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Study of Lanreotide Autogel in Non-functioning Entero-pancreatic Endocrine Tumours (CLARINET)

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ClinicalTrials.gov Identifier: NCT00353496
Recruitment Status : Completed
First Posted : July 18, 2006
Results First Posted : February 18, 2015
Last Update Posted : March 6, 2015
Sponsor:
Information provided by (Responsible Party):
Ipsen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Endocrine Tumors
Interventions Drug: lanreotide (Autogel formulation)
Drug: Placebo
Enrollment 264
Recruitment Details 264 subjects were screened at 48 investigational sites in 14 countries (Austria, Belgium, Czech Republic, Denmark, France, Germany, India, Italy, Poland, Slovakia, Spain, Sweden, United Kingdom and the United States of America). 204 subjects were randomised to receive study treatment in the Intent to treat (ITT) population.
Pre-assignment Details  
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks. Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.
Period Title: Overall Study
Started 101 103
Completed 85 [1] 86
Not Completed 16 17
Reason Not Completed
Adverse Event             1             0
Protocol Violation             2             2
Withdrawal by Subject             3             4
Physician Decision             6             9
Not otherwise specified             4             2
[1]
Patients who completed specified assessments or met primary efficacy endpoint criteria for an event.
Arm/Group Title Lanreotide (Autogel Formulation) Placebo Total
Hide Arm/Group Description 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks. Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks. Total of all reporting groups
Overall Number of Baseline Participants 101 103 204
Hide Baseline Analysis Population Description
Analysis based on intent-to-treat (ITT) population comprised of 204 subjects.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 101 participants 103 participants 204 participants
63  (10) 62  (11) 63  (11)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 103 participants 204 participants
Female
48
  47.5%
49
  47.6%
97
  47.5%
Male
53
  52.5%
54
  52.4%
107
  52.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 103 participants 204 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
2
   2.0%
5
   4.9%
7
   3.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
2
   2.0%
2
   1.9%
4
   2.0%
White
97
  96.0%
96
  93.2%
193
  94.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Time since diagnosis   [1] 
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 101 participants 103 participants 204 participants
32.6  (46.1) 34.4  (41.4) 33.5  (43.7)
[1]
Measure Description: Time relative to baseline visit (Week 1).
Neuroendocrine tumour (NET) origin   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 101 participants 103 participants 204 participants
Pancreas 42 49 91
Midgut 33 40 73
Hindgut 11 3 14
Unknown/Other 15 11 26
[1]
Measure Description: Primary tumour characteristics.
Chromogranin A   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 101 participants 103 participants 204 participants
≤1 × ULN 33 34 67
1–2 × ULN 25 18 43
>2 × ULN 41 48 89
Unknown 2 3 5
[1]
Measure Description: Chromogranin A is an NET marker. ULN: upper limit of normal.
1.Primary Outcome
Title Progression-Free Survival (PFS)
Hide Description Time from randomization to first documentation of disease progression, or death. Disease progression centrally assessed using Response Evaluation Criteria in Solid Tumours (RECIST) v1.0
Time Frame From randomisation up to the last tumour assessment (scheduled at 96 weeks). Radiological scans were performed every 12 weeks during the first year and every 24 weeks during the second year
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects.
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description:
lanreotide (Autogel formulation): 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Overall Number of Participants Analyzed 101 103
Median (95% Confidence Interval)
Unit of Measure: Weeks
NA [1] 
(NA to NA)
72
(48.6 to 96.0)
[1]
Not available as median not reached during the 96 week fixed duration study.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lanreotide (Autogel Formulation), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments No p-value adjustment for multiple comparisons.
Method Log Rank
Comments The log rank test was stratified according to progression status at baseline and prior therapy.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
0.30 to 0.73
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Patients Alive & Without Disease Progression
Hide Description Percentage of patients still ongoing (or completing at Week 96) without centrally assessed disease progression or death at Weeks 48 and 96.
Time Frame Week 48 & 96
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects.
