Lanreotide Autogel and Pegvisomant Combination Therapy in Acromegalic Patients

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.