Acromegaly
Conditions
Brief summary
The objectives of the protocol is to determine the maximum tolerated dose and to investigate the pharmacokinetics of a single dose of lanreotide PRF in subjects with acromegaly.
Interventions
DRUGLanreotide PRF
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of acromegaly. * Provided written informed consent prior to any study related procedures. * Between 18 and 75 years of age inclusive. * Female of non-childbearing potential or male. Non-childbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired). * Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use a medically accepted, effective method of contraception (i.e. condom) for the duration of the study (maximum of 7.5 months). * Treatment with a stable dose of either octreotide LAR or lanreotide Autogel for at least 3 months immediately prior to study entry, with confirmation of disease control during this treatment period (documentation of age adjusted IGF 1 \<1.3 x upper limit of normal (ULN), based on local laboratory results, during screening period). * If the subject is receiving treatment for hypertension, the dose has been stable for at least 1 month prior to study entry. * Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.
Exclusion criteria
* Has undergone radiotherapy within 2 years prior to study entry. * Has been treated with a dopamine agonist and/or GH receptor antagonist or has undergone pituitary surgery within 3 months prior to study entry. * Is anticipated to require pituitary surgery or radiotherapy during the study. * Has clinically significant hepatic abnormalities and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3 x ULN and/or alkaline phosphatase (AP) ≥2.5 x ULN and/or total bilirubin ≥1.5 x ULN and/or gamma-glutamyl transpeptidase (GGT) ≥2.5 x ULN during the Screening period (central laboratory results) or a history of these findings when on somatostatin analogue (SSTa) treatment. * Has clinically significant pancreatic abnormalities and/or amylase and/or lipase ≥1.5 x ULN during the Screening period (central laboratory results). * Has any significant renal abnormalities and/or creatinine ≥1.5 x ULN during the screening period (central laboratory results). * Has uncontrolled diabetes (glycosylated haemoglobin (HbA1c) ≥9%, centrally assessed during the Screening period), or has diabetes treated with insulin for less than 6 months prior to study entry. * Has any known uncontrolled cardiovascular disease or had any of the following within 6 months of Screening: ventricular or atrial dysrhythmia ≥grade 2, bradycardia ≥grade 2, electrocardiogram (ECG) QT interval corrected (QTc) prolonged ≥grade 2, myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications. * Use of any hormone replacement therapy (HRT) with oestrogens. * Has symptomatic gallstones/ sludge at the Screening Visit echography (local assessment) OR is asymptomatic but has echography showing clear evidence of impending inflammation such as localised mucosal thickening suggesting the subject is at high risk of developing acute disease. Subjects with asymptomatic gallstones/ sludge and otherwise normal echography may be entered at the discretion of the investigator. * Has abnormal findings during the Screening period, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject's safety. * Has been treated with any other investigational medicinal product (IMP) prior to the first study visit without undergoing a washout period of seven times the elimination half-life of the investigational compound. * Has a known hypersensitivity to any of the test materials or related compounds. * Is likely to require treatment during the study with drugs that are not permitted by the study protocol. * Has a history of, or known current, problems with alcohol or drug abuse. * Has any mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs. | From Day 1 up to Week 25. | 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. |
| PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). | 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 Cmax values were determined using non-compartmental analysis. |
| PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). | 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. |
| PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). | 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. |
| PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85). | 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. |
| PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Summary of Number of Subjects With AEs. | From Day -42 up to Week 25. | 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. |
| PK Analysis of Glycofurol Excipients: Cmax. | 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. |
| PK Analysis of Glycofurol Excipients: Tmax. | 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. |
| PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t). | 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. |
| PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | From Baseline (pre-dose) up to Week 25. | 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. |
| PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | 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. |
| PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | 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. |
| PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | 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. |
| PD Analysis: Mean Change From Baseline in Prolactin. | 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. |
Countries
Belgium, Czechia, France, Germany, Italy, Lithuania, Netherlands, Poland, Romania, Russia, Spain, United Kingdom
Participant flow
Recruitment details
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).