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description:
lanreotide (Autogel formulation): 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Overall Number of Participants Analyzed 101 103
Measure Type: Number
Unit of Measure: Percentage of participants
Week 48 66 49
Week 96 53 25
3.Secondary Outcome
Title Pharmacokinetic Profile of Lanreotide
Hide Description Pharmacokinetic Profile of Lanreotide assessed by mean serum concentration at specified timepoints
Time Frame Week 4, 12, 24, 36, 48, 72, 96
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis based on the intent-to-treat (ITT) population which comprised 101 randomised subjects who received lanreotide
Arm/Group Title Lanreotide (Autogel Formulation)
Hide Arm/Group Description:
lanreotide (Autogel formulation): 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.
Overall Number of Participants Analyzed 101
Mean (Standard Deviation)
Unit of Measure: ng/mL
At Week 4 predose (n=81) 2.5  (0.46)
At Week 12 predose (n=87) 5.0  (0.42)
At Week 24 predose (n=74) 6.1  (0.44)
At Week 36 predose (n=67) 6.2  (0.39)
At Week 48 predose (n=62) 6.6  (0.45)
At Week 72 predose (n=52) 6.8  (0.44)
At Week 96 predose (n=48) 6.6  (0.39)
4.Secondary Outcome
Title Change in the Global Health Status Quality of Life Assessment
Hide Description Transformed scores from European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire responses (QLQ)-C30. Questionnaire response scores range from 0 to 100. Higher scores indicate best possible Quality of Life.
Time Frame Week 12 to Week 96 (last visit)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis based on the intent-to-treat (ITT) population which comprised 193 randomised subjects with valid assessment.
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description:
lanreotide (Autogel formulation): 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Overall Number of Participants Analyzed 95 98
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-5.2  (3.7) -4.9  (3.7)
5.Secondary Outcome
Title Percentage of Patients With a Greater Than or Equal to 50% Decrease in Plasma Chromogranin A (CgA) Levels
Hide Description [Not Specified]
Time Frame Week 12 to Week 96 (last visit)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis based on the subgroup of subjects with an elevated plasma CgA values. Subjects with a gastrinoma were excluded from the analysis.
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description:
lanreotide (Autogel formulation): 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Overall Number of Participants Analyzed 64 64
Measure Type: Number
Unit of Measure: percentage of participants
42.2 4.7
6.Secondary Outcome
Title Percentage of Patients Still Alive Based on Available Overall Survival Data
Hide Description Overall survival defined as the time from randomisation to death due to any cause. Subjects were followed for overall survival beyond study completion/withdrawal via annual telephone contact until the last subject completed the study.
Time Frame Randomisation to death or last visit, up to 321 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis based on the intent-to-treat (ITT) population which comprised 204 randomised subjects.
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description:
lanreotide (Autogel formulation): 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Placebo: Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 2 years.
Overall Number of Participants Analyzed 101 103
Measure Type: Number
Unit of Measure: percentage of participants
84 77
Time Frame Total exposure to treatment was 138.0 subject years for lanreotide vs 123.6 subject years for placebo.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Lanreotide (Autogel Formulation) Placebo
Hide Arm/Group Description 120mg administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks. Saline solution 0.9% administered via deep subcutaneous injection every 28 days for a maximum period of 96 weeks.
