Trial Outcomes & Findings for Study to Determine the Maximum Tolerated Dose, Safety and Tolerability of a Single Dose of Lanreotide Prolonged Release Formulation (PRF) in Subjects With Acromegaly (NCT NCT02396953)

Last Updated: 2019-04-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

28 participants

Primary outcome timeframe

From Day 1 up to Week 25.

Results posted on

2019-04-25

Participant Flow

This was an open-label, dose-ascending study to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of a single dose of lanreotide prolonged release formulation (PRF). 17 centres recruited adult subjects with acromegaly into 3 lanreotide PRF treatment cohorts (180 milligrams \[mg\], 270 mg and 360 mg).

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.

Participant milestones

Participant milestones
Measure	180 mg Lanreotide PRF 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 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).	270 mg Lanreotide PRF 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.	360 mg Lanreotide PRF 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.
Overall Study STARTED	9	9	10
Overall Study COMPLETED	5	6	7
Overall Study NOT COMPLETED	4	3	3

Reasons for withdrawal

Reasons for withdrawal
Measure	180 mg Lanreotide PRF 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 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).	270 mg Lanreotide PRF 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.	360 mg Lanreotide PRF 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.
Overall Study Withdrawal by Subject	0	0	1
Overall Study Insulin like Growth Factor-1 increased	3	2	2
Overall Study Personal Reasons	1	1	0

Baseline Characteristics

Study to Determine the Maximum Tolerated Dose, Safety and Tolerability of a Single Dose of Lanreotide Prolonged Release Formulation (PRF) in Subjects With Acromegaly

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.	Total n=28 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants	9 Participants n=7 Participants	7 Participants n=5 Participants	24 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
Age, Continuous	57.4 years STANDARD_DEVIATION 7.2 • n=5 Participants	52.1 years STANDARD_DEVIATION 8.7 • n=7 Participants	56.2 years STANDARD_DEVIATION 11.6 • n=5 Participants	55.3 years STANDARD_DEVIATION 9.4 • n=4 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	15 Participants n=4 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	13 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants	9 Participants n=7 Participants	10 Participants n=5 Participants	28 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Prior Acromegaly Medication Octreotide Long Acting Release (LAR)	9 Participants n=5 Participants	7 Participants n=7 Participants	7 Participants n=5 Participants	23 Participants n=4 Participants
Prior Acromegaly Medication Lanreotide Autogel	0 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants

PRIMARY outcome

Timeframe: From Day 1 up to Week 25.

Population: The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs.	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

Population: 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. Only subjects with data available for analysis and who were not pre-treated with lanreotide are presented.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=7 Participants 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.	360 mg Lanreotide PRF n=6 Participants 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.
PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax).	19.0 nanograms/millilitre (ng/mL) Standard Deviation 15.7	14.0 nanograms/millilitre (ng/mL) Standard Deviation 10.3	20.5 nanograms/millilitre (ng/mL) Standard Deviation 5.86

PRIMARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=7 Participants 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.	360 mg Lanreotide PRF n=6 Participants 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.
PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax).	0.250 days Interval 0.167 to 1.0	0.253 days Interval 0.167 to 1.0	0.250 days Interval 0.167 to 0.333

PRIMARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=7 Participants 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.	270 mg Lanreotide PRF n=5 Participants 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.	360 mg Lanreotide PRF n=4 Participants 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.
PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2).	54.2 days Standard Deviation 17.0	61.7 days Standard Deviation 13.9	63.1 days Standard Deviation 13.3

PRIMARY outcome

Timeframe: From Baseline (pre-dose) up to Day 85

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. Sample 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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=7 Participants 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.	360 mg Lanreotide PRF n=6 Participants 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.
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85).	161 ng*day/mL Standard Deviation 97.6	179 ng*day/mL Standard Deviation 54.2	265 ng*day/mL Standard Deviation 87.1

PRIMARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=3 Participants 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.	270 mg Lanreotide PRF n=2 Participants 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.	360 mg Lanreotide PRF n=3 Participants 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.
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞).	NA ng*day/mL Standard Deviation NA When more than 1/3 of the values did not fulfil accuracy determination rules, the descriptive statistics were not calculated.	NA ng*day/mL Standard Deviation NA When more than 1/3 of the values did not fulfil accuracy determination rules, the descriptive statistics were not calculated.	NA ng*day/mL Standard Deviation NA When more than 1/3 of the values did not fulfil accuracy determination rules, the descriptive statistics were not calculated.

SECONDARY outcome

Timeframe: From Day -42 up to Week 25.

Population: The safety population was all subjects who received the single dose of lanreotide PRF and had at least one post baseline safety assessment.

