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Alimentary Pharmacology and Therapeutics

Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting – randomised clinical study subset data J. M. Wo*, N. Ejskjaer , P. M. Hellstro¨mà, R. A. Malik§, J. C. Pezzullo–, L. Shaughnessy**, P. Charlton**, G. Kosutic** & R. W. McCallum  

*Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA.   Department of Medicine MEA (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, DK, USA. à Gastroenterology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. § Division of Cardiovascular Medicine, University of Manchester, Manchester, UK. – Department of Medicine, Georgetown University Medical Center, Washington DC, USA. **Tranzyme Inc., Durham, NC, USA.    Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine, El Paso, Texas, USA.

SUMMARY

Correspondence to: Dr G. Kosutic, Tranzyme Inc., 4819 Emperor Blvd, Ste 400, Durham, NC 27703, USA. E-mail: [email protected]

Results At baseline, 23 patients had a mean severity score for GCSI Nausea ⁄ Vomiting of 4.45  0.44. Statistically significant improvements over placebo occurred in the 80 lg ⁄ kg group for end of treatment changes from baseline in GCSI Nausea ⁄ Vomiting subscale (reduction in score of )3.82  0.76, P = 0.011) and the GCSI Total score ()3.14  0.78, P = 0.016) and were maintained at the 30-day follow-up assessment ()2.02  1.63, P = 0.073 and )1.99  1.33, P = 0.032 respectively). The proportion of days with vomiting was reduced significantly (P = 0.05) in the 80 lg ⁄ kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days).

Publication data Submitted 23 November 2010 First decision 9 December 2010 Resubmitted 16 December 2010 Accepted 16 December 2010 EV Pub Online 7 January 2011

Background Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and malnutrition due to inadequate caloric and fluid intake. TZP-101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis. Aim To assess effects of TZP-101 in diabetic gastroparesis patients with severe nausea ⁄ vomiting and baseline severity scores of ‡3.5 (range: 0–5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea ⁄ Vomiting subscale. Methods Patients were hospitalised and received four single daily 30-min infusions of one of six TZP-101 doses (range 20–600 lg ⁄ kg) or placebo. Efficacy was assessed by symptom improvement.

Conclusions TZP-101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP-101, supporting further investigation of TZP-101 in the management of severe gastroparesis. Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2010.04567.x

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J. M. Wo et al. INTRODUCTION Severe gastroparesis is characterised by refractory symptoms, inability to maintain nutrition orally, and frequent emergency department visits and ⁄ or hospitalisations.1 Nausea and vomiting are present in 70–90% of patients with gastroparesis,2, 3 and, in addition to being the most bothersome symptoms reported by patients,4 contribute to multiple health issues,5–7 including electrolyte disturbances and dehydration, and increased healthcare utilisation.8 These symptoms may also decrease work performance and ability to function socially.9 In diabetic patients with gastroparesis,10 severe nausea and vomiting can impact on glycaemic control and nutritional status.11, 12 Current management of refractory nausea and vomiting due to gastroparesis includes rehydration with IV fluids, intensive management of high glucose levels (in diabetic patients) and treatment with intravenously administered prokinetic and anti-emetic agents.13 Currently available pharmaceutical options for patients with severe gastroparesis and frequent nausea and vomiting are insufficient, with a consequent need for lengthy stays in hospital, which may eventually require surgical or other invasive interventions (e.g. gastric electrical stimulation and ⁄ or jejunostomy).14–16 Thus, there is an unmet medical need for a well-tolerated pharmacological option that alleviates severe nausea and vomiting. TZP-101 (ulimorelin) is a first-in-class macrocyclic peptidomimetic with potent binding affinity for the ghrelin receptor, also known as the growth hormone secretagogue receptor (hGHS-R1a).17 Ghrelin is a peptide hormone produced primarily in the gastric mucosa that coordinates gastrointestinal (GI) motility.18, 19 Pharmacological doses of exogenous ghrelin have significant GI prokinetic effects in patients with both idiopathic and diabetic gastroparesis. TZP-101 accelerates gastric emptying in adults with diabetic gastroparesis,20, 21 and improves recovery of GI motility following bowel resection.22 The pharmacokinetics of TZP-101 in patients with gastroparesis and healthy subjects are comparable and there is little accumulation of TZP-101 after multiple dosing.23 Administration of TZP-101 is well tolerated and safety profiles are similar in placebo and TZP-101 treatment groups.20–22 In a phase 2 trial in adult patients with type 1 or 2 diabetes, daily intravenous TZP-101 for 4 days demonstrated clinically and statistically significant improvements in several gastroparesis-related symptoms, including nausea and vomiting, postprandial fullness ⁄ early satiety and loss of appetite.21 This study also 680

