Acromegaly
Conditions
Brief summary
The main aim of this study is to assess the efficacy of the co-administration of lanreotide Autogel 120 mg (administered via deep sub-cutaneous injections every 28 days) and pegvisomant (administered at 40 to 120 mg per week via sub-cutaneous injection given once or twice a week) on IGF-1 levels over 28 weeks in acromegalic patients. The primary endpoint will be the percentage of acromegalic patients with normalised (age and sex adjusted) IGF-1 level at the end of the co-treatment period.
Interventions
120 mg administered via deep subcutaneous injection every 28 days over 28 weeks.
DRUGPegvisomant
Administered at 40 to 120 mg per week via subcutaneous injection once or twice a week over 28 weeks.
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
* The patient must have had documentation supporting the diagnosis of acromegaly, including elevated GH and/or IGF-1 levels * The patient is treated with pegvisomant, because of IGF-1 level remaining above ULN when treated with somatostatin analogue, on a daily basis for at least 3 months and has normal (age and sex adjusted) IGF-1 level, or IGF-1 level above the upper limit of normal (ULN) after treatment with pegvisomant 30 mg per day, OR the patient is treated with lanreotide Autogel or octreotide LAR for at least 6 months including 3 months at the highest marketed dose and has a serum IGF-1 level above ULN, 28 days after the last injection * At the end of the run-in period, The patient has a serum IGF-1 level above 1.2 x ULN, or a serum IGF-1 level between ULN and 1.2 x ULN and a serum GH nadir \> 1 µg/L (assessed by an OGTT), 28 days after the 3rd injection of lanreotide Autogel 120 mg OR the patient is diabetic and has a serum IGF-1 level above 1.2 ULN, 28 days after the 3rd injection of lanreotide Autogel 120 mg
Exclusion criteria
* The patient has undergone pituitary surgery or radiotherapy within 6 months prior to study entry, or it is anticipated that it will be done during the study * The patient has already been treated with a somatostatin analogue associated with a GH antagonist * The patient has received dopamine agonist within 6 weeks prior to the study entry * The patient has abnormal hepatic function at study entry (defined as AST, ALT, GGT, alkaline phosphatase, prothrombin time or total bilirubin above 2 ULN) * The patient is at risk of pregnancy or is lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at Visit (V) 1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to investigational medicinal product (IMP) administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at the end of the co-administration period are presented. The last observation carried forward (LOCF) was used to replace missing IGF-1 values. |
| Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Diabetic Status at Baseline | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at the end of the co-administration period, summarised by diabetic status are presented. The denominator used to calculate percentages was the number of subjects in each subgroup (diabetic and non diabetic). The LOCF approach was used to replace missing IGF-1 values. |
| Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at the end of the co-administration period, summarised by previous treatment and by final pegvisomant dose are presented. The denominator used to calculate percentages was the number of subjects in each subgroup, comprising previous treatment with pegvisomant, lanreotide Autogel and octreotide long acting repeatable (LAR) and final pegvisomant dose as either 40 mg, 60 mg or 80 mg once a week or 40 mg or 60 mg twice per week. The LOCF approach was used to replace missing IGF-1 values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Twelve-lead ECG recordings were performed at V2, V3 and V11. Sinus rhythm, heart rate, PR interval, RR interval, QRS interval and QT interval were measured and QTcF was calculated. The change in mean ECG parameter for PR interval, QRS interval, QT interval, RR interval and QTcF from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Mean Glycosylated Haemoglobin (HbA1C) During the Co-administration Period; Assessed in Non Diabetic and Diabetic Subjects | V3 (Week 12; Baseline) up to V11 (Week 44) | Glycosylated haemoglobin (HbA1C) was measured at V2, V3 and V11 (or in case of premature discontinuation, at the early withdrawal visit). The change in mean HbA1C in diabetic and non diabetic subjects from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Liver Function Test Parameters During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Blood samples for clinical laboratory tests were taken at V1, V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). During the co-administration period, hepatic toxicity was assessed at each visit (V5 to V10) by measuring alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase, gamma glutamyl transferase (GGT), prothrombin time and total bilirubin. The change in mean ALT, AST, GGT and alkaline phosphatase from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Total Bilirubin During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Blood samples for clinical laboratory tests were taken at V1, V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). During the co-administration period, hepatic toxicity was assessed at each visit (V5 to V10) by measuring ALT, AST, alkaline phosphatase, GGT, prothrombin time and total bilirubin. The change in mean total bilirubin from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Prothrombin Time (Expressed as a Percentage of Normal) During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Blood samples for clinical laboratory tests were taken at V1, V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). During the co-administration period, hepatic toxicity was assessed at each visit (V5 to V10) by measuring ALT, AST, alkaline phosphatase, GGT, prothrombin time and total bilirubin. Prothrombin time was expressed as a percentage of the time taken for a control blood sample to clot (designated as 100%) and the mean change from Baseline to V11 and to LVA is presented. |
| Number of Subjects With Putative Antibodies to Lanreotide and to Pegvisomant During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Presence of putative antibodies to lanreotide and antibodies to pegvisomant were assessed prior to IMP administration at V2, V4 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The number of subjects with putative antibodies to lanreotide and to pegvisomant during the co-administration period (Baseline up to V11) is presented. |
| Percentage of Subjects With a Normalised (Age and Sex Adjusted) IGF-1 Level at Any Time During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at least once during the co-administration period, summarised by 'while taking the final dose during co-administration' and 'at any time during co-administration' are presented. |
| Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V1 (Screening) up to V11 (Week 44) | Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. The percentage of subjects with a normalised (age and sex adjusted) IGF-1 level is presented. The denominator used to calculate the percentages was the number of ITT population subjects with an assessment at the visit. In addition to the data for each individual visit, the last value available (LVA) data is also presented. None of the ITT population subjects had serum IGF-1 normalised at V3, consistent with the criterion to continue in the study and be treated in the co-administration period. |
| Change From Baseline in Serum IGF-1 Levels (Expressed as Z-scores) During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | The change in serum IGF-1 levels, expressed as z-scores calculated using the age and sex specific mean and standard deviation \[SD\] values from Baseline to V11 and to LVA are presented. A z-score between +/- 2 indicates a normal IGF-1 concentration. |
| Change From Baseline in Acromegaly Symptoms During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Acromegaly symptoms, including arthralgia, excessive perspiration, fatigue, headache and soft tissue swelling were assessed with scores ranging from 0 (no symptoms) to 8 (severe, incapacitating symptoms). Symptoms were assessed by the subject in paper format before any other procedure planned during the visit. The change in acromegaly symptoms from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | The ACROQoL is a health-related quality of life (QoL) questionnaire for patients with acromegaly consisting of 22 items measured on a 5-point Likert-type scale that assesses frequency of occurrence (always to never) or degree of agreement (completely agree to completely disagree) with the statements. The ACROQoL consists of questions that evaluate physical (8 items) and psychological aspects related to appearance and personal relations (7 items each). Answers are transformed to a percentage value, where 100 is the maximal (best) and 0 the minimum (worse) score depicting self-perceived quality QoL. An increase in ACROQoL score is associated with an improved QoL. The change in ACROQoL global score, physical and psychological dimension scores and appearance and personal relationships sub-dimension scores from Baseline to V11 and to LVA are presented. Relnship = Relationship; Dim = Dimension. |
| Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | At V2 (Day 1; Run-in), V3 (Week 12; Baseline) and V11 (Week 44) | The correlation between the changes in ACROQoL (expressed as standardised scores and undertaken for global score, physical and psychological dimension scores and appearance and personal relationships sub-dimension scores) over the run-in period (V3 minus V2) and co-administration period (V11 and LVA minus V3) with the corresponding changes in z-score for the IGF-1 level is presented. A decrease in IGF-1 z-score represents an improvement and an increase in ACROQoL score represents an improvement. Spearman's rank correlation (r) values are presented for change from V2 to V3 (Baseline) and from Baseline to V11/LVA for each of the specified ACROQoL categories. Corr = Correlation; Dim = Dimension; Relnship = Relationship. |
| Change From Baseline in Mean Weight From Baseline During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Weight was recorded at V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The change in mean weight from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Mean Supine Systolic and Diastolic Blood Pressure (BP) During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Blood pressure (supine after resting for 3 minutes) was recorded at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The change in mean BP (systolic and diastolic) from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Mean Supine Heart Rate During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Heart rate (supine after resting for 3 minutes) was recorded at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The change in mean heart rate from Baseline to V11 and to LVA are presented. |
| Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Twelve-lead ECG recordings were performed at V2, V3 and V11. Sinus rhythm, heart rate, PR interval, RR interval, QRS interval and QT interval were measured and heart rate corrected QT interval using the Fridericia method (QTcF) was calculated. The change in ECG mean heart rate from Baseline to V11 and to LVA is presented. |
| Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | A gallbladder ultrasound was performed at V2, V3, and V11 (or in case of premature study discontinuation, at the early withdrawal visit). Presence of lithiasis and sludge was recorded. Number of subjects who developed or resolved lithiasis and developed or resolved sludge, comparing Baseline to V11 and to LVA are presented. |
| Change From Baseline in Mean Pituitary Tumour Size During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Pituitary tumour size was assessed by Magnetic Resonance Imaging at V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The two longest diameters of the pituitary tumour were to be measured. The change in mean pituitary tumour size from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Mean Blood Glucose Maximum Concentration (Cmax) From Oral Glucose Tolerance Test (OGTT) During the Co-administration Period; Assessed in Non Diabetic Subjects | V3 (Week 12; Baseline) up to V11 (Week 44) | Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean blood glucose Cmax (as determined from OGTT) from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Mean Fasting Insulin Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects | V3 (Week 12; Baseline) up to V11 (Week 44) | Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean fasting insulin concentration from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Mean Fasting Glucose Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects | V3 (Week 12; Baseline) up to V11 (Week 44) | Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean fasting glucose concentration from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Mean Fasting Insulin / Glucose Ratio During the Co-administration Period; Assessed in Non Diabetic Subjects | V3 (Week 12; Baseline) up to V11 (Week 44) | Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean fasting insulin / glucose ratio from Baseline to V11 and to LVA is presented. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Prolactin Levels During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum samples were assessed for prolactin levels at V1, V2, V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). The change in mean prolactin levels from Baseline to V11 and to LVA is presented. |