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| 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 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. | 9 |
| 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. | 9 |
| 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. | 10 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Insulin like Growth Factor-1 increased | 3 | 2 | 2 |
| Overall Study | Personal Reasons | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 180 mg Lanreotide PRF | 270 mg Lanreotide PRF | 360 mg Lanreotide PRF | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 9 Participants | 7 Participants | 24 Participants |
| Age, Continuous | 57.4 years STANDARD_DEVIATION 7.2 | 52.1 years STANDARD_DEVIATION 8.7 | 56.2 years STANDARD_DEVIATION 11.6 | 55.3 years STANDARD_DEVIATION 9.4 |
| Prior Acromegaly Medication Lanreotide Autogel | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Prior Acromegaly Medication Octreotide Long Acting Release (LAR) | 9 Participants | 7 Participants | 7 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 9 Participants | 10 Participants | 28 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 6 / 9 | 7 / 9 | 7 / 10 |
| serious Total, serious adverse events | 1 / 9 | 0 / 9 | 1 / 10 |
Outcome results
Primary
Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs.
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 180 mg Lanreotide PRF | Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs. | 0 participants |
| 270 mg Lanreotide PRF | Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs. | 0 participants |
| 360 mg Lanreotide PRF | Determination of the Maximum Tolerated Dose (MTD) by Number of Subjects With DLTs. | 0 participants |
Primary
PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2).
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 180 mg Lanreotide PRF | PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). | 54.2 days | Standard Deviation 17 |
| 270 mg Lanreotide PRF | PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). | 61.7 days | Standard Deviation 13.9 |
| 360 mg Lanreotide PRF | PK Analysis of Lanreotide: Apparent Terminal Elimination Half-life (t1/2). | 63.1 days | Standard Deviation 13.3 |
Primary
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞).
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 180 mg Lanreotide PRF | PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). | NA ng*day/mL |
| 270 mg Lanreotide PRF | PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). | NA ng*day/mL |
| 360 mg Lanreotide PRF | PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUC0-∞). | NA ng*day/mL |
Primary
PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85).
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.
Time frame: From Baseline (pre-dose) up to Day 85
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 180 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85). | 179 ng*day/mL | Standard Deviation 54.2 |
| 360 mg Lanreotide PRF | PK Analysis of Lanreotide: Area Under the Serum Concentration-time Curve From Time 0 to 85 Days (AUC0-85). | 265 ng*day/mL | Standard Deviation 87.1 |
Primary
PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax).
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 180 mg Lanreotide PRF | PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). | 19.0 nanograms/millilitre (ng/mL) | Standard Deviation 15.7 |
| 270 mg Lanreotide PRF | PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). | 14.0 nanograms/millilitre (ng/mL) | Standard Deviation 10.3 |
| 360 mg Lanreotide PRF | PK Analysis of Lanreotide: Maximum Observed Serum Concentration (Cmax). | 20.5 nanograms/millilitre (ng/mL) | Standard Deviation 5.86 |
Primary
PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax).
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 180 mg Lanreotide PRF | PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). | 0.250 days |
| 270 mg Lanreotide PRF | PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). | 0.253 days |
| 360 mg Lanreotide PRF | PK Analysis of Lanreotide: Time to Reach Maximum Serum Concentration (Tmax). | 0.250 days |
Secondary
Overall Summary of Number of Subjects With AEs.
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 5 | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | AEs leading to death | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Related TEAEs | 2 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | TEAEs | 6 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 1 | 1 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 3 | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 4 | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 2 | 3 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | SAEs | 1 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 3 | 2 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 5 | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 2 | 2 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Serious TEAEs | 1 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 4 | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 1 | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Serious related TEAEs | 0 participants |
| 180 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | TEAEs leading to study drug withdrawal | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 4 | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | TEAEs | 7 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Related TEAEs | 3 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | TEAEs leading to study drug withdrawal | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | SAEs | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Serious TEAEs | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Serious related TEAEs | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | AEs leading to death | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 1 | 3 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 2 | 4 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 3 | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 5 | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 1 | 1 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 2 | 2 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 3 | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 4 | 0 participants |
| 270 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 5 | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Related TEAEs | 4 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 5 | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Serious TEAEs | 1 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 5 | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 1 | 3 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | SAEs | 1 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 4 | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 2 | 1 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | TEAEs leading to study drug withdrawal | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | TEAEs | 7 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 2 | 1 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst related TEAE: Grade 3 | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 3 | 1 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 1 | 5 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | AEs leading to death | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Worst TEAE: Grade 4 | 0 participants |
| 360 mg Lanreotide PRF | Overall Summary of Number of Subjects With AEs. | Serious related TEAEs | 0 participants |
Secondary
PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4).