showed that a single, daily dose of 80 lg ⁄ kg was the most effective dose. TZP-101 30-min IV infusion is in development for management of acutely presenting severe symptoms related to gastroparesis – typically severe vomiting and nausea that can result in the need for hospitalisation or emergency room care. Therefore, it was of most relevance to evaluate TZP-101 effects in the cohort of patients with severe nausea and vomiting at entry. This report describes the subset analysis data for patients with severe nausea and vomiting enrolled in the phase 2 study described above.21

METHODS A multicentre, randomised, double-blind, placebo-controlled, dose-ranging study was conducted from September 2007 to January 2009 at eight study centres: four sites in the USA and one site each in Denmark, Norway, Sweden and the UK (Clinical Trial Registry NCT 00612014). All participants gave written informed consent and the study protocol was approved by the Institutional Review Boards ⁄ Ethics Committees for each study site prior to patient screening. Detailed methods of study participants, randomisation and blinding procedures have been previously described.21 Adult men and women (18–80 years) with type 1 or 2 diabetes mellitus and documented diagnosis of gastroparesis were electively admitted to a hospital and randomised to receive daily doses of intravenous TZP-101 or placebo for 4 days. Gastroparesis symptoms were evaluated using the Gastroparesis Cardinal Symptom Index (GCSI), which uses a six-point scale ranging from none (0) to very severe (5).24 This was performed to determine the severity of nine symptoms, individually, and grouped by the three subscales Nausea ⁄ Vomiting, Postprandial Fullness ⁄ Early Satiety as well as Bloating, and by the GCSI Total score.24 Prior to hospital admission, enrolled patients completed a 24-h recall GCSI questionnaire25 daily for 4 days to determine baseline GI symptom severity. Delayed gastric emptying was measured by scintigraphy or breath test at screening or within 6 months of the study. Other screening assessments included determination of the percentage HbA1c and fasting pancreatic polypeptide (PP) levels and assessment of autonomic neuropathy using the Michigan Neuropathy Screening Instrument (MNSI)26 and cardiovascular autonomic dysfunction measurements that included beat-to-beat heart rate variation (abnormal defined as a difference £10 beats ⁄ min in a supine patient breathing 6 times ⁄ min) and orthostatic hypotension evaluation (abnormal Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd

Randomised clinical trial: TZP-101 improves severe gastroparesis symptoms defined as a fall in systolic blood pressure of ‡20 mmHg or diastolic blood pressure ‡10 mmHg 3 min after standing up). Patients using medications affecting gastric motility (either acceleration or delay) were eligible for the study if they had been taking a stable dose of the medication for at least 3 weeks prior to screening and they agreed to continue the same dosing regimen throughout the dosing portion of the study. For the in-patient portion of the study, insulin was administered to patients as required. On the whole, for the in-patient and follow-up periods, patients continued standards of care for managing their diabetes and gastroparesis recommended by their physicians. Subset of patients with severe nausea and vomiting Patients with a baseline severity score of ‡3.5 on the GCSI Nausea ⁄ Vomiting subscale were selected for post hoc analysis of the effects of TZP-101 on symptoms of severe nausea and vomiting. This criterion was used as at least two of the three symptoms that make up this subscale would need to be categorised as severe or very severe to achieve at least a score of 3.5. The primary efficacy parameter for this subset was the change from baseline for the GCSI Nausea ⁄ Vomiting subscale at the end of treatment (day 4) and at the follow-up visit (day 30). Baseline was defined as the mean of the four daily scores prior to hospital admission. Other endpoints included GCSI individual symptom scores, subscale scores and total score.5 The average number of days patients vomited during the treatment period was also evaluated. During each dosing day, patients completed the modified six-item Gastroparesis Symptom Assessment just prior to the start of the infusion and every 30 min until 4 h after the start of the infusion. In the evening of each dosing day, the 24-h recall GCSI questionnaire assessing the symptoms for the previous 24 h period was completed. Safety Safety was evaluated by daily assessment of adverse events and injection site reactions, and vital signs, blood glucose (measured each day prior to and 2 h after each meal and before bedtime), orthostatic hypotension, and 12-lead ECGs (monitored pre-dosing and 45 and 90 min and 4 h after the start of each infusion. Clinical and laboratory evaluations, including physical examination and haematology, were performed the day after final dosing prior to discharge from the hospital. Patient safety was monitored by phone call on day 7 and at the follow-up Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd

