Clinical Trial Results:
A single centre, pilot trial of YF476 in patients with chronic atrophic gastritis, hypergastrinaemia and type I gastric carcinoids
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Summary
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EudraCT number |
2007-002916-24 |
Trial protocol |
GB |
Global end of trial date |
25 Feb 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Feb 2021
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First version publication date |
05 Feb 2021
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Other versions |
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Summary report(s) |
07-504 SOTR |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
T-008
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
HMR code: 07-504 | ||
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Sponsors
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Sponsor organisation name |
Trio Medicines Ltd
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Sponsor organisation address |
PO Box 53346, London, United Kingdom, NW10 7XU
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Public contact |
Dr Malcolm Boyce, Trio Medicines Ltd, +44 2089614130, mboyce@triomedicines.com
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Scientific contact |
Dr Malcolm Boyce, Trio Medicines Ltd, +44 2089614130, mboyce@triomedicines.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Feb 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Feb 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Feb 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary:
To assess if netazepide (YF476) is an effective medical treatment for type I gastric carcinoids.
Secondary:
To assess the tolerability and safety of netazepide (YF476); and
To assess the effect of netazepide (YF476) on plasma concentration and transcript profiles of biomarkers such as chromogranin A (CgA).
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Protection of trial subjects |
Before the trial started, we did a risk assessment to identify and manage risks to the trial patients. We determined that the overall risk to the patients was negligible because:
1. netazepide has a good safety profile in non-clinical and clinical studies;
2. the expected netazepide exposure during the study was within the safe limits seen in non-clinical studies;
3. the safety testing and assessments were adequate based on our clinical experience of netazepide; and
4. any risks were adequately mitigated by safety assessments, and by the medical cover provided by the investigator site.
All study procedures and information given to the subjects were reviewed and approved by a research ethics committee. To minimise anxiety in the subjects and to ensure that they were fully informed about the trial, subjects were asked to read and sign an information and consent form (ICF). The ICF gave details:
1. about netazepide, including risks of taking it;
2. of inclusion and exclusion criteria;
3. of lifestyle restrictions and risks/disadvantages of taking part in the study;
4. of procedures during the study, including the amount of blood to be donated; and
5. about payment and clinical studies in general.
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Background therapy |
There wasn't any background therapy. | ||
Evidence for comparator |
No comparator was used. | ||
Actual start date of recruitment |
04 Jan 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 8
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Worldwide total number of subjects |
8
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EEA total number of subjects |
8
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
3
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Screening started on 04 Jan 2011. | |||||||||
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Pre-assignment
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Screening details |
Patients, aged ≥ 18 years, deemed otherwise healthy based on medical history, physical findings, electrocardiogram (ECG) and laboratory values; that had gastric carcinoids associated with chronic atrophic gastritis (CAG) and hypergastrinaemia; who attended the outpatient clinic of the principal investigator; and could give fully-informed consent | |||||||||
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Period 1
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Period 1 title |
Overall trial
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Overall enrollment and completion of all participants | |||||||||
Arm description |
The study was done over 12 visits: patients took a dose of netazepide (YF476) 50 mg by mouth, once daily at home, every day for 12 weeks (up to Visit 6). Patients didn't take netazepide (YF476) between Visits 6 and 8, for at least 23 weeks. Patients were then prescribed netazepide capsules at Visit 8, to take every day as before, for 52 more weeks until Visit 12. There was at least 3 weeks between each visit. In the event, all participants attended all visits. | |||||||||
Arm type |
No intervention | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Overall dosing | |||||||||
Arm description |
The dosing and compliance of all participants in the study. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
netazepide
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Investigational medicinal product code |
YF476
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
At Visit 1, patients didn't receive netazepide, as they were being screened at this visit.
Between Visits 2-6, the patients took netazepide (YF476) 50 mg once daily with breakfast, apart from one patient, who accidently took 25 mg, instead of 50 mg, up until Visit 4. Patients stopped taking netazepide (YF476) between Visits 6 and 7, for 12 weeks.
Patients resumed taking netazepide (YF476) 50 mg at Visit 8, at least 23 weeks after Visit 7. Between Visits 8-12, patients took netazepide (YF476) 50 mg once daily with breakfast.