All-Cause Mortality
Lanreotide (Autogel Formulation) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Lanreotide (Autogel Formulation) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   25/101 (24.75%)      32/103 (31.07%)    
Blood and lymphatic system disorders     
Anaemia  1  3/101 (2.97%)  3 0/103 (0.00%)  0
Cardiac disorders     
Aortic valve stenosis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Cardiac failure  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Coronary artery disease  1  0/101 (0.00%)  0 2/103 (1.94%)  2
Myocardial infarction  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Pericarditis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Ear and labyrinth disorders     
Vertigo  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Endocrine disorders     
Hyperthyroidism  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Toxic nodular goitre  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  1/101 (0.99%)  1 1/103 (0.97%)  1
Abdominal pain lower  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Abdominal pain upper  1  2/101 (1.98%)  2 0/103 (0.00%)  0
Ascites  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Constipation  1  1/101 (0.99%)  1 1/103 (0.97%)  1
Diarrhoea  1  0/101 (0.00%)  0 2/103 (1.94%)  3
Diverticulum  1  0/101 (0.00%)  0 1/103 (0.97%)  2
Gastrointestinal haemorrhage  1  1/101 (0.99%)  2 2/103 (1.94%)  2
Haematemesis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Ileus  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Inguinal hernia  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Intestinal obstruction  1  2/101 (1.98%)  2 1/103 (0.97%)  1
Large intestine perforation  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Nausea  1  1/101 (0.99%)  1 2/103 (1.94%)  3
Peptic ulcer  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Vomiting  1  4/101 (3.96%)  4 2/103 (1.94%)  3
General disorders     
Chills  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Pyrexia  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Hepatobiliary disorders     
Bile duct stenosis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Biliary fistula  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Cholelithiasis  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Cholestasis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Hepatic failure  1  2/101 (1.98%)  2 0/103 (0.00%)  0
Hepatic necrosis  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Hyperbilirubinaemia  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Jaundice  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Jaundice cholestatic  1  0/101 (0.00%)  0 1/103 (0.97%)  2
Immune system disorders     
Anaphylactic reaction  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Infections and infestations     
Gastroenteritis  1  0/101 (0.00%)  0 2/103 (1.94%)  2
Infected dermal cyst  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Liver abscess  1  2/101 (1.98%)  2 0/103 (0.00%)  0
Orchitis  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Pneumonia  1  2/101 (1.98%)  2 0/103 (0.00%)  0
Pulmonary tuberculosis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Sepsis  1  2/101 (1.98%)  2 0/103 (0.00%)  0
Urinary tract infection  1  3/101 (2.97%)  3 1/103 (0.97%)  4
Urosepsis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Injury, poisoning and procedural complications     
Anastomotic ulcer  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Humerus fracture  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Radius fracture  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Metabolism and nutrition disorders     
Dehydration  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Diabetes mellitus  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Electrolyte imbalance  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Hypercalcaemia  1  1/101 (0.99%)  2 0/103 (0.00%)  0
Hyperglycaemia  1  2/101 (1.98%)  2 0/103 (0.00%)  0
Hypoglycaemia  1  0/101 (0.00%)  0 2/103 (1.94%)  2
Hypokalaemia  1  0/101 (0.00%)  0 1/103 (0.97%)  2
Musculoskeletal and connective tissue disorders     