clinic visit on day 30 after administration of the last dose of study medication. Statistical analyses The sample size and numbers of patients assigned to each dose were determined by adaptive randomisation as previously described.21 A set of a priori comparisons of interest were specified: between the combined ‘All TZP-101’ dose groups and the placebo group, and between the TZP-101 80 lg ⁄ kg dose group and the placebo group. Baseline characteristics and changes in GCSI Total, subscale and individual symptom scores from baseline to dosing day 4 and to the day 30 follow-up visit were compared between All TZP-101 and placebo groups by the unpaired Student’s t-test, or by the nonparametric Mann–Whitney U-test if required by non-normality of the data. In addition, changes over time in individual GCSI symptom scores, subscales and GCSI Total score were analysed by linear mixed-effects models with terms for day, dose and day · dose interaction, and with subject as a random factor. The dose · day interaction term directly indicated TZP-101 efficacy by quantifying the difference between the slopes of the placebo and TZP-101 lines fitted to the score-vs.-day data, with each subject having a separate ‘intercept’ (fitted day-0 value). Significant efficacy was inferred when the coefficient(s) of the intercept term(s) were significantly different from zero. Changes from baseline in the number of vomiting days were compared between placebo and TZP-101 using either the Student’s t-test, or the nonparametric Mann– Whitney U-test. Data are presented as mean  standard deviation (s.d.). All efficacy analyses were based on two-sided tests, with P £ 0.05 considered significant.

RESULTS Seventy-eight patients were randomised and 76 patients received at least one dose of study drug in the described phase 2 study. Results for the entire study population have been previously published.21 Twenty-three of the 76 treated patients met the criteria for the severe nausea and vomiting subset. A flow diagram of patients in the study is shown in Figure 1. Patient demographics and baseline characteristics for this subset are shown in Tables 1 and 2. The 23 patients had a Nausea ⁄ Vomiting subscale severity score (mean  s.d.) of 4.45  0.44 (severe to very severe) at baseline. All patients had delayed gastric emptying at baseline as confirmed by a mean retention of 30  18% at 4-h of radiolabelled meal 681

J. M. Wo et al. (scintigraphy data in 15 patients) or by a mean t1 ⁄ 2 in gastric emptying time of 145.38  24.05 min (acetate breath test in eight patients). The average patient age was 42.3  13.2 years, mean body mass index was 27.4  5.1 and 61% of patients were female. Fifteen patients had Type 1 diabetes and eight had Type 2 diabetes. The mean autonomic neuropathy score was 2 of 4. A mean HbA1c of 8.4 (range: 5.6–12.6) per cent indicated less than optimal glucose control. Of the 23 patients, 17 were randomised to receive TZP-101 and 6 to receive placebo. Five patients received the 80 lg ⁄ kg dose, the dose identified as most effective in the primary analysis of the study.21 Two, four, three, one and two patients received 20, 40, 160, 320 or 600 lg ⁄ kg of TZP101 respectively. Given the small number of patients in each dose group, all results are presented for placebo vs. the 80 lg ⁄ kg dose group and placebo vs. the All TZP101 dose group. There were no differences in demographics or baseline characteristics between the placebo and TZP-101 groups as shown in Tables 1 and 2.

Randomised patients n = 78

Patients who received at least one dose of study medication n = 76

Subset of patients with severe Nausea and Vomiting n = 23

Placebo

80 µg/kg

n=6

n=5

AII TZP-101 n = 17

Completed

Completed

n=6

n = 17

Efficacy results Severity of nausea and vomiting markedly decreased in patients treated with TZP-101 as compared with placebo. Nausea ⁄ Vomiting subscale scores in the placebo group were 2.72  1.25 and 4.00  0.60 at the day 4 and day

Figure 1 | Patient progression in the study.

