Clinical Trial Results:
Phase IIA, open label, dose ascending study to determine the maximum tolerated dose, safety and tolerability, pharmacokinetics and pharmacodynamics of a single dose of lanreotide prolonged release formulation in subjects with acromegaly previously treated and controlled with either ocreotide Long Acting Release or lanreotide Autogel.
Summary
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EudraCT number |
2014-002389-62 |
Trial protocol |
GB BE DE NL CZ LT ES IT PL |
Global end of trial date |
28 Nov 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Nov 2018
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First version publication date |
09 Nov 2018
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Other versions |
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 |
8-55-52030-309
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02396953 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Ipsen
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Sponsor organisation address |
65 quai George Gorse, Boulogne Billancourt, France, 92100
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Public contact |
Medical Director, Ipsen, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Ipsen, clinical.trials@ipsen.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 |
28 Nov 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Nov 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Nov 2017
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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 |
The primary objective of the study was to identify the maximum tolerated dose (MTD) and to investigate the pharmacokinetics (PK) of a single dose of lanreotide prolonged release formulation (PRF) in subjects with acromegaly.
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Protection of trial subjects |
The study was conducted under the provisions of the Declaration of Helsinki in accordance with the International Council for Harmonisation Consolidated Guideline on Good Clinical Practice and in compliance with Independent Ethics Committees /Institutional Review Boards and informed consent regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Mar 2015
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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 |
Netherlands: 1
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Country: Number of subjects enrolled |
Romania: 3
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Lithuania: 2
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Country: Number of subjects enrolled |
Russian Federation: 11
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Worldwide total number of subjects |
28
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EEA total number of subjects |
17
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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) |
24
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
This was an open-label, dose-ascending study to assess the PK, pharmacodynamics (PD), safety and tolerability of a single dose of lanreotide PRF. 17 centres recruited adult subjects with acromegaly into 3 lanreotide PRF treatment cohorts (180 milligrams [mg], 270 mg and 360 mg). | ||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Screening of subjects took place 28 to 42 days before administration of study treatment (Day −42 to Day −28). Overall, 60 subjects were screened during this run-in period; 32 of whom were screening failures and 28 subjects were enrolled and treated with lanreotide PRF. | ||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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180 mg Lanreotide PRF | ||||||||||||||||||||||||||||
Arm description |
On Day 1, 3 initial subjects in Cohort 1 received a subcutaneous injection of 180 mg lanreotide PRF and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a Dose Limiting Toxicity (DLT), 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the Data Review committee (DRC) would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until end of study (EOS) at Week 25 or early withdrawal (EW). | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Lanreotide PRF
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Investigational medicinal product code |
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Other name |
Lanreotide acetate
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Pharmaceutical forms |
Prolonged-release solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock on Day 1 of the 12 week treatment period. The formulation was supplied in prefilled syringe and delivered 180 mg lanreotide base.
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Arm title
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270 mg Lanreotide PRF | ||||||||||||||||||||||||||||
Arm description |
On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Lanreotide PRF
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Investigational medicinal product code |
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Other name |
Lanreotide acetate
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Pharmaceutical forms |
Prolonged-release solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock on Day 1 of the 12 week treatment period. The formulation was supplied in a prefilled syringe and delivered 270 mg lanreotide base.
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Arm title
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360 mg Lanreotide PRF | ||||||||||||||||||||||||||||
Arm description |
On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Lanreotide PRF
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Investigational medicinal product code |
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Other name |
Lanreotide acetate
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Pharmaceutical forms |
Prolonged-release solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock on Day 1 of the 12 week treatment period. The formulation was supplied in a prefilled syringe and delivered 360 mg lanreotide base.
