ELECT: An Efficacy and Safety Study of Somatuline Depot (Lanreotide) Injection to Treat Carcinoid Syndrome

• Sponsor: Ipsen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00774930
• Collaborator: (none)
• Enrollment: 115
• Locations: 54
• Arms: 2
• Duration (Months): 79
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study was to determine whether monthly deep subcutaneous (s.c.) injections of lanreotide Autogel (Somatuline Depot) were effective and safe in controlling diarrhoea and flushing by reducing the usage of s.c. short-acting octreotide as a rescue medication to control symptoms in subjects with carcinoid syndrome.

Condition or Disease	Intervention/Treatment	Phase
Carcinoid Syndrome	Drug: Lanreotide; Drug: Placebo	Phase 3

Detailed Description

This study consisted of a Screening period, conducted up to 4 months before randomisation, followed by three phases: a 16-week, double blind (DB), randomised, placebo-controlled phase; a 32-week initial open label (IOL) phase; and a long term open label extension (LTOLE) phase.

The DB phase evaluated lanreotide Autogel versus placebo in subjects with a history of carcinoid syndrome (flushing and/or diarrhoea). This was followed by a 32-week IOL phase in which all subjects received lanreotide Autogel 120 mg every 4 weeks. Subjects in countries where lanreotide Autogel had not been approved for the treatment of carcinoid syndrome, who were well-controlled at the end of the 32-week IOL phase and chose to continue to receive lanreotide Autogel, were given the option of participating in a LTOLE phase. The LTOLE phase of the study was planned to end at least 2 years after the last subject had completed his/her participation in the 32-week IOL phase or when marketing approval for the treatment of symptoms of carcinoid syndrome had been obtained in the respective countries (whichever occurred first) or at any time the study was terminated by the Sponsor. The actual overall duration of the study was 6.5 years. During the LTOLE phase all subjects continued to be treated with lanreotide Autogel 120 mg every 4 weeks.

The study planned to enrol approximately 100 adult subjects worldwide. Screening continued until 115 subjects were enrolled in the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double Blind, Randomized Placebo Controlled Clinical Trial Investigating the Efficacy and Safety of Somatuline Depot (Lanreotide) Injection in the Treatment of Carcinoid Syndrome
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lanreotide Autogel (Somatuline Depot) 120 mg Subjects received deep s.c. lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase). After completing the DB phase (or if they met criteria for early roll over [ERO]) the subjects entered the IOL phase during which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. During the LTOLE phase, subjects continued treatment with lanreotide Autogel 120 mg deep s.c. every 4 weeks until at least 2 years after the last subject completed the IOL phase or when marketing approval for the treatment of symptoms of carcinoid syndrome was obtained [whichever occurred first]).	Drug: Lanreotide; deep s.c. injection, 120 mg, every 4 weeks (±3 days).; Other Names: Somatuline Somatuline Depot Somatuline Autogel Lanreotide Autogel
Placebo Comparator: Placebo (DB) and lanreotide Autogel 120 mg in IOL and LTOLE Subjects