Table 1 | Summary of demographics and baseline characteristics Placebo (n = 6)

Parameter Mean age  s.d. (years)

TZP-101 80 lg ⁄ kg All TZP-101 (n = 5) (n = 17)

All patients (n = 23)

38.3  13.5

36.2  8.4

43.7  13.2

42.3  13.2

3 (50)

2 (40)

6 (35)

9 (39)

3 (50)

3 (60)

11 (65)

14 (61)

28.1  4.3

28.4  5.4

27.2  5.4

27.4  5.1

4 (67)

4 (80)

11 (65)

15 (65)

Gender, n (%) Male Female 2

Mean body mass index  s.d. (kg ⁄ m ) Diabetes, n (%) Type 1 Type 2 Mean duration of diabetes (years) Mean duration of gastroparesis (years)

2 (33)

1 (20)

6 (35)

8 (35)

13.4  10.4

8.6  8.0

15.2  13.1

14.7  12.2

5.5  6.4

3.8  3.7

3.3  3.0

3.8  4.1

Mean gastric emptying  s.d. (n) Scintigraphy, % retained 4 h

34.75  13.1 (4)

Breath test, t½ min

145.5  17.7 (2)

37.00  27.5 (5) NA

27.5  20.8 (11) 145.33  27.3 (6)

29.92  18.3 (15) 145.38  24.1 (8)

Mean HbA1c  s.d. (%)

7.6  1.7

8.1  2.1

8.7  1.8

8.4  1.8

Mean fasting PP levels  s.d. (pg ⁄ mL)

190  77

210  159

179  181

182  158

Mean autonomic neuropathy score*  s.d. (0–4)

1.83  1.60

1.60  0.89

2.35  1.11

2.22  1.24

* Autonomic neuropathy based on orthostatic hypotension and beat-to-beat variation diagnostic tests.

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Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd

Randomised clinical trial: TZP-101 improves severe gastroparesis symptoms Table 2 | Baseline GCSI scores (mean  s.d.) TZP-101 80 lg ⁄ kg (n = 5)

Parameter

Placebo (n = 6)

All TZP-101 (n = 17)

All patients (n = 23)

GCSI Total score

3.80  0.70

4.14  0.46

3.95  0.51

3.91  0.56

4.25  0.42

4.42  0.08

4.09  0.40

4.13  0.40

Postprandial Fullness ⁄ Early Satiety subscale

3.66  1.18

4.03  0.77

3.89  0.82

3.83  0.91

Bloating subscale

3.50  1.32

3.98  0.75

3.92  1.08

3.81  1.13

4.21  0.49

4.30  0.41

3.78  0.81

3.89  0.76

Nausea

4.46  0.49

4.70  0.41

4.44  0.44

4.45  0.44

Retching

4.08  0.52

4.25  0.25

3.94  0.52

3.98  0.51

Stomach fullness

3.91  0.92

4.00  0.88

3.96  0.95

3.91  0.92

Early satiety

3.71  1.38

4.05  0.65

3.76  1.17

3.75  1.19

Excessive fullness

3.83  1.14

4.20  0.84

4.18  0.86

4.09  0.93

Loss of appetite

3.29  1.91

3.85  0.88

3.65  0.74

3.55  1.12

Bloating

3.79  0.95

4.00  0.88

4.00  1.04

3.95  1.00

Abdominal distension

3.21  1.70

3.95  0.72

3.84  1.21

3.67  1.34

Subscale scores Nausea ⁄ Vomiting subscale

Individual scores Vomiting

* Mean measurements for daily scores were recorded for the 4 days prior to admission. GCSI scores were recorded using a sixpoint scale ranging from none (0) to very severe (5).