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Baseline characteristics reporting groups
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Reporting group title |
180 mg Lanreotide PRF
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Reporting group description |
On Day 1, 3 initial subjects in Cohort 1 received a subcutaneous injection of 180 mg lanreotide PRF and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a Dose Limiting Toxicity (DLT), 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the Data Review committee (DRC) would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until end of study (EOS) at Week 25 or early withdrawal (EW). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
270 mg Lanreotide PRF
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Reporting group description |
On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
360 mg Lanreotide PRF
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Reporting group description |
On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
180 mg Lanreotide PRF
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Reporting group description |
On Day 1, 3 initial subjects in Cohort 1 received a subcutaneous injection of 180 mg lanreotide PRF and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a Dose Limiting Toxicity (DLT), 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the Data Review committee (DRC) would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until end of study (EOS) at Week 25 or early withdrawal (EW). | ||
Reporting group title |
270 mg Lanreotide PRF
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Reporting group description |
On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||
Reporting group title |
360 mg Lanreotide PRF
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Reporting group description |
On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||
Subject analysis set title |
Lanreotide PK Set: 180 mg Lanreotide PRF
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. The lanreotide PK dataset included the 9 subjects from the PK valid population who were not pre-treated with lanreotide and who received 1 deep subcutaneous injection of 180 mg lanreotide PRF.
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Subject analysis set title |
Lanreotide PK Set: 270 mg Lanreotide PRF
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. The lanreotide PK dataset included the 7 subjects from the PK valid population who were not pre-treated with lanreotide and who received 1 deep subcutaneous injection of 270 mg lanreotide PRF. The 2 subjects previously treated with a stable dose of lanreotide Autogel were expected to have a detectable pre-dose concentration and it was considered relevant to exclude them.
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Subject analysis set title |
Lanreotide PK Set: 360 mg Lanreotide PRF
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. The lanreotide PK dataset included 6 subjects from the PK valid population who were not pre-treated with lanreotide and who received 1 deep subcutaneous injection of 360 mg lanreotide PRF. The 3 subjects previously treated with a stable dose of lanreotide Autogel were expected to have a detectable pre-dose concentration and it was considered relevant to exclude them.
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Subject analysis set title |
Glycofurol PK Set: 180 mg Lanreotide PRF
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. This glycofurol dataset included 9 subjects from the PK valid population who had a sufficient number of serum glycofurol concentrations to estimate the main glycofurol PK parameters and who received 1 deep subcutaneous injection of 180 mg lanreotide PRF.
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Subject analysis set title |
Glycofurol PK Set: 270 mg Lanreotide PRF
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PK valid population consisted of subjects who received at least 1 dose and had no major protocol deviations affecting the PK variables, and who had a sufficient number of serum lanreotide concentrations to estimate the main PK parameters. This glycofurol dataset included 9 subjects from the PK valid population who had a sufficient number of serum glycofurol concentrations to estimate the main glycofurol PK parameters and who received 1 deep subcutaneous injection of 270 mg lanreotide PRF.
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End point title |
Determination of the MTD by Number of Subjects With DLTs. [1] | ||||||||||||
End point description |
The MTD was defined based on the DLTs observed in each cohort. A DLT was defined as an adverse event (AE) (excluding anorexia and fatigue) or an abnormal laboratory value occurring within the first week (up to Week 2) following lanreotide PRF administration and during the entire study duration, assessed as unrelated to acromegaly, intercurrent illness or concomitant medications and which met any of the pre-established toxicity criteria. If no DLTs were reported then no MTD could be defined. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment.
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End point type |
Primary
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End point timeframe |
From Day 1 up to Week 25.