| Percentage of Subjects With Serum GH Levels Lesser or Equal to 2.5 ng/mL During the Study | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum samples were assessed for GH levels at the same timepoints as the IGF-1 sample at V1 and V2 and during the OGTT (non diabetic subjects only) at V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). Five samples were taken over 2 hours in order to assess GH nadir and confirm the subject's eligibility before entering the co-administration period. For diabetic subjects, the OGTT was replaced by a measurement of GH level on a blood sample taken at the same time as IGF-1 at V3 and V11 (or at the early withdrawal visit). The percentage of subjects with serum GH levels ≤ 2.5 ng/mL at Baseline, V11 and LVA is presented. |
| Change From Baseline in Acid Labile Subunit Levels From Baseline During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum samples were assessed for acid labile subunit levels at V1, V2, V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). The change in mean acid labile subunit levels from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Serum GH Levels During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum samples were assessed for GH levels at the same timepoints as the IGF-1 sample at V1 and V2 and during the OGTT (non diabetic subjects only) at V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). Five samples were taken over 2 hours in order to assess GH nadir and confirm the subject's eligibility before entering the co-administration period. For diabetic subjects, the OGTT was replaced by a measurement of GH level on a blood sample taken at the same time as IGF-1 at V3 and V11 (or at the early withdrawal visit). The change in mean serum GH levels from Baseline to V11 and to LVA is presented. |
| Change From Baseline in Serum GH Binding Protein Levels During the Co-administration Period | V3 (Week 12; Baseline) up to V11 (Week 44) | Serum samples were assessed for GH binding protein levels at V1, V2, V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). The change in mean serum GH binding protein from Baseline to V11 and to LVA is presented. |
Countries
Czechia, Denmark, France, Germany, Greece, Italy, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
The study was a multicentre, open, single arm, sequential study where subjects were recruited to 25 study centres across 10 European countries. Subjects were enrolled to the study from 02 October 2006 (first subject enrolled) until 27 October 2008 (last subject completed).
Pre-assignment details
A total of 125 patients were screened. Subjects were assigned to treatment if they met all inclusion and none of the exclusion criteria. 92 subjects received treatment during the run-in period and 57 subjects received treatment during the co-administration period.
Participants by arm
| Arm | Count |
|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration Eligible subjects were entered into the co-administration period during which they received both lanreotide Autogel and pegvisomant concomitantly for 28 weeks. The lanreotide Autogel dose during the co-administration period was fixed at 120 mg and was administered by one deep s.c. injection every 28 days. Pegvisomant was administered once or twice a week via s.c. injection. The starting dose was 60 mg once a week dose. Dose adaptation of pegvisomant could then be made every 8 weeks based on IGF-1 levels taken 4 weeks after previous dose adaptation and by the third titration, subjects could receive either 40 mg, 60 mg or 80 mg once a week or 40 mg or 60 mg twice per week. | 57 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Co-administration Period | Adverse Event | 5 |
| Enrolment Through Start Treatment | Did not meet entry criteria | 32 |
| Enrolment Through Start Treatment | Withdrawal by Subject | 1 |
| Run-in Period | Adverse Event | 2 |
| Run-in Period | Claustrophobia | 1 |
| Run-in Period | Protocol Violation | 4 |
Baseline characteristics
| Characteristic | Lanreotide Autogel + Pegvisomant Co-administration |
|---|---|
| Age, Continuous | 51.6 years STANDARD_DEVIATION 12.7 |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 57 |
| other Total, other adverse events | 30 / 57 | 41 / 57 |
| serious Total, serious adverse events | 2 / 57 | 8 / 57 |
Outcome results
Primary
Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period
Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at Visit (V) 1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to investigational medicinal product (IMP) administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at the end of the co-administration period are presented. The last observation carried forward (LOCF) was used to replace missing IGF-1 values.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period | 57.9 percentage of subjects |
Comparison: The percentage of subjects (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: <0.0001Exact test
Primary
Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Diabetic Status at Baseline
Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at the end of the co-administration period, summarised by diabetic status are presented. The denominator used to calculate percentages was the number of subjects in each subgroup (diabetic and non diabetic). The LOCF approach was used to replace missing IGF-1 values.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects within each of the two subgroups analysed for each category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Diabetic Status at Baseline | Non Diabetic Subjects | 63.2 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Diabetic Status at Baseline | Diabetic Subjects | 47.4 percentage of subjects |
Comparison: The percentage of subjects in the subgroup diabetic subjects (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: 0.084Exact test
Comparison: The percentage of subjects in the subgroup non diabetic subjects (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: <0.0001Exact test
Primary
Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant
Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at the end of the co-administration period, summarised by previous treatment and by final pegvisomant dose are presented. The denominator used to calculate percentages was the number of subjects in each subgroup, comprising previous treatment with pegvisomant, lanreotide Autogel and octreotide long acting repeatable (LAR) and final pegvisomant dose as either 40 mg, 60 mg or 80 mg once a week or 40 mg or 60 mg twice per week. The LOCF approach was used to replace missing IGF-1 values.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects within each individual subgroup analysed for each category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Final Dose Pegvisomant: 40 mg/week | 76.9 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Final Dose Pegvisomant: 60 mg 2x/week | 0 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Previous Treatment: Pegvisomant | 46.2 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Previous Treatment: Lanreotide Autogel | 54.2 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Previous Treatment: Octreotide LAR | 70.0 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Final Dose Pegvisomant: 60 mg/week | 61.5 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Final Dose Pegvisomant: 80 mg/week | 75.0 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Acromegaly With a Normalised (Age and Sex Adjusted) IGF-1 Level at the End of the Co-administration Period; Summarised by Previous Treatment and by Final Dose of Pegvisomant | Final Dose Pegvisomant: 40 mg 2x/week | 60.0 percentage of subjects |