Back pain  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Pain in extremity  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Spinal osteoarthritis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder cancer  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Bronchial carcinoma  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Endometrial adenocarcinoma  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Metastases to liver  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Oesophageal carcinoma  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Nervous system disorders     
Dizziness  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Spinal cord compression  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Psychiatric disorders     
Confusional state  1  0/101 (0.00%)  0 3/103 (2.91%)  3
Renal and urinary disorders     
Renal failure  1  1/101 (0.99%)  2 0/103 (0.00%)  0
Renal failure acute  1  1/101 (0.99%)  1 1/103 (0.97%)  1
Reproductive system and breast disorders     
Cervical dysplasia  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Respiratory, thoracic and mediastinal disorders     
Hypoxia  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Pleural effusion  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Pulmonary embolism  1  1/101 (0.99%)  1 1/103 (0.97%)  1
Vascular disorders     
Circulatory collapse  1  1/101 (0.99%)  1 1/103 (0.97%)  1
Hypertensive crisis  1  1/101 (0.99%)  1 0/103 (0.00%)  0
Vena cava thrombosis  1  0/101 (0.00%)  0 1/103 (0.97%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lanreotide (Autogel Formulation) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   88/101 (87.13%)      92/103 (89.32%)    
Gastrointestinal disorders     
Abdominal discomfort  1  5/101 (4.95%)  8 3/103 (2.91%)  4
Abdominal pain  1  23/101 (22.77%)  32 18/103 (17.48%)  34
Abdominal pain upper  1  7/101 (6.93%)  7 9/103 (8.74%)  15
Constipation  1  11/101 (10.89%)  13 14/103 (13.59%)  16
Diarrhoea  1  35/101 (34.65%)  57 37/103 (35.92%)  75
Flatulence  1  12/101 (11.88%)  13 9/103 (8.74%)  12
Nausea  1  15/101 (14.85%)  28 13/103 (12.62%)  22
Vomiting  1  17/101 (16.83%)  21 10/103 (9.71%)  28
General disorders     
Asthenia  1  8/101 (7.92%)  8 6/103 (5.83%)  6
Fatigue  1  11/101 (10.89%)  15 16/103 (15.53%)  18
Injection site pain  1  8/101 (7.92%)  30 4/103 (3.88%)  10
Oedema peripheral  1  5/101 (4.95%)  5 7/103 (6.80%)  12
Pyrexia  1  4/101 (3.96%)  6 6/103 (5.83%)  7
Hepatobiliary disorders     
Cholelithiasis  1  15/101 (14.85%)  16 7/103 (6.80%)  7
Infections and infestations     
Nasopharyngitis  1  9/101 (8.91%)  10 17/103 (16.50%)  23
Upper respiratory tract infection  1  3/101 (2.97%)  5 6/103 (5.83%)  6
Urinary tract infection  1  8/101 (7.92%)  13 11/103 (10.68%)  13
Investigations     
Pancreatic enzymes decreased  1  6/101 (5.94%)  7 0/103 (0.00%)  0
Weight decreased  1  9/101 (8.91%)  9 9/103 (8.74%)  10
Metabolism and nutrition disorders     
Decreased appetite  1  10/101 (9.90%)  11 9/103 (8.74%)  11
Dehydration  1  5/101 (4.95%)  7 1/103 (0.97%)  1
Diabetes mellitus  1  9/101 (8.91%)  9 4/103 (3.88%)  5
Musculoskeletal and connective tissue disorders     
Arthralgia  1  10/101 (9.90%)  15 10/103 (9.71%)  11
Back pain  1  11/101 (10.89%)  12 11/103 (10.68%)  11
Muscle spasms  1  5/101 (4.95%)  5 4/103 (3.88%)  4
Musculoskeletal pain  1  7/101 (6.93%)  8 3/103 (2.91%)  6
Nervous system disorders     
Dizziness  1  9/101 (8.91%)  12 1/103 (0.97%)  1
Headache  1  16/101 (15.84%)  19 11/103 (10.68%)  19
Lethargy  1  5/101 (4.95%)  13 4/103 (3.88%)  4
Respiratory, thoracic and mediastinal disorders     
Cough  1  5/101 (4.95%)  5 3/103 (2.91%)  8
Dyspnoea  1  6/101 (5.94%)  7 1/103 (0.97%)  2
Oropharyngeal pain  1  5/101 (4.95%)  5 3/103 (2.91%)  4
Skin and subcutaneous tissue disorders     
Alopecia  1  5/101 (4.95%)  5 4/103 (3.88%)  4
Pruritus  1  5/101 (4.95%)  5 5/103 (4.85%)  17
Rash  1  7/101 (6.93%)  8 3/103 (2.91%)  3
Vascular disorders     
Flushing  1  4/101 (3.96%)  4 6/103 (5.83%)  6
Hypertension  1  13/101 (12.87%)  16 5/103 (4.85%)  5
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director Endocrinology
Organization: Ipsen
Phone: clinical.trials@ipsen.com
EMail: clinical.trials@ipsen.com
Layout table for additonal information
Responsible Party: Ipsen
ClinicalTrials.gov Identifier: NCT00353496     History of Changes
Other Study ID Numbers: 2-55-52030-726
2005-004904-35 ( EudraCT Number )
First Submitted: July 17, 2006
First Posted: July 18, 2006
Results First Submitted: January 15, 2015
Results First Posted: February 18, 2015
Last Update Posted: March 6, 2015