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 13 | 0.100 picomole/litre (L) | Standard Deviation 0.59 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 13 | 0.191 picomole/litre (L) | Standard Deviation 0.912 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 13 | 1.80 picomole/litre (L) | Standard Deviation 3.59 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 25 (EOS/EW) | 0.295 picomole/litre (L) | Standard Deviation 0.626 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 2 | -0.02 picomole/litre (L) | Standard Deviation 1.43 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 5 | 0.33 picomole/litre (L) | Standard Deviation 2.52 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 2 | -0.164 picomole/litre (L) | Standard Deviation 0.517 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 5 | -0.170 picomole/litre (L) | Standard Deviation 0.705 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 25 (EOS/EW) | 1.06 picomole/litre (L) | Standard Deviation 2.39 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 13 | 0.438 picomole/litre (L) | Standard Deviation 0.481 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 5 | 0.170 picomole/litre (L) | Standard Deviation 0.452 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 2 | -0.374 picomole/litre (L) | Standard Deviation 0.479 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT3: Week 25 (EOS/EW) | 0.396 picomole/litre (L) | Standard Deviation 0.684 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 13 | -0.46 picomole/litre (L) | Standard Deviation 1.39 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 5 | -0.67 picomole/litre (L) | Standard Deviation 2.19 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 2 | -0.68 picomole/litre (L) | Standard Deviation 1.07 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Free Triiodothyroxine (FT3) and Free Thyroxine (FT4). | FT4: Week 25 (EOS/EW) | 0.38 picomole/litre (L) | Standard Deviation 2.03 |
Secondary
PD Analysis: Mean Change From Baseline in Growth Hormone (GH).
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.
Time frame: From Baseline (pre-dose) up to Week 13.
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | Week 5 | 0.268 ng/mL | Standard Deviation 0.344 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | Week 13 | 0.667 ng/mL | Standard Deviation 0.473 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | Week 5 | 0.367 ng/mL | Standard Deviation 0.926 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | Week 13 | 0.684 ng/mL | Standard Deviation 0.863 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | Week 5 | -0.228 ng/mL | Standard Deviation 0.777 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Growth Hormone (GH). | Week 13 | 0.003 ng/mL | Standard Deviation 1.761 |
Secondary
PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1).
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 13 | 111.1 ng/mL | Standard Deviation 129.3 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: 6 hours post-dose | -7.1 ng/mL | Standard Deviation 17.2 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 5 | 27.9 ng/mL | Standard Deviation 32.8 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 9 | 71.4 ng/mL | Standard Deviation 72.7 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 17 | 96.2 ng/mL | Standard Deviation 43.8 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 21 | 135.5 ng/mL | Standard Deviation 80.5 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 25 (EOS/EW) | 136.4 ng/mL | Standard Deviation 83.5 |
| 270 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: Week 5 | -32.0 ng/mL | Standard Deviation 49.5 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: Week 9 | 25.2 ng/mL | Standard Deviation 33.6 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | Old Reagent: 6 hours post-dose | -46.5 ng/mL | Standard Deviation 46.7 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: Week 25 (EOS/EW) | 64.1 ng/mL | Standard Deviation 68 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: Week 13 | 47.1 ng/mL | Standard Deviation 43.9 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: 6 hours post-dose | -11.6 ng/mL | Standard Deviation 15.9 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: Week 21 | 56.9 ng/mL | Standard Deviation 35.6 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: Week 5 | 1.3 ng/mL | Standard Deviation 38.4 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Insulin-like Growth Factor 1 (IGF-1). | New Reagent: Week 17 | 40.9 ng/mL | Standard Deviation 46.8 |
Secondary
PD Analysis: Mean Change From Baseline in Prolactin.