Comparison: The percentage of subjects in the subgroup previously treated with pegvisomant (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: 0.1654Exact test
Comparison: The percentage of subjects in the subgroup previously treated with lanreotide Autogel (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: 0.0115Exact test
Comparison: The percentage of subjects in the subgroup previously treated with octreotide LAR (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: 0.0003Exact test
Secondary
Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period
The ACROQoL is a health-related quality of life (QoL) questionnaire for patients with acromegaly consisting of 22 items measured on a 5-point Likert-type scale that assesses frequency of occurrence (always to never) or degree of agreement (completely agree to completely disagree) with the statements. The ACROQoL consists of questions that evaluate physical (8 items) and psychological aspects related to appearance and personal relations (7 items each). Answers are transformed to a percentage value, where 100 is the maximal (best) and 0 the minimum (worse) score depicting self-perceived quality QoL. An increase in ACROQoL score is associated with an improved QoL. The change in ACROQoL global score, physical and psychological dimension scores and appearance and personal relationships sub-dimension scores from Baseline to V11 and to LVA are presented. Relnship = Relationship; Dim = Dimension.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Global Score: Change at V11 | 2.4 units on a scale | Standard Deviation 9.1 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Global Score: Change at LVA | 2.2 units on a scale | Standard Deviation 8.8 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Physical Dimensions Score: Change at V11 | 4.2 units on a scale | Standard Deviation 12 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Physical Dimensions Score: Change at LVA | 3.5 units on a scale | Standard Deviation 12 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Psychological Dimensions Score: Change at V11 | 1.3 units on a scale | Standard Deviation 10.4 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Psychological Dimensions Score: Change at LVA | 1.4 units on a scale | Standard Deviation 10 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Appearance Sub-Dimension Score: Change at V11 | 3.8 units on a scale | Standard Deviation 13 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Appearance Sub-Dimension Score: Change at LVA | 3.7 units on a scale | Standard Deviation 12.4 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Personal Relnship Sub-Dim Score: Change at V11 | -0.1 units on a scale | Standard Deviation 12.7 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Quality of Life (ACROQoL) Assessments During the Co-administration Period | Personal Relnship Sub-Dim Score: Change at LVA | -0.9 units on a scale | Standard Deviation 12.2 |
Secondary
Change From Baseline in Acromegaly Symptoms During the Co-administration Period
Acromegaly symptoms, including arthralgia, excessive perspiration, fatigue, headache and soft tissue swelling were assessed with scores ranging from 0 (no symptoms) to 8 (severe, incapacitating symptoms). Symptoms were assessed by the subject in paper format before any other procedure planned during the visit. The change in acromegaly symptoms from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Fatigue: Change at V11 | -0.2 units on a scale | Standard Deviation 1.6 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Fatigue: Change at LVA | -0.2 units on a scale | Standard Deviation 1.5 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Arthralgia: Change at V11 | -0.7 units on a scale | Standard Deviation 1.5 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Arthralgia: Change at LVA | -0.6 units on a scale | Standard Deviation 1.6 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Excessive Perspiration: Change at V11 | -0.4 units on a scale | Standard Deviation 1.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Excessive Perspiration: Change at LVA | -0.4 units on a scale | Standard Deviation 1.8 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Headache: Change at V11 | -0.4 units on a scale | Standard Deviation 1.6 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Headache: Change at LVA | -0.3 units on a scale | Standard Deviation 1.6 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Soft Tissue Swelling: Change at V11 | -0.6 units on a scale | Standard Deviation 1.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acromegaly Symptoms During the Co-administration Period | Soft Tissue Swelling: Change at LVA | -0.6 units on a scale | Standard Deviation 1.8 |
Secondary
Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate During the Co-administration Period
Twelve-lead ECG recordings were performed at V2, V3 and V11. Sinus rhythm, heart rate, PR interval, RR interval, QRS interval and QT interval were measured and heart rate corrected QT interval using the Fridericia method (QTcF) was calculated. The change in ECG mean heart rate from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of IMP drug during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate During the Co-administration Period | Change at V11 | -2.8 bpm | Standard Deviation 11 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate During the Co-administration Period | Change at LVA | -2.2 bpm | Standard Deviation 11.2 |
Secondary
Change From Baseline in Liver Function Test Parameters During the Co-administration Period
Blood samples for clinical laboratory tests were taken at V1, V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). During the co-administration period, hepatic toxicity was assessed at each visit (V5 to V10) by measuring alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase, gamma glutamyl transferase (GGT), prothrombin time and total bilirubin. The change in mean ALT, AST, GGT and alkaline phosphatase from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in each individual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | ALT: Change at LVA | 7.8 IU/L | Standard Deviation 23.2 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | Alkaline Phosphatase: Change at LVA | -0.8 IU/L | Standard Deviation 15.4 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | AST: Change at V11 | 3.3 IU/L | Standard Deviation 10.7 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | AST: Change at LVA | 4.5 IU/L | Standard Deviation 13 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | ALT: Change at V11 | 4.1 IU/L | Standard Deviation 11.7 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | GGT: Change at V11 | -1.0 IU/L | Standard Deviation 17.8 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | GGT: Change at LVA | 1.5 IU/L | Standard Deviation 20.8 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Liver Function Test Parameters During the Co-administration Period | Alkaline Phosphatase: Change at V11 | -1.7 IU/L | Standard Deviation 14.5 |