30 assessment respectively. Scores in the 80 lg ⁄ kg dose group were 0.60  0.68 and 2.40  1.67, on day 4 and day 30 respectively and 1.22  1.52 and 2.65  1.76 in the All TZP-101 group. Figure 2a shows the changes from baseline at day 4, and day 30 for the Nausea ⁄ Vomiting subscale. At end of treatment (day 4), the reductions in nausea and vomiting were statistically significant ()3.82  0.76, P = 0.011) or approached significance ()2.88  1.43, P = 0.055) for the 80 lg ⁄ kg and All TZP101 dose group compared with placebo, respectively. At the 30-day follow-up period off the study drug, the improvement of nausea and vomiting appeared to persist for the 80 lg ⁄ kg and all TZP-101 dose groups, but did not reach statistical significance ()2.02  1.63 P = 0.073 and )1.45  1.66, 0.123 respectively). Figure 2b shows the Total GCSI scores and individual scores for placebo, all TZP-101 doses and those after 4 days of treatment. Statistically significant changes from baseline occurred in the TZP-101 group for the total GCSI score, and individual scores for nausea, vomiting, and unable to finish a meal. At the 30-day follow-up assessment, the change from baseline for the 80 lg ⁄ kg TZP-101 total GCSI score remained statistically significant ()1.99  1.33, P = 0.032). The course of improvement of the Nausea ⁄ Vomiting subscale and the course of improvement in Vomiting only Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd

over the 4-day treatment period are shown in Figure 3. After 1 day of intravenous study drug, all patients (including patients receiving placebo) showed improvement. However, during the following 3 dosing days, patients on placebo reverted to the same level of symptom severity as immediately prior to entry into the study, whereas patients receiving TZP-101 had a decrease in symptom severity that was maintained for all treatment days. The number of days during which patients experienced vomiting during the run-in and treatment period was determined and the results are shown in Figure 4. Nineteen patients (five in the placebo, and 14 in All TZP-101 dose groups; five in the 80 lg ⁄ kg) experienced near-daily vomiting (4 ⁄ 4 days for the placebo and 80 lg ⁄ kg groups and 3.86 ⁄ 4 days for the All TZP-101 group) during the 4-day ‘run-in’ period. During the 4day treatment period, the number of days with vomiting episodes was reduced to 3.20  0.84, 1.20  1.10 and 1.00  1.36 for the placebo, 80 lg ⁄ kg and All TZP-101 dose groups respectively. The changes from baseline for the 80 lg ⁄ kg, and All TZP-101 dose groups were statistically significant (P = 0.054 and 0.001 respectively). In addition to severe nausea and vomiting at baseline, all patients had other significant symptoms characteristic of gastroparesis such as postprandial fullness ⁄ early satiety and bloating. Baseline scores for GCSI Total score, sub683

J. M. Wo et al. (a)

80 µg/kg TZP-101 (n = 5)

Placebo (n = 6)

All TZP-101 (n = 17)

0 –1 –2 –3 0.133 –4

0.073 0.055

0.011

–5

Day 4 (b) Total GCSI score

Nausea

30 Day follow-up

Retching Vomiting Stomach Unable to Excess finish fullness fullness meal

Loss of Bloating Abdominal distension appetite

0

–1

–2

–3 0.21 0.32 0.26 0.60 –4

0.016 0.12

0.091 0.18 0.22 0.65

0.033 0.11

0.068 0.20

0.078 0.57 0.04 0.16

0.001 0.12

Figure 2 | Changes from baseline for the GCSI Nausea ⁄ Vomiting subscale scores at the End of Treatment (day 4) and at Follow-up (30-day) (a) and for GCSI Total score and individual symptom scores on day 4 (b). Negative changes indicate improvements from baseline scores, which range from 0 to 5 with 5 being the most severe. Baseline and post-treatment scores are given in the text and Table 2. P-values are shown below the bars.

scale scores and individual scores of all 23 patients are shown in Table 2. Figure 2b shows the improvements (changes from baseline) at the end of treatment for individual GCSI symptom scores and total GCSI score for the placebo, 80 lg ⁄ kg TZP-101 group and All TZP-101 dose groups. For the 80 lg ⁄ kg TZP-101 group, there were numerical improvements for all scores ranging from 1.1 684

(bloating) to 2.9 points (total score). The observed benefit was statistically significant in the 80 lg ⁄ kg TZP-101 group for individual symptom scores for nausea, vomiting and early satiety (not able to finish a meal) and for the GCSI Total score. The improvement in the GCSI Total score remained statistically significant at the 30-day follow-up assessment: GCSI Total score was 2.15  1.39 with a Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd

GCSI Nausea/Vomiting subscale score

Randomised clinical trial: TZP-101 improves severe gastroparesis symptoms 5

(a)

4 3 2 1 0 Day 0

Day 1

Day 2

Day 3

Day 4

Treatment day

Figure 3 | Change in mean Nausea ⁄ Vomiting subscale scores (a) and Vomiting scores (b) over time. The slopes for days 1–4 in (a) are significantly different for the 80 lg ⁄ kg group vs. placebo (P < 0.001) and All TZP-101 vs. placebo (P = 0.004), and in (b) for 80 lg ⁄ kg group vs. placebo (P = 0.008) and All TZP-101 vs. placebo (P = 0.005).