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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: As this was a dose ascending study, no comparative analyses were performed. |
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No statistical analyses for this end point |
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End point title |
PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). [2] | ||||||||||||||||
End point description |
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide Cmax values were determined using non-compartmental analysis. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
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End point type |
Primary
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End point timeframe |
From Baseline (pre-dose) up to Day 85
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Notes [2] - 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: As this was a dose ascending study, no comparative analyses were performed. |
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No statistical analyses for this end point |
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End point title |
PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). [3] | ||||||||||||||||
End point description |
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Median serum lanreotide Tmax values were determined using non-compartmental analysis. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
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End point type |
Primary
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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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: As this was a dose ascending study, no comparative analyses were performed. |
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No statistical analyses for this end point |
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End point title |
PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). [4] | ||||||||||||||||
End point description |
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide t1/2 values were determined using non-compartmental analysis. Only values fulfilling the determination rules for t1/2 were analysed. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
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End point type |
Primary
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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Notes [4] - 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: As this was a dose ascending study, no comparative analyses were performed. |
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No statistical analyses for this end point |
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End point title |
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85). [5] | ||||||||||||||||
End point description |
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-85 values were determined using non-compartmental analysis. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
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End point type |
Primary
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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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: As this was a dose ascending study, no comparative analyses were performed. |
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No statistical analyses for this end point |
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End point title |
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). [6] | ||||||||||||||||
End point description |
Blood samples for determination of lanreotide serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8,12 and 24 hours post-dose, on Days 3 and 5 and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF administration. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Mean serum lanreotide AUC0-∞ values were determined using non-compartmental analysis. Only values fulfilling the accuracy determination rules for AUC0-∞ were analysed. Only
subjects with data available for analysis and who were not pre-treated with lanreotide are presented.
9999999 = not determined (i.e. when more than 1/3 of the values did not fulfil accuracy determination rules, the descriptive statistics were not calculated).
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End point type |
Primary
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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Notes [6] - 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: As this was a dose ascending study, no comparative analyses were performed. |
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No statistical analyses for this end point |
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End point title |
Overall Summary of Number of Subjects With AEs. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
AEs reported by the investigators using the National Cancer Institute–Common Toxicity Criteria (NCI CTCAE) classification (Version 4.03) and incidence of all reported treatment emergent AEs (TEAEs) and serious AEs (SAEs) are presented by dose cohort for the safety population. AEs were assigned to a NCI CTCAE Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. TEAEs were defined as any AE that occurs during the active phase of the study (between the start of the 3 month treatment period and 3 months after the end of study treatment). The worst intensity of TEAES at each grade are reported for all and for related TEAES. In the event of multiple occurrences of the same AEs being reported by the same subject, the maximum intensity and the most serious causality were reported.
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End point type |
Secondary
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End point timeframe |
From Day -42 up to Week 25.
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No statistical analyses for this end point |
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End point title |
PK Analysis of Glycofurol Excipients: Cmax. | ||||||||||||||||||
End point description |
Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Mean serum N1- glycofurol and N2-glycofurol Cmax values were determined using non-compartmental analysis. Only subjects with data available for analysis are presented. Due to bioanalytical issues, no results for the excipient N1-glycofurol and N2-glycofurol for 360 mg Lanreotide PRF (cohort 3) were available at the time of the PK analysis.
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End point type |
Secondary
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End point timeframe |
From Baseline (pre-dose) up to Day 5.
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No statistical analyses for this end point |
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End point title |
PK Analysis of Glycofurol Excipients: Tmax. | ||||||||||||||||||
End point description |
Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Median serum N1-glycofurol and N2-glycofurol Tmax values were determined using non-compartmental analysis. Only subjects with data available for analysis are presented. Due to bioanalytical issues, no results for the excipient N1-glycofurol and N2-glycofurol for 360 mg Lanreotide PRF (cohort 3) were available at the time of the PK analysis.
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End point type |
Secondary
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End point timeframe |
From Baseline (pre-dose) up to Day 5.
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No statistical analyses for this end point |
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End point title |
PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). | ||||||||||||||||||||||||
End point description |
Blood samples for determination of the excipients (N1-glycofurol and N2-glycofurol) serum concentrations were collected at Baseline (pre-dose), at 1, 2, 4, 6, 8, 12 and 24 hours post-dose and on Days 3 and 5. Mean serum N1-glycofurol and N2-glycofurol AUC0-∞ and AUC0-t values were determined using non-compartmental analysis. Only AUC0-∞ values fulfilling the accuracy determination rules were analysed. Due to bioanalytical issues, no results for the excipient N1-glycofurol and N2-glycofurol for 360 mg Lanreotide PRF (cohort 3) were available at the time of the PK analysis.