Secondary
Change From Baseline in Mean Blood Glucose Maximum Concentration (Cmax) From Oral Glucose Tolerance Test (OGTT) During the Co-administration Period; Assessed in Non Diabetic Subjects
Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean blood glucose Cmax (as determined from OGTT) from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Assessed in non diabetic subjects only (n = 38). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Blood Glucose Maximum Concentration (Cmax) From Oral Glucose Tolerance Test (OGTT) During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at V11 | 0.53 millimoles per litre (mmol/L) | Standard Deviation 1.72 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Blood Glucose Maximum Concentration (Cmax) From Oral Glucose Tolerance Test (OGTT) During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at LVA | 0.61 millimoles per litre (mmol/L) | Standard Deviation 1.69 |
Secondary
Change From Baseline in Mean Fasting Glucose Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects
Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean fasting glucose concentration from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Assessed in non diabetic subjects only (n = 38). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Fasting Glucose Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at V11 | -0.05 mmol/L | Standard Deviation 0.71 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Fasting Glucose Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at LVA | -0.09 mmol/L | Standard Deviation 0.69 |
Secondary
Change From Baseline in Mean Fasting Insulin Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects
Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean fasting insulin concentration from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Assessed in non diabetic subjects only (n = 38). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Fasting Insulin Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at V11 | -12.7 picomoles per litre (pmol/L) | Standard Deviation 41.5 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Fasting Insulin Concentration During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at LVA | -11.7 picomoles per litre (pmol/L) | Standard Deviation 40.8 |
Secondary
Change From Baseline in Mean Fasting Insulin / Glucose Ratio During the Co-administration Period; Assessed in Non Diabetic Subjects
Glucose tolerance was only evaluated in non diabetic subjects. Glucose tolerance was assessed based on measurement of fasting blood glucose and insulin levels taken at V2 and OGTT performed at V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). A dose of 75 g oral glucose was given to subjects and blood samples then taken at 30, 60, 90 and 120 minutes after oral glucose to measure glucose, insulin and GH levels, and to evaluate the GH nadir level. The OGTT was performed after the assessment of IGF-1 and all safety laboratory tests, but before IMPs administration at V3. Glucose, insulin and GH levels were assessed before OGTT in fasting conditions and at the same time as IGF-1 assessment. The change in mean fasting insulin / glucose ratio from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Assessed in non diabetic subjects only (n = 38). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Fasting Insulin / Glucose Ratio During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at V11 | -2.61 ratio | Standard Deviation 8.12 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Fasting Insulin / Glucose Ratio During the Co-administration Period; Assessed in Non Diabetic Subjects | Change at LVA | -2.33 ratio | Standard Deviation 7.94 |
Secondary
Change From Baseline in Mean Glycosylated Haemoglobin (HbA1C) During the Co-administration Period; Assessed in Non Diabetic and Diabetic Subjects
Glycosylated haemoglobin (HbA1C) was measured at V2, V3 and V11 (or in case of premature discontinuation, at the early withdrawal visit). The change in mean HbA1C in diabetic and non diabetic subjects from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis (56 overall for diabetic + non-diabetic subjects).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Glycosylated Haemoglobin (HbA1C) During the Co-administration Period; Assessed in Non Diabetic and Diabetic Subjects | Non Diabetic Subjects: Change at LVA | 0.05 percentage | Standard Deviation 0.21 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Glycosylated Haemoglobin (HbA1C) During the Co-administration Period; Assessed in Non Diabetic and Diabetic Subjects | Diabetic Subjects: Change at V11 | -0.05 percentage | Standard Deviation 0.71 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Glycosylated Haemoglobin (HbA1C) During the Co-administration Period; Assessed in Non Diabetic and Diabetic Subjects | Diabetic Subjects: Change at LVA | -0.05 percentage | Standard Deviation 0.69 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Glycosylated Haemoglobin (HbA1C) During the Co-administration Period; Assessed in Non Diabetic and Diabetic Subjects | Non Diabetic Subjects: Change at V11 | 0.05 percentage | Standard Deviation 0.2 |
Secondary
Change From Baseline in Mean Pituitary Tumour Size During the Co-administration Period
Pituitary tumour size was assessed by Magnetic Resonance Imaging at V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The two longest diameters of the pituitary tumour were to be measured. The change in mean pituitary tumour size from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Pituitary Tumour Size During the Co-administration Period | Change at V11 | 2.4 mm^3 | Standard Deviation 729.7 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Pituitary Tumour Size During the Co-administration Period | Change at LVA | 6.3 mm^3 | Standard Deviation 707.6 |
Secondary
Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period