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Period 2
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Period 2 title |
netazepide (YF476)
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Is this the baseline period? |
No | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
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Arms
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Arm title
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netazepide (YF476) 50 mg fed | |||||||||
Arm description |
- | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
netazepide 50 mg
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Investigational medicinal product code |
YF476
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Participants took an oral dose of netazepide (YF476) 50 mg, daily, with breakfast.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
All participants enrolled in the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Overall enrollment and completion of all participants
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Reporting group description |
The study was done over 12 visits: patients took a dose of netazepide (YF476) 50 mg by mouth, once daily at home, every day for 12 weeks (up to Visit 6). Patients didn't take netazepide (YF476) between Visits 6 and 8, for at least 23 weeks. Patients were then prescribed netazepide capsules at Visit 8, to take every day as before, for 52 more weeks until Visit 12. There was at least 3 weeks between each visit. In the event, all participants attended all visits. | ||
Reporting group title |
Overall dosing
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Reporting group description |
The dosing and compliance of all participants in the study. | ||
Reporting group title |
netazepide (YF476) 50 mg fed
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Reporting group description |
- | ||
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End point title |
Mean number of type 1 tumours [1] | ||||||||||||||||||||
End point description |
At each gastroscopy a patient underwent, the number of tumours for that patient was counted.
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End point type |
Primary
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End point timeframe |
Each patient's tumours were monitored throughout the study; patients underwent gastroscopy and gastric biopsies on Visits 2, 4, 6, 7, 8, 10 and 12.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not done. |
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| Notes [2] - Except Visit 8, where n was 7. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Mean size of the largest tumour [3] | ||||||||||||||||||||||
End point description |
The size of a patient's tumours was measured at each gastroscopy. A pair of standard biopsy forceps was used as an internal standard, for size correction between saved images of the tumours.
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End point type |
Primary
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End point timeframe |
Each patient's tumours were monitored throughout the study; patients underwent gastroscopy and gastric biopsies on Visits 2, 4, 6, 7, 8, 10 and 12.
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not done. |
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| Notes [4] - Except Visit 8, where n was 7. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Histology of tumour biopsies [5] | ||||||||||||||
End point description |
Biopsies were taken at gastroscopy and were classified.
Histology classifications:
NET = neuroendocrine tumour
ECL-D = ECL-cell dysplasia
ECL-L = linear ECL-cell hyperplasia
ECL-M = micronodular ECL-cell hyperplasia
Note that these classifications are not mutually exclusive.
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End point type |
Primary
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End point timeframe |
Each patient's tumours were monitored throughout the study; patients underwent gastroscopy and gastric biopsies on Visits 2, 4, 6, 7, 8, 10 and 12.
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis was not done. |
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Attachments |
Histology of tumour biopsies |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Peak plasma concentrations of netazepide (YF476) | ||||||||||||||||||||||||
End point description |
Nominal blood sampling times were used to calculate the median (range) and mean (SD) drug concentrations at each time point. Linear and semi-logarithmic plots of the mean (± standard error) concentration-time data was prepared.
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End point type |
Secondary
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End point timeframe |
Blood samples were taken 1 hour after the patients took netazepide (YF476) 50 mg with breakfast, for assay of the peak concentration of netazepide (YF476). These samples were taken on Visits 3-6, and Visits 9-12.
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| Notes [6] - Except Visits 9-11, where n was 7. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Trough plasma concentrations of netazepide (YF476) | ||||||||||||||||||||||||
End point description |
Nominal blood sampling times were used to calculate the median (range) and mean (SD) drug concentrations at each time point. Linear and semi-logarithmic plots of the mean (± standard error) concentration-time data was prepared.
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End point type |
Secondary
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End point timeframe |
Blood samples were taken before the patients took netazepide (YF476) 50 mg with breakfast, for assay of the trough concentration of netazepide (YF476). These samples were taken on Visits 3-6, and Visits 9-12.
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| Notes [7] - Except Visits 9, 11 and 12, where n was 5; and Visit 10, where n was 6. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Plasma CgA concentrations | ||||||||||||||||||||||||||||||
End point description |
Chromogranin A (CgA) is a biomarker of ECL-cell activity. Blood samples were taken to measure levels of CgA in the plasma.
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End point type |
Secondary
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End point timeframe |
Blood samples were taken, after an overnight fast and before the patients took netazepide (YF476) 50 mg, for assay of concentrations of chromogranin A (CgA) in the plasma. These samples were taken on Visit 1 and Visits 3-12.