(b)

GCSI Vomiting score

5

PBO (n = 5)

3 2 1 0 Day 0

Safety results The safety results for the 23 patients in the Nausea and Vomiting severe subset population are similar to results previously presented for the total study population.21

Number of days with vomiting

80 µg/kg TZP-101 (n = 5)

All TZP-101 (n = 14)

0.174

4 3.5 3

0.054 0.001

2.5 2 1.5 1 0.5 0 Run in period

ª 2011 Blackwell Publishing Ltd

Day 1

Day 2

Day 3

Day 4

There were no clinically relevant differences between TZP-101 and placebo-treated patients in clinical or laboratory evaluations, and safety profiles were similar in the placebo and TZP-101 groups. Similar percentages of patients receiving placebo or TZP-101 experienced at least one adverse event: 47% (n = 8 ⁄ 17) of patients receiving TZP-101 and 50% (n = 3 ⁄ 6) of patients in the placebo group. None of the adverse events appeared to be dose related. One of five patients (20%) in the 80 lg ⁄ kg dose group had one adverse event. The most common adverse events for all the TZP-101 dose groups combined were headache (n = 2, 12%), nausea (n = 2, 12%). In the placebo group, headache was reported by one patient (17%). The majority of events in both the placebo (n = 4) and TZP-101 groups (n = 23) were mild or moderate: 3 ⁄ 4 mild (75%) and no moderate events in the placebo group and 12 ⁄ 23 mild (52%) and 10 ⁄ 23 (43%) moderate events in all the TZP-101 groups.

Treatment period

Figure 4 | Number of days during the 4-day run in period and the 4-day treatment period on which patients experienced vomiting. P-values for changes from baseline are shown above bars. Aliment Pharmacol Ther 2011; 33: 679–688

All TZP-101 (n = 14)

4

change from baseline of )1.99  1.33 vs. )0.97  1.26 in the placebo group (P = 0.032).

Placebo (n = 5)

80 µg/kg (n = 5)

DISCUSSION This analysis of a subset of patients with diabetic gastroparesis with severe nausea and vomiting and moderately to severely delayed gastric emptying shows that intravenous TZP-101 treatment for 4 days improved 685

J. M. Wo et al. nausea and vomiting, and inability to finish a meal, and, to a lesser extent, retching. Overall, gastroparesis symptoms improved, which is consistent with the results observed in the total population.21 The magnitude of improvement in total score was significant and clinically meaningful, and was sustained at the 30-day follow-up assessment. In the present study, the average improvement (decrease in score) from baseline over placebo in GCSI Total scores for patients in the 80 lg ⁄ kg group (previously shown to be the most efficacious dose21) was >1.8 points. Considering that the GCSI Total symptom scoring method reflects improvement with as little as a 0.5- to 0.75-point decrease,24, 27 this represents a notable recovery. The GCSI Nausea ⁄ Vomiting subscale data for the 80 lg ⁄ kg TZP-101 group showed an average improvement over placebo of 2.3 points at the end of treatment. Improvements in scores were sustained at the 30-day follow-up visit in patients receiving TZP-101, with an improvement over placebo of 1.8 points, although the results were not statistically significant. Similar results were observed for the entire cohort receiving TZP-101 in the phase 2 study that were statistically significant, as previously reported.21 Although the mechanism behind this sustained improvement in vomiting is not known, patients with drug-refractory gastroparesis undergoing temporary, short-term gastric electrical stimulation have experienced sustained improvement in vomiting frequency.28 The severity of nausea and vomiting experienced by the patients in this subset was exemplified by almost daily vomiting prior to treatment. Those who received TZP-101 had clinically meaningful and statistically significant reductions in vomiting frequency (from 100% of days with vomiting prior treatment to 25% of days during the treatment period) compared with placebo. Improvements in both the frequency and severity of nausea and vomiting may have significant impact on patients whose symptoms can disrupt the ability to perform normal daily activities, including even the maintenance of oral nutrition, and lead to both increased frequency and duration of hospitalisations.8 Quantifying the number of days without vomiting as an endpoint may be used in future clinical trials assessing the effectiveness of GI motility drugs. This concept is under consideration as an efficacy endpoint by the Food and Drug Administration. There was a significant placebo effect immediately on day 1 of study drug, but the efficacy of TZP-101 occurred rapidly after day 1. The severity of nausea and vomiting symptoms rebounded in the placebo group, but scores continued to improve in the TZP-101 groups. 686