Twelve-lead ECG recordings were performed at V2, V3 and V11. Sinus rhythm, heart rate, PR interval, RR interval, QRS interval and QT interval were measured and QTcF was calculated. The change in mean ECG parameter for PR interval, QRS interval, QT interval, RR interval and QTcF from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in each individual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | PR Interval: Change at V11 | 1.1 milliseconds (ms) | Standard Deviation 15.8 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | QTcF: Change at V11 | -1.8 milliseconds (ms) | Standard Deviation 16.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | PR Interval: Change at LVA | 1.3 milliseconds (ms) | Standard Deviation 15.5 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | QRS Interval: Change at V11 | 0.1 milliseconds (ms) | Standard Deviation 10.1 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | QRS Interval: Change at LVA | 0.3 milliseconds (ms) | Standard Deviation 10.1 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | QT Interval: Change at V11 | 4.0 milliseconds (ms) | Standard Deviation 29.7 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | QT Interval: Change at LVA | 2.4 milliseconds (ms) | Standard Deviation 29.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | RR Interval: Change at V11 | 34.7 milliseconds (ms) | Standard Deviation 175.4 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | RR Interval: Change at LVA | 27.6 milliseconds (ms) | Standard Deviation 174.8 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean PR Interval, QRS Interval, QT Interval, RR Interval and QTcF During the Co-administration Period | QTcF: Change at LVA | -2.2 milliseconds (ms) | Standard Deviation 16.6 |
Secondary
Change From Baseline in Mean Supine Heart Rate During the Co-administration Period
Heart rate (supine after resting for 3 minutes) was recorded at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The change in mean heart rate from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Supine Heart Rate During the Co-administration Period | Change at V11 | -3.1 beats per minute (bpm) | Standard Deviation 12.6 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Supine Heart Rate During the Co-administration Period | Change at LVA | -2.5 beats per minute (bpm) | Standard Deviation 12.7 |
Secondary
Change From Baseline in Mean Supine Systolic and Diastolic Blood Pressure (BP) During the Co-administration Period
Blood pressure (supine after resting for 3 minutes) was recorded at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The change in mean BP (systolic and diastolic) from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Supine Systolic and Diastolic Blood Pressure (BP) During the Co-administration Period | Supine Systolic BP: Change at LVA | 0.2 millimetres mercury (mmHg) | Standard Deviation 16.6 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Supine Systolic and Diastolic Blood Pressure (BP) During the Co-administration Period | Supine Diastolic BP: Change at V11 | -0.1 millimetres mercury (mmHg) | Standard Deviation 11.4 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Supine Systolic and Diastolic Blood Pressure (BP) During the Co-administration Period | Supine Systolic BP: Change at V11 | -0.4 millimetres mercury (mmHg) | Standard Deviation 17.1 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Supine Systolic and Diastolic Blood Pressure (BP) During the Co-administration Period | Supine Diastolic BP: Change at LVA | -0.3 millimetres mercury (mmHg) | Standard Deviation 11.5 |
Secondary
Change From Baseline in Mean Weight From Baseline During the Co-administration Period
Weight was recorded at V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The change in mean weight from Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Weight From Baseline During the Co-administration Period | Change at V11 | -0.3 kilograms (kg) | Standard Deviation 2.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Mean Weight From Baseline During the Co-administration Period | Change at LVA | -0.3 kilograms (kg) | Standard Deviation 2.9 |
Secondary
Change From Baseline in Prothrombin Time (Expressed as a Percentage of Normal) During the Co-administration Period
Blood samples for clinical laboratory tests were taken at V1, V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). During the co-administration period, hepatic toxicity was assessed at each visit (V5 to V10) by measuring ALT, AST, alkaline phosphatase, GGT, prothrombin time and total bilirubin. Prothrombin time was expressed as a percentage of the time taken for a control blood sample to clot (designated as 100%) and the mean change from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Prothrombin Time (Expressed as a Percentage of Normal) During the Co-administration Period | Change at V11 | -3.7 percentage of time | Standard Deviation 16 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Prothrombin Time (Expressed as a Percentage of Normal) During the Co-administration Period | Change at LVA | -3.6 percentage of time | Standard Deviation 15.2 |
Secondary
Change From Baseline in Serum IGF-1 Levels (Expressed as Z-scores) During the Co-administration Period
The change in serum IGF-1 levels, expressed as z-scores calculated using the age and sex specific mean and standard deviation \[SD\] values from Baseline to V11 and to LVA are presented. A z-score between +/- 2 indicates a normal IGF-1 concentration.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Serum IGF-1 Levels (Expressed as Z-scores) During the Co-administration Period | Change at LVA | -4.25 z-score | Standard Deviation 4 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Serum IGF-1 Levels (Expressed as Z-scores) During the Co-administration Period | Change at V11 | -4.50 z-score | Standard Deviation 4.01 |
Secondary
Change From Baseline in Total Bilirubin During the Co-administration Period
Blood samples for clinical laboratory tests were taken at V1, V2, V3 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). During the co-administration period, hepatic toxicity was assessed at each visit (V5 to V10) by measuring ALT, AST, alkaline phosphatase, GGT, prothrombin time and total bilirubin. The change in mean total bilirubin from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant). Only evaluable subjects with an assessment at the specified visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Total Bilirubin During the Co-administration Period | Change at V11 | -1.3 micromoles per litre | Standard Deviation 2.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Total Bilirubin During the Co-administration Period | Change at LVA | -1.2 micromoles per litre | Standard Deviation 2.8 |
Secondary
Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period
The correlation between the changes in ACROQoL (expressed as standardised scores and undertaken for global score, physical and psychological dimension scores and appearance and personal relationships sub-dimension scores) over the run-in period (V3 minus V2) and co-administration period (V11 and LVA minus V3) with the corresponding changes in z-score for the IGF-1 level is presented. A decrease in IGF-1 z-score represents an improvement and an increase in ACROQoL score represents an improvement. Spearman's rank correlation (r) values are presented for change from V2 to V3 (Baseline) and from Baseline to V11/LVA for each of the specified ACROQoL categories. Corr = Correlation; Dim = Dimension; Relnship = Relationship.