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 13 | -1.9 mU/L | Standard Deviation 66.5 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 2 | -33.2 mU/L | Standard Deviation 54.9 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 25 (EOS/EW) | 19.3 mU/L | Standard Deviation 53.5 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 5 | -10.4 mU/L | Standard Deviation 53.2 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 13 | 33.9 mU/L | Standard Deviation 78.5 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 5 | 16.3 mU/L | Standard Deviation 81.2 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 2 | 37.6 mU/L | Standard Deviation 36.1 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 25 (EOS/EW) | 58.3 mU/L | Standard Deviation 86.6 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 5 | 0.3 mU/L | Standard Deviation 50.7 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 2 | 1.0 mU/L | Standard Deviation 49.3 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 25 (EOS/EW) | -3.1 mU/L | Standard Deviation 55.9 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Prolactin. | Week 13 | -6.4 mU/L | Standard Deviation 47.1 |
Secondary
PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH).
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 2 | -0.222 mIU/L | Standard Deviation 0.562 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 5 | -0.156 mIU/L | Standard Deviation 0.577 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 13 | -0.404 mIU/L | Standard Deviation 0.71 |
| 180 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 25 (EOS/EW) | -0.480 mIU/L | Standard Deviation 0.593 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 25 (EOS/EW) | 0.073 mIU/L | Standard Deviation 0.45 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 2 | 0.119 mIU/L | Standard Deviation 0.315 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 13 | -0.060 mIU/L | Standard Deviation 0.897 |
| 270 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 5 | 0.062 mIU/L | Standard Deviation 0.67 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 25 (EOS/EW) | 0.235 mIU/L | Standard Deviation 0.671 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 5 | 0.051 mIU/L | Standard Deviation 0.534 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 13 | 0.601 mIU/L | Standard Deviation 1.08 |
| 360 mg Lanreotide PRF | PD Analysis: Mean Change From Baseline in Thyroid Stimulating Hormone (TSH). | Week 2 | 0.047 mIU/L | Standard Deviation 0.844 |
Secondary
PK Analysis of Glycofurol Excipients: AUC0-∞ and Area Under the Serum Concentration Time Curve From Time 0 to Last Quantifiable Timepoint (AUC0-t).
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.
Time frame: From Baseline (pre-dose) up to Day 5.
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 180 mg Lanreotide PRF | 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 |
| 270 mg Lanreotide PRF | 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 | 1360 ng*h/mL | Standard Deviation 285 |
| 270 mg Lanreotide PRF | 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 | 1049 ng*h/mL | Standard Deviation 195 |
| 270 mg Lanreotide PRF | 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 | 1082 ng*h/mL | Standard Deviation 238 |
| 270 mg Lanreotide PRF | 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 | 1359 ng*h/mL | Standard Deviation 282 |
Secondary
PK Analysis of Glycofurol Excipients: Cmax.
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.
Time frame: From Baseline (pre-dose) up to Day 5.
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 are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 180 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Cmax. | N1-glycofurol | 75.4 ng/mL | Standard Deviation 65.6 |
| 180 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Cmax. | N2-glycofurol | 79.7 ng/mL | Standard Deviation 72.1 |
| 270 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Cmax. | N1-glycofurol | 61.7 ng/mL | Standard Deviation 17.2 |
| 270 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Cmax. | N2-glycofurol | 62.1 ng/mL | Standard Deviation 18.4 |
Secondary
PK Analysis of Glycofurol Excipients: Tmax.
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.
Time frame: From Baseline (pre-dose) up to Day 5.
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 are presented.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 180 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Tmax. | N2-glycofurol | 2.00 hours |
| 180 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Tmax. | N1-glycofurol | 2.00 hours |
| 270 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Tmax. | N1-glycofurol | 2.00 hours |
| 270 mg Lanreotide PRF | PK Analysis of Glycofurol Excipients: Tmax. | N2-glycofurol | 2.00 hours |