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Attachments |
Netazepide-CgA concentrations relationship |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Serum gastrin concentrations | ||||||||||||||||||||||||||||||
End point description |
Serum gastrin is a biomarker for gastric acid production, and mediates gene expression associated with cell division, invasion, angiogenesis and anti-apoptotic activity. Blood samples were taken to measure levels of gastrin in the serum.
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End point type |
Secondary
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End point timeframe |
Blood samples were taken, after an overnight fast and before the patients took netazepide (YF476) 50 mg, for assay of concentrations of gastrin in the serum. These samples were taken on Visit 1 and Visits 3-12.
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Attachments |
Netazepide-Gastrin concentrations relationship |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Safety and tolerability: adverse events | ||||||||
End point description |
Overall number of participants with at least 1 adverse event (AE). A breakdown of AEs by system organ
class and preferred term is presented in 'Adverse events'.
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End point type |
Secondary
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End point timeframe |
Each subject was monitored throughout the study (from screening until follow-up).
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| No statistical analyses for this end point | |||||||||
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End point title |
Safety: values of potential clinical concern | ||||||||||||||
End point description |
Clinical laboratory results, vitals signs and electrocardiogram (ECG) results that were outside acceptable limits and/or that changed from baseline by a pre-determined amount. Abnormal physical examination results.
Reference ranges were not used in this study, as the standard HMR reference ranges are for healthy volunteers. The sponsor agreed that only the investigator’s opinion on the clinical significance of an out-of-range laboratory result, for example, was important. The measurements taken at screening were used as the baseline.
In the event, all physical examination and clinical laboratory results were considered to be of no clinical concern. No vital signs were considered to be of potential clinical importance. There was only 1 abnormal ECG finding of potential clinical significance, where the QRS axis of Patient 01 was unknown.
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End point type |
Secondary
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End point timeframe |
From baseline to last visit.
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Each subject was monitored throughout the study (from screening until follow-up).
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Adverse event reporting additional description |
The investigator or delegate questioned the subjects about adverse events (AEs) using a non-leading
question, such as 'How're you feeling?'. The investigator also recorded AEs reported spontaneously.
Other clinically significant changes in the safety assessments could also be recorded as an AE if criteria, described in the protocol, were met.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15
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Reporting groups
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Reporting group title |
netazepide (YF476) 50 mg
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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25 Oct 2010 |
The purpose of the amendment was to reduce some of the restrictions on medications given concomitantly with netazepide (YF476).
In vitro inhibition studies of netazepide (YF476), with CYP450 enzymes, found no inhibition of CYP2C9 by netazepide (YF476) at the concentrations tested; and that the likelihood of an interaction with CYP2C8 and CYP3A4 was 'possible' and 'remote', respectively.
The sponsor therefore removed the restrictions in the protocol on concomitant medications metabolised by CYP2C9 and have softened the restrictions on medications metabolised by CYP3A4 and CYP2C8. |
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18 Jan 2012 |
The purpose of this amendment was to allow patients who had completed the original protocol to receive netazepide (YF476) for up to another 12 months.
In another trial, of a gastrin receptor antagonist with very poor bioavailability, a patient's type 1 gastric carcinoids (GCs) regressed substantially after 4 weeks. So 12 weeks' treatment with netazepide (YF476), as described in the original protocol, was deemed long enough to eradicate type 1 GCs. However, preliminary results indicated that although 12 weeks' treatment reduced the number and size of the GCs, it did not eradicate them.
For that reason, the protocol was amended to include another 12 months' treatment. It was expected that extended treatment with netazepide (YF476) could eradicate type 1 GCs and minimise the risk of malignancy, as netazepide (YF476) was well tolerated, reduced the number and size of the GCs, reduced circulating CgA to within normal range, and there was an increase in CgA to pre-treatment levels after stopping netazepide (YF476). |
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16 Sep 2013 |
The purpose of the amendment was to bring the protocol in line with an updated version of the Investigator's Brochure (IB; version 14, dated 19 July 2013), and to change the definition of the end of the trial.
The sponsor updated the protocol in line with the updated reference safety information in the new version of the IB, so that co-administration of netazepide (YF476) with medicines that are CYP3A4 substrates was allowed.
According to the Human Tissue Act, tissue samples that were taken during gastroscopies cannot be stored or analysed after the study has been declared over. To allow time for sample analysis, the sponsor changed the definition of the end of the trial to 'the last visit of the last subject, or completion of bioanalysis, whichever is later'.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
