinical relevance of these changes is underscored by GCSI symptom validation data that identify decreases of 0.5–0.75 point as clinically important improvements.17,21

Delayed gastric emptying was required for study entrance (in addition to clinical symptoms and diagnosis of gastroparesis) and distinguished study participants from patients with other gastrointestinal disorders. However, the severity of symptom scores for GCSI total, subscales, and individual symptoms at baseline and at the end-of-treatment did not correlate with the degree of delay in gastric emptying, nor did the end-of-treatment changes in these symptom scores correlate with changes in gastric emptying. The lack of statistically significant improvement over placebo in gastric emptying in patients receiving TZP-102 may be attributed to the improvement in gastric emptying on placebo during the study. This disconnect between gastric emptying speed and gastroparesis symptoms is consistent with findings from other reports in diabetic gastroparesis trials.7,8 In a systematic review of clinical trials of gastroparesis of diverse etiologies, Sturm and colleagues concluded that there is no relationship between improvements in gastric emptying and gastroparesis symptoms.7 Jones et al. found no, or weak, correlations between gastroparesis symptoms and gastric emptying.8 Patient-defined outcomes as endpoints in gastroparesis studies are therefore particularly important to establish efficacy of treatment, as measurements of gastric emptying do not reliably predict improvement in patient symptoms. The validity of gastric emptying measurements for assessing improvements in gastroparesis in clinical settings continues to be questioned and discussed,9 albeit suggestive of plausible mechanism22 in this arena although interestingly coupled with a demonstrable order effect in a crossover setting.

Patient and physician assessments of overall 28-day treatment benefit (using the OTE questionnaire) correlated well with the degree of symptom improvement using the GCSI. Gastroparesis is a disease with symptoms that can wax and wane in severity,23 however, it is encouraging that the GCSI responder analysis which required at least 50% improvement at both of the two last on-treatment efficacy assessments demonstrated a greater percentage of responders in each TZP-102 dose group than placebo.

While a limitation of our study is that the GCSI instrument does not have sufficiently robust validation data in patients with diabetic gastroparesis and is a recollected assessment of severity, the use of several instruments to assess symptomatology was advantageous. In addition, the results of this study should be interpreted in the context of the exploratory nature of the analyses and inherent multiple comparisons. Finally, we must acknowledge the potential effects of acute glycemia on symptoms, gastric emptying and the response to promotility drugs,24–26 while we anticipate that the double-blind, randomized, placebo-controlled design will in large measure address real life disparities in this regard. We did not observe a correlation between preprandial blood glucose levels and gastric T1/2 within the context of this study; while we acknowledge that a correlation between gastric emptying and glycemia has been observed in healthy volunteers, our data and that of some other authors, show that this is not as clear in diabetic patients.27,28

TZP-102 had no effect on body weight or glycemic control (fasting, postprandial glucose, and HbA1c levels) during the course of treatment for 28 days in patients with diabetes. No safety issues were evident.

As the ghrelin pathway positively regulates both GH and IGF-I and has been shown to increase GH in diabetic patients with gastroparesis,13 we examined TZP-102 effects on GH and IGF-I levels. There were no changes in GH levels at the 10- and 20-mg TZP-102 doses, and transient peaks were observed at the 40-mg dose of uncertain clinical consequence. At that dose, repeat assessments of GH did not indicate development of tachyphylaxis after dosing with TZP-102 for 28 days. There were no apparent differences between baseline and day 28 serum IGF-I concentrations in any of the treatment groups or correlation between IGF-1 and TZP-102 plasma levels.

In conclusion, oral administration of TZP-102 for 28 days significantly improved gastroparesis symptoms with a rapid onset visible from the first week of treatment in patients with diabetes mellitus, and was very well-tolerated with no safety concerns. The lack of correlation between improvement in symptoms and improvement in gastric emptying emphasizes the need to use patient-reported outcomes in determining clinically significant treatment effects in gastroparesis, particularly as there may be alternative contributing factors which remain incompletely defined (e.g., impaired gastric accommodation, visceral hypersensitivity). Overall, the data indicate that TZP-102 represents a promising oral pharmacological option to address an unmet medical need for patients whose day-to-day quality of life is impaired by gastroparesis. Further explorations in larger number of patients and longer duration of therapy are warranted, and two 12-week treatment studies evaluating longer term activity will more fully characterize this novel investigational drug.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

The authors appreciate the dedication of all study staff at participating centers, study coordinators, and the commitment of enrolled patients. We also acknowledge the dedication, foresight and hard work from study inception of Dr. Gordana Kosutic, Dr. Laura Shaughnessy, and Dr. Philippa Charlton while at Tranzyme, Inc. In addition to nine investigator-authors, we acknowledge the contributions and participation of the following investigators: US:TV Nowak, AJ Lembo, CF Barish, L Hazan. Denmark: H-H Lervang, KB Yderstraede. Poland: J Muszynski, M Gorska, J Loba.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

This study was funded in full by Tranzyme, Inc. Initial data analyses were undertaken by John Pezzullo and Stat-Tech Services who both received funding from Tranzyme, Inc.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

NE has served as a speaker, a consultant and/or an advisory board member for Novo Nordisk, Eli Lilly, Pfizer, GSK, Bayer, Tranzyme and The Danish Diabetic Association and has received research funding from The Danish Diabetic Association, Novo Nordisk and Eli Lilly. RAM has served as a speaker, a consultant and/or an advisory board member for Eli Lilly, Pfizer, Novo Nordisk, Astra Zeneca, MSD, and Tranzyme, and has received research funding from MSD, Pfizer, and Tranzyme. MMJ has received research funding from Sucampo, Astra-Zeneca, Shire, Tranzyme, Salix, and Mundipharma. JMW, PMH and GD have indicated no current conflicting/competing interests to declare. TE has served as a speaker for Salix and has received research funding from Astra Zeneca and Tranzyme. LT has served as a speaker, a consultant and/or an advisory board member for BMS and Novo Nordisk, and has received research funding from NovoNordisk, BMS, MSD, Abbott, Amgen, Boehringer Ingelheim, Medtronic, ReAplix, Rheoscience, Tranzyme, Inc., and the Danish Diabetes Association. RWM has been on the Advisory Board of Smart Pill Corporation. He has been a consultant for Tranzyme, Inc., Prostrakam Pharm and Medtronic Corporation, and has received Research funding from Tranzyme and Takada. EM, JQ and FR are employees of Tranzyme, Inc.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

NE, JMW, TE, MMJ, GD, LT, RAM, PMH and RWM were investigators in the study who actively enrolled eligible patients in addition to scientific contributions. All authors had complete access to the data that supports the publication, participated in analysis, writing, reviewing, and editing manuscript drafts and approved the final draft of the manuscript for submission.

References

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  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Funding
  9. Disclosure
  10. Author contributions
  11. References
  12. Supporting Information

Figure  S1. Linear regression of gastric T½ vs absolute blood glucose.

FilenameFormatSizeDescription
NMO_12064_sm_FigureS1.jpg180KSupporting info item

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