Time frame: At V2 (Day 1; Run-in), V3 (Week 12; Baseline) and V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V2 to V3 for Global Score | -0.16 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V3 to V11/LVA for Global Score | 0.09 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V2 to V3 for Physical Dim | -0.17 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V3 to V11/LVA for Physical Dim | 0.14 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V2 to V3 for Psychological Dim | -0.1 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V3 to V11/LVA for Psychological Dim | 0.08 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V2 to V3 for Appearance | -0.12 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V3 to V11/LVA for Appearance | 0.04 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V2 to V3 for Personal Relnship | -0.01 correlation value |
| Lanreotide Autogel + Pegvisomant Co-administration | Correlation Between the Changes in ACROQoL Assessments With the Corresponding Changes in Z-score of IGF-1 Levels Over the Run-in Period and Co-administration Period | Corr: Change V3 to V11/LVA; Personal Relnship | 0.02 correlation value |
Secondary
Number of Subjects With Putative Antibodies to Lanreotide and to Pegvisomant During the Co-administration Period
Presence of putative antibodies to lanreotide and antibodies to pegvisomant were assessed prior to IMP administration at V2, V4 and V11 (or in case of premature study discontinuation, at the early withdrawal visit). The number of subjects with putative antibodies to lanreotide and to pegvisomant during the co-administration period (Baseline up to V11) is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Putative Antibodies to Lanreotide and to Pegvisomant During the Co-administration Period | Antibodies for Lanreotide | 4 Number of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Putative Antibodies to Lanreotide and to Pegvisomant During the Co-administration Period | Antibodies for Pegvisomant | 6 Number of subjects |
Secondary
Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period
A gallbladder ultrasound was performed at V2, V3, and V11 (or in case of premature study discontinuation, at the early withdrawal visit). Presence of lithiasis and sludge was recorded. Number of subjects who developed or resolved lithiasis and developed or resolved sludge, comparing Baseline to V11 and to LVA are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The Safety population was defined as all subjects who received at least one dose of each IMP during the co-administration period (i.e. one dose of lanreotide Autogel 120 mg and one dose of pegvisomant).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Developed Sludge: V11 vs V3 | 3 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Resolved Sludge: V11 vs V3 | 5 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Developed Lithiasis: V11 vs V3 | 1 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Resolved Lithiasis: V11 vs V3 | 1 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Developed Sludge: LVA vs V3 | 3 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Resolved Sludge: LVA vs V3 | 5 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Developed Lithiasis: LVA vs V3 | 2 participants |
| Lanreotide Autogel + Pegvisomant Co-administration | Number of Subjects With Shift in Presence/Absence of Lithiasis and/or Sludge During Co-administration Period | Resolved Lithiasis: LVA vs V3 | 1 participants |
Secondary
Percentage of Subjects With a Normalised (Age and Sex Adjusted) IGF-1 Level at Any Time During the Co-administration Period
Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. Percentage of subjects with a normalised (age and sex adjusted) IGF-1 level at least once during the co-administration period, summarised by 'while taking the final dose during co-administration' and 'at any time during co-administration' are presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With a Normalised (Age and Sex Adjusted) IGF-1 Level at Any Time During the Co-administration Period | At Any Time During Co-administration | 78.9 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With a Normalised (Age and Sex Adjusted) IGF-1 Level at Any Time During the Co-administration Period | While Taking Final Dose During Co-administration | 66.7 percentage of subjects |
Comparison: The percentage of subjects in the subgroup 'while taking final dose during co-administration' (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: <0.0001Exact test
Comparison: The percentage of subjects in the subgroup 'at any time during co-administration' (denoted as pnor) was compared to the minimum clinically relevant (theoretical) percentage of 30%, using an exact test based on the binomial distribution. The test was an upper-tailed test of H0: pnor ≤ 0.3 versus H1: pnor \> 0.3.p-value: <0.0001Exact test
Secondary
Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment
Serum IGF-1 is a well known and validated marker of acromegaly. IGF-1 assessments were performed at V1, V2, V3, V5, V7, V9 and V11 (or in case of premature study discontinuation, at the early withdrawal visit) and were based on a single serum sample taken in fasting conditions, prior to IMP administration. The percentage of subjects with a normalised (age and sex adjusted) IGF-1 level is presented. The denominator used to calculate the percentages was the number of ITT population subjects with an assessment at the visit. In addition to the data for each individual visit, the last value available (LVA) data is also presented. None of the ITT population subjects had serum IGF-1 normalised at V3, consistent with the criterion to continue in the study and be treated in the co-administration period.
