Lanreotide Autogel and Pegvisomant Combination Therapy in Acromegalic Patients

Acromegaly Clinical Trial

Official title:

Phase III, Multicentre, Open Study to Assess the Efficacy and Safety Profiles of the Co-administration of Lanreotide Autogel 120 mg (Administered Via Deep Subcutaneous Injections Every 28 Days) and Pegvisomant 40 to 120 mg Per Week (Administered Via Subcutaneous Route Once or Twice a Week) in Acromegalic Patients Failing to Respond to Lanreotide Autogel 120 mg Alone

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00383708
• Other study ID #: 2-55-52030-727
• Status: Completed
• Phase: Phase 3
• Start date: October 2006
• Est. completion date: October 2008

Study information

• Verified date: September 2022
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 125
• Est. completion date: October 2008
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acromegaly

Intervention

Drug:
• lanreotide (Autogel formulation)
120 mg administered via deep subcutaneous injection every 28 days over 28 weeks.
• Pegvisomant
Administered at 40 to 120 mg per week via subcutaneous injection once or twice a week over 28 weeks.

Locations

Country	Name	City	State
Czechia	University Hospital, Charles University	Hradec Kralove
Czechia	Charles University	Prague
Denmark	Aarhus Kommunehospital	Aarhus
France	Groupe Hospitalier Henri Mondor- Albert Chenevier	Créteil Cedex
France	Hôpital Bicêtre	Le Kremlin-Bicêtre
France	Clinique Marc Linquette	Lille Cedex
France	Hôpital de la Timone	Marseille Cedex
France	CHU de Rangueil	Toulouse
Germany	Charite Campus Mitte	Berlin
Germany	Klinikum Johann Wolfgang Goethe-Universität	Frankfurt
Germany	Medizinische Klinik Innenstadt	Munchen
Greece	Anticancer Hospital Metaxa Piraeus	Piraeus
Italy	Universitá degli Studi di Milano	Milano
Italy	University Federico II	Napoli
Italy	Universitá di Torino	Torino
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Dept. of Internal Medicine Erasmus MC	Rotterdam
Spain	Hospital General de Alicante	Alicante
Spain	Clínica Puerta de Hierro	Madrid
Spain	Hospital Clínico Universitario de Santiago de Compostela	Santiago de Compostela
Sweden	Sahlgrenska University Hospital	Göteborg
Sweden	Uppsala University Hospital	Uppsala
United Kingdom	Christie Hospital and Holt Radium Institute	Manchester
United Kingdom	Royal Hallamshire Hospital	Sheffield

Sponsors (1)

Lead Sponsor	Collaborator
Ipsen

Countries where clinical trial is conducted

Czechia,  Denmark,  France,  Germany,  Greece,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

References & Publications (1)

van der Lely AJ, Bernabeu I, Cap J, Caron P, Colao A, Marek J, Neggers S, Birman P. Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analog — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	V3 (Week 12; Baseline) up to V11 (Week 44)
Other	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.	V3 (Week 12; Baseline) up to V11 (Week 44)
Other	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.	V3 (Week 12; Baseline) up to V11 (Week 44)
Other	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.	V3 (Week 12; Baseline) up to V11 (Week 44)
Other	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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V1 (Screening) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	At V2 (Day 1; Run-in), V3 (Week 12; Baseline) and V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)
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.	V3 (Week 12; Baseline) up to V11 (Week 44)