Placebo responses are influenced by both conscious expectation and unconscious conditioning regarding treatment29 and the in-patient research setting that possibly included hydration and supportive care, may have created an environment that influenced the subjective assessment of symptom severity provided by patients during the first day of the study. TZP-101 appears to be safe and well tolerated, and no safety issues have been identified either in the total patient population21 or in the subset population. The incidence, severity and relationship of adverse events to study drug were similar in the TZP-101 and placebo groups. This benign side effect profile represents an important improvement over current prokinetic drugs for gastroparesis, such as metoclopramide, which is associated with central nervous system side effects that are often not tolerated by patients needing ongoing treatment or by macrolide antibiotics, which may induce intestinal cramping and diarrhoea.1, 6 As was reported for the entire study population,21 no acute hyperglycaemia was associated with TZP-101 administration. An inherent weakness of this subset analysis is the small number of patients, and future studies of TZP-101 are planned using a larger sample size of patients with severe, acutely presenting symptoms. Nevertheless, the relatively small number of the most severely affected patients with diabetic gastroparesis makes pilot or subset studies the most practical initial approach for investigating new treatment options. Given the heterogeneous nature of gastroparesis, stratification of patients by symptom type and severity may provide useful information for predicting therapeutic responses.30–32 In summary, TZP-101 was able to reduce severe nausea and vomiting as well as overall symptoms substantially and significantly in a subset of the most refractory diabetic gastroparesis patients. These observations support a future role of this GI motility agent as a potent therapy of gastroparesis.

ACKNOWLEDGEMENTS Declaration of personal interests: J. Wo has served as a speaker, a consultant and ⁄ or an advisory board member for Medtronic, Takeda Pharmaceuticals and Prometheus and has received research funding from Takeda Pharmaceuticals, Santarus, Furiex Pharma and Tranzyme, Inc. N. Ejskjaer 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 Aliment Pharmacol Ther 2011; 33: 679–688 ª 2011 Blackwell Publishing Ltd

Randomised clinical trial: TZP-101 improves severe gastroparesis symptoms Lilly. P. M. Hellstro¨m has served as a speaker, a consultant and ⁄ or an advisory board member for AstraZeneca, GlaxoSmithKline, Nycomed, Rose Pharma and Tranzyme, Inc., and has received research funding from AstraZeneca, GlaxoSmithKline and Tranzyme, Inc. R. Malik has served as a speaker, a consultant and ⁄ or an advisory board member for Eli Lilly, Pfizer, Novo Nordisk, Astra Zeneca, MSD and Tranzyme, Inc., and has received research funding from MSD, Pfizer and Tranzyme, Inc. R. McCallum has served as a speaker, a consultant and ⁄ or an advisory board member for Smart Pill and Tranzyme, Inc., and has received research funding

from Takada and Tranzyme, Inc. J.C. Pezzullo is a consultant to Tranzyme, Inc. L. Shaughnessy, P. Charlton and G. Kosutic are employees of Tranzyme, Inc. L. Shaughnessy, P. Charlton and G. Kosutic own stock options in Tranzyme, Inc. Declaration of funding interests: The study was funded by Tranzyme, Inc. The preparation of this article was funded in part by Tranzyme, Inc. Initial data analyses were undertaken by John Pezzullo, an independent consultant who received funding from Tranzyme, Inc. Medical writing support was provided by Patrice C. Ferriola of KZE PharmAssociates and was funded by Tranzyme, Inc.

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