Time frame: V1 (Screening) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V1 (Screening) | 17.5 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V2 (Day 1) | 24.5 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V5 (Week 20) | 56.4 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V9 (Week 36) | 57.7 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V7 (Week 28) | 48.1 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | V11 (Week 44) | 61.5 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Normalised (Age and Sex Adjusted) IGF-1 at Each Assessment | LVA | 57.9 percentage of subjects |
Other Pre-specified
Change From Baseline in Acid Labile Subunit Levels From Baseline During the Co-administration Period
Serum samples were assessed for acid labile subunit levels at V1, V2, V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). The change in mean acid labile subunit levels from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acid Labile Subunit Levels From Baseline During the Co-administration Period | Change at V11 | -561 milli IU per millilitre (mIU/mL) | Standard Deviation 528 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Acid Labile Subunit Levels From Baseline During the Co-administration Period | Change at LVA | -541 milli IU per millilitre (mIU/mL) | Standard Deviation 522 |
Other Pre-specified
Change From Baseline in Prolactin Levels During the Co-administration Period
Serum samples were assessed for prolactin levels at V1, V2, V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). The change in mean prolactin levels from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Prolactin Levels During the Co-administration Period | Change at V11 | -0.1 micrograms per litre (mcg/L) | Standard Deviation 8.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Prolactin Levels During the Co-administration Period | Change at LVA | -0.4 micrograms per litre (mcg/L) | Standard Deviation 8.8 |
Other Pre-specified
Change From Baseline in Serum GH Binding Protein Levels During the Co-administration Period
Serum samples were assessed for GH binding protein levels at V1, V2, V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). The change in mean serum GH binding protein from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Serum GH Binding Protein Levels During the Co-administration Period | Change at V11 | 841 pmol/L | Standard Deviation 302 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Serum GH Binding Protein Levels During the Co-administration Period | Change at LVA | 811 pmol/L | Standard Deviation 320 |
Other Pre-specified
Change From Baseline in Serum GH Levels During the Co-administration Period
Serum samples were assessed for GH levels at the same timepoints as the IGF-1 sample at V1 and V2 and during the OGTT (non diabetic subjects only) at V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). Five samples were taken over 2 hours in order to assess GH nadir and confirm the subject's eligibility before entering the co-administration period. For diabetic subjects, the OGTT was replaced by a measurement of GH level on a blood sample taken at the same time as IGF-1 at V3 and V11 (or at the early withdrawal visit). The change in mean serum GH levels from Baseline to V11 and to LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Serum GH Levels During the Co-administration Period | Change at V11 | 6.6 nanograms per millilitre (ng/mL) | Standard Deviation 9.9 |
| Lanreotide Autogel + Pegvisomant Co-administration | Change From Baseline in Serum GH Levels During the Co-administration Period | Change at LVA | 6.6 nanograms per millilitre (ng/mL) | Standard Deviation 9.7 |
Other Pre-specified
Percentage of Subjects With Serum GH Levels Lesser or Equal to 2.5 ng/mL During the Study
Serum samples were assessed for GH levels at the same timepoints as the IGF-1 sample at V1 and V2 and during the OGTT (non diabetic subjects only) at V3 and V11 (or at the early withdrawal visit in case of premature discontinuation). Five samples were taken over 2 hours in order to assess GH nadir and confirm the subject's eligibility before entering the co-administration period. For diabetic subjects, the OGTT was replaced by a measurement of GH level on a blood sample taken at the same time as IGF-1 at V3 and V11 (or at the early withdrawal visit). The percentage of subjects with serum GH levels ≤ 2.5 ng/mL at Baseline, V11 and LVA is presented.
Time frame: V3 (Week 12; Baseline) up to V11 (Week 44)
Population: The ITT population was defined as all co-administered subjects (treated with at least one dose of each of the two IMPs within the co-administration period) having at least one baseline and at least one post-baseline assessment of the primary efficacy endpoint. Only evaluable subjects with assessments at each specified visit included in analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Serum GH Levels Lesser or Equal to 2.5 ng/mL During the Study | At V3 | 38.6 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Serum GH Levels Lesser or Equal to 2.5 ng/mL During the Study | At V11 | 25.0 percentage of subjects |
| Lanreotide Autogel + Pegvisomant Co-administration | Percentage of Subjects With Serum GH Levels Lesser or Equal to 2.5 ng/mL During the Study | At LVA | 22.8 percentage of subjects |