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. 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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
Overall Summary of Number of Subjects With AEs. TEAEs	6 participants	7 participants	7 participants
Overall Summary of Number of Subjects With AEs. Related TEAEs	2 participants	3 participants	4 participants
Overall Summary of Number of Subjects With AEs. TEAEs leading to study drug withdrawal	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. Serious TEAEs	1 participants	0 participants	1 participants
Overall Summary of Number of Subjects With AEs. Serious related TEAEs	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. SAEs	1 participants	0 participants	1 participants
Overall Summary of Number of Subjects With AEs. AEs leading to death	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. Worst TEAE: Grade 1	1 participants	3 participants	5 participants
Overall Summary of Number of Subjects With AEs. Worst TEAE: Grade 2	3 participants	4 participants	1 participants
Overall Summary of Number of Subjects With AEs. Worst TEAE: Grade 3	2 participants	0 participants	1 participants
Overall Summary of Number of Subjects With AEs. Worst TEAE: Grade 4	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. Worst TEAE: Grade 5	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. Worst related TEAE: Grade 1	0 participants	1 participants	3 participants
Overall Summary of Number of Subjects With AEs. Worst related TEAE: Grade 2	2 participants	2 participants	1 participants
Overall Summary of Number of Subjects With AEs. Worst related TEAE: Grade 3	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. Worst related TEAE: Grade 4	0 participants	0 participants	0 participants
Overall Summary of Number of Subjects With AEs. Worst related TEAE: Grade 5	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Day 5.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF 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.
PK Analysis of Glycofurol Excipients: Cmax. N1-glycofurol	75.4 ng/mL Standard Deviation 65.6	61.7 ng/mL Standard Deviation 17.2	—
PK Analysis of Glycofurol Excipients: Cmax. N2-glycofurol	79.7 ng/mL Standard Deviation 72.1	62.1 ng/mL Standard Deviation 18.4	—

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Day 5.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF 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.
PK Analysis of Glycofurol Excipients: Tmax. N2-glycofurol	2.00 hours Interval 1.0 to 3.92	2.00 hours Interval 1.0 to 4.0	—
PK Analysis of Glycofurol Excipients: Tmax. N1-glycofurol	2.00 hours Interval 1.0 to 3.92	2.00 hours Interval 1.0 to 4.0	—

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Day 5.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF 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.
PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). AUC0-∞: N1-glycofurol	779 ng*h/mL Standard Deviation 205	1049 ng*h/mL Standard Deviation 195	—
PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). AUC0-∞: N2-glycofurol	1008 ng*h/mL Standard Deviation 268	1359 ng*h/mL Standard Deviation 282	—
PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). AUC0-t: N1-glycofurol	783 ng*h/mL Standard Deviation 193	1082 ng*h/mL Standard Deviation 238	—
PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). AUC0-t: N2-glycofurol	1007 ng*h/mL Standard Deviation 257	1360 ng*h/mL Standard Deviation 285	—

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

Population: 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.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: 6 hours post-dose	-1.8 ng/mL Standard Deviation 18.9	-7.1 ng/mL Standard Deviation 17.2	-46.5 ng/mL Standard Deviation 46.7
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: Week 5	2.4 ng/mL Standard Deviation 41.3	27.9 ng/mL Standard Deviation 32.8	-32.0 ng/mL Standard Deviation 49.5
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: Week 9	72.3 ng/mL Standard Deviation 61.3	71.4 ng/mL Standard Deviation 72.7	—
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: Week 13	53.4 ng/mL Standard Deviation 67.9	111.1 ng/mL Standard Deviation 129.3	—
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: Week 17	48.3 ng/mL Standard Deviation 62.7	96.2 ng/mL Standard Deviation 43.8	—
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: Week 21	72.4 ng/mL Standard Deviation 84.4	135.5 ng/mL Standard Deviation 80.5	—
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). Old Reagent: Week 25 (EOS/EW)	86.3 ng/mL Standard Deviation 81.4	136.4 ng/mL Standard Deviation 83.5	—
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: 6 hours post-dose	—	6.0 ng/mL Standard Deviation 5.7	-11.6 ng/mL Standard Deviation 15.9
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: Week 5	—	3.0 ng/mL Standard Deviation 8.5	1.3 ng/mL Standard Deviation 38.4
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: Week 9	—	13.0 ng/mL Standard Deviation 9.9	25.2 ng/mL Standard Deviation 33.6
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: Week 13	—	30.0 ng/mL Standard Deviation 43.8	47.1 ng/mL Standard Deviation 43.9
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: Week 17	—	20.5 ng/mL Standard Deviation 17.7	40.9 ng/mL Standard Deviation 46.8
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: Week 21	—	65.0 ng/mL Standard Deviation 58.0	56.9 ng/mL Standard Deviation 35.6
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). New Reagent: Week 25 (EOS/EW)	—	45.5 ng/mL Standard Deviation 17.7	64.1 ng/mL Standard Deviation 68.0