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End point type |
Secondary
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End point timeframe |
From Baseline (pre-dose) up to Day 5.
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Notes [7] - AUC0-∞: 8 subjects analysed. [8] - AUC0-∞: 8 subjects analysed. |
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No statistical analyses for this end point |
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End point title |
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected for the determination of IGF-1 in serum at Baseline (pre-dose), 6 hours post-dose and at Weeks 5, 9 and 13. Samples were also collected during follow-up at Weeks 17, 21 and 25 (or EW). Serum concentrations of IGF-1 were calculated using the Immulite 2000 Platform for all subjects in the safety population. The production of the reagent kits was stopped by the vendor during the study. The old reagent kits were used for Cohorts 1 and 2 until their expiry date and then the kits were switched to a new reagent and used for remaining subjects in Cohorts 2 and 3. Summary data for serum concentrations of IGF-1 were obtained using both methods (old and new reagent) and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented. 9999999 = not calculable.
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End point type |
Secondary
|
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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Notes [9] - Old : Weeks 13, 17 (n=7), 21 (n=5) New: all weeks (n=0) [10] - Old Reagent: 6 h (n=8) Weeks 17 (n=6), 21 (n=4) New Reagent: all weeks (n= 2) [11] - Old: 6 h (n=4) Weeks 5 (n=2), 9-25 (n=0) New: 6 h & Weeks 9 (n=9), 17 (n=8), 21 (n=7) |
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No statistical analyses for this end point |
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End point title |
PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | ||||||||||||||||||||||||
End point description |
GH cycle assessments were performed by taking 5 samples in the morning (with a sample taken every 30 minutes for 2 hours) at Baseline (pre-dose), Week 5 and Week 13. Summary data for the mean of the 5 samplings of the GH cycle were generated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
|
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End point type |
Secondary
|
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End point timeframe |
From Baseline (pre-dose) up to Week 13.
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Notes [12] - Week 13 (n=7) |
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No statistical analyses for this end point |
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End point title |
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected for the determination of FT3 and FT4 in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentrations of FT3 and FT4 were calculated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
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End point type |
Secondary
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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Notes [13] - Week 13 (n=7) [14] - FT4: Week 25 (n=8) [15] - Weeks 2&5 (n=9) |
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No statistical analyses for this end point |
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End point title |
PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | ||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected for the determination of TSH in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentrations of TSH were calculated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
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End point type |
Secondary
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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Notes [16] - Week 13 (n=7) [17] - Week 25 (n=8) [18] - Weeks 2&5 (n=9) |
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No statistical analyses for this end point |
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End point title |
PD Analysis: Mean Change From Baseline in Prolactin. | ||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected for the determination of prolactin in serum at Baseline (pre-dose) and at Weeks 2, 5, 13 and 25 (or EW). Summary data for serum concentration of prolactin were calculated and the mean change from Baseline at each time point is presented. The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment. Only subjects with data available for analysis are presented.
|
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End point type |
Secondary
|
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End point timeframe |
From Baseline (pre-dose) up to Week 25.
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Notes [19] - Week 13 (n=7) [20] - Week 25 (n=8) [21] - Week 2&5 (n=9) |
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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 assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration.
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Adverse event reporting additional description |
TEAES were monitored for the safety population which was defined as all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
|
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Reporting groups
|
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Reporting group title |
180 mg Lanreotide PRF
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Reporting group description |
On Day 1, 3 initial subjects in Cohort 1 received 180 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. The dose escalation proceeded with a 3+3+3 scheme. If 0 or 1 out of the 3 dosed subjects had experienced a DLT, 3 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed the dose to be escalated to 270 mg (Cohort 2). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
270 mg Lanreotide PRF
|
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Reporting group description |
On Day 1, 1 initial subject in Cohort 2 received 270 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 2 subjects were treated and reviewed on a 1+2+2+2+2 scheme. If no DLT was experienced, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have stopped, and the dose was declared the maximum administered dose. If ≤3 DLTs had been observed in the 9 treated subjects and the overall safety was in line with the known lanreotide safety profile, the DRC would have allowed dose to be escalated to 360 mg (Cohort 3). At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
360 mg Lanreotide PRF
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Reporting group description |
On Day 1, 2 initial subjects in Cohort 3 received 360 mg lanreotide PRF by a single deep subcutaneous injection in the superior, external quadrant of the buttock and a 12-week treatment period then commenced. Cohort 3 subjects were treated and reviewed on a 2+2+2+3 scheme. An additional subject was also dosed in this cohort as it was considered unethical to exclude an eligible subject. If 0 or 1 subject had experienced a DLT, 2 more subjects would have been dosed with the same dose. If more than 3 out of 9 subjects had experienced a DLT, dose escalation would have been stopped and the dose was declared the maximum administered dose. At the end of the treatment period subjects continued to be assessed over a 12-week follow up period until EOS at Week 25 or EW. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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19 Nov 2014 |
To provide clarification on questions received from the authorities associated with safety monitoring, the PK of lanreotide PRF, the dose escalation criteria and the dose selection rationale. |
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12 Jun 2015 |
To extend the planned study period to January 2017.
To include the option for home visits on Weeks 4, 7, 11, 15, 19 and 23.
To increase the IGF-1 limit from within the normal range to <1.3 x upper limit of normal (ULN) and clarify that the assessment during the Screening period must be analysed by the central laboratory.
To reduce the period in which the subject had had radiotherapy from 3 years to 2 years prior to study entry.
To clarify that any significant renal abnormalities and/or creatinine values ≥1.5 x ULN should be measured during the Screening period and must be analysed
by the central laboratory.
To include an opportunity to re-test the screening IGF-1 value once if it was just above the 1.3 x ULN limit.
To include an option for the Sponsor to conduct an interim analysis in relation to the clinical development of lanreotide PRF. |
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27 Jul 2015 |
To allow up to 3 subjects previously controlled on lanreotide Autogel to be enrolled per cohort of 9.
To amend the title of the protocol to reflect this change to the subjects enrolled from just octreotide LAR to either octreotide LAR or lanreotide Autogel.
To allow the screening for subject enrolment regarding IGF-1 levels to be assessed on an IGF-1 level analysed at a local laboratory instead of only at the central laboratory.
To update the number of IGF-1 samples and total blood volumes to account for the additional sample collected during screening for assessment by local laboratory.
To add an additional subgroup analysis due to the change in subjects eligible for the study - from only octreotide LAR to either octreotide LAR or lanreotide Autogel.
To add the possibility not to perform Day 5, according to PK excipient data further to DRC review. If the t1/2 of the excipient was short there was no need to follow it any longer. Also, the excipient PK may have also been removed on Day 3.
To add a ±2 day window for Day 1 and 2. |
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22 Mar 2016 |
To allow the addition of safety information gathered from the phase I study D-FR-52030-345 conducted with lanreotide PRF for transparency reasons.
To increase the frequency of DRC meetings to ensure closer subject safety monitoring.
To extend the study timelines and increase the number of participating sites.
To allow more flexibility for the run-in period by extending the run-in period up to 6 weeks under specified circumstances. |
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16 Dec 2016 |
To allow inclusion of subjects with asymptomatic gallstones or sludge, and the re-screening of subjects who previously failed this exclusion criteria.
To change the DRC frequency for Cohort 3 from 2+2+2+2+1 to 2+2+2+3.
To better clarify the follow-up and reporting of AEs.
To include details of withdrawal of consent for biobanking in the protocol for clarity and amend the procedure for the shipment of biobanking samples. |
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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. | |||
No glycofurol excipient PK results are available for 360mg Lanreotide PRF at this time. A total of 28 subjects were allowed to enrol rather than the 27 subjects planned as it was considered unethical not to enrol a consented eligible subject. |