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Week 13.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
PD Analysis: Mean Change From Baseline in Growth Hormone (GH). Week 5	0.268 ng/mL Standard Deviation 0.344	0.367 ng/mL Standard Deviation 0.926	-0.228 ng/mL Standard Deviation 0.777
PD Analysis: Mean Change From Baseline in Growth Hormone (GH). Week 13	0.667 ng/mL Standard Deviation 0.473	0.684 ng/mL Standard Deviation 0.863	0.003 ng/mL Standard Deviation 1.761

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT3: Week 2	-0.278 picomole/litre (L) Standard Deviation 0.518	-0.164 picomole/litre (L) Standard Deviation 0.517	-0.374 picomole/litre (L) Standard Deviation 0.479
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT3: Week 5	-0.132 picomole/litre (L) Standard Deviation 0.429	-0.170 picomole/litre (L) Standard Deviation 0.705	0.170 picomole/litre (L) Standard Deviation 0.452
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT3: Week 13	0.100 picomole/litre (L) Standard Deviation 0.590	0.191 picomole/litre (L) Standard Deviation 0.912	0.438 picomole/litre (L) Standard Deviation 0.481
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT3: Week 25 (EOS/EW)	0.268 picomole/litre (L) Standard Deviation 0.388	0.295 picomole/litre (L) Standard Deviation 0.626	0.396 picomole/litre (L) Standard Deviation 0.684
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT4: Week 2	0.50 picomole/litre (L) Standard Deviation 1.58	-0.02 picomole/litre (L) Standard Deviation 1.43	-0.68 picomole/litre (L) Standard Deviation 1.07
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT4: Week 5	1.18 picomole/litre (L) Standard Deviation 2.31	0.33 picomole/litre (L) Standard Deviation 2.52	-0.67 picomole/litre (L) Standard Deviation 2.19
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT4: Week 13	1.69 picomole/litre (L) Standard Deviation 2.16	1.80 picomole/litre (L) Standard Deviation 3.59	-0.46 picomole/litre (L) Standard Deviation 1.39
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). FT4: Week 25 (EOS/EW)	0.81 picomole/litre (L) Standard Deviation 2.55	1.06 picomole/litre (L) Standard Deviation 2.39	0.38 picomole/litre (L) Standard Deviation 2.03

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). Week 2	-0.222 mIU/L Standard Deviation 0.562	0.119 mIU/L Standard Deviation 0.315	0.047 mIU/L Standard Deviation 0.844
PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). Week 5	-0.156 mIU/L Standard Deviation 0.577	0.062 mIU/L Standard Deviation 0.670	0.051 mIU/L Standard Deviation 0.534
PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). Week 13	-0.404 mIU/L Standard Deviation 0.710	-0.060 mIU/L Standard Deviation 0.897	0.601 mIU/L Standard Deviation 1.080
PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). Week 25 (EOS/EW)	-0.480 mIU/L Standard Deviation 0.593	0.073 mIU/L Standard Deviation 0.450	0.235 mIU/L Standard Deviation 0.671

SECONDARY outcome

Timeframe: From Baseline (pre-dose) up to Week 25.

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.

Outcome measures

Outcome measures
Measure	180 mg Lanreotide PRF n=9 Participants 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.	270 mg Lanreotide PRF n=9 Participants 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.	360 mg Lanreotide PRF n=10 Participants 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.
PD Analysis: Mean Change From Baseline in Prolactin. Week 2	-33.2 mU/L Standard Deviation 54.9	37.6 mU/L Standard Deviation 36.1	1.0 mU/L Standard Deviation 49.3
PD Analysis: Mean Change From Baseline in Prolactin. Week 5	-10.4 mU/L Standard Deviation 53.2	16.3 mU/L Standard Deviation 81.2	0.3 mU/L Standard Deviation 50.7
PD Analysis: Mean Change From Baseline in Prolactin. Week 13	-1.9 mU/L Standard Deviation 66.5	33.9 mU/L Standard Deviation 78.5	-6.4 mU/L Standard Deviation 47.1
PD Analysis: Mean Change From Baseline in Prolactin. Week 25 (EOS/EW)	19.3 mU/L Standard Deviation 53.5	58.3 mU/L Standard Deviation 86.6	-3.1 mU/L Standard Deviation 55.9

Adverse Events

180 mg Lanreotide PRF

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

270 mg Lanreotide PRF

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

360 mg Lanreotide PRF

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	180 mg Lanreotide PRF n=9 participants at risk 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.	270 mg Lanreotide PRF n=9 participants at risk 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.	360 mg Lanreotide PRF n=10 participants at risk 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.
Musculoskeletal and connective tissue disorders Arthralgia	11.1% 1/9 • Number of events 1 • Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration. 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.	0.00% 0/9 • Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration. 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.	10.0% 1/10 • Number of events 1 • Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration. 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.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/9 • Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration. 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.	0.00% 0/9 • Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration. 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.	10.0% 1/10 • Number of events 1 • Each subject was assessed for TEAEs over an approximate 6 month period. TEAEs were collected over the 32 month study duration. 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.

Other adverse events

Additional Information

Medical Director

Ipsen

Phone: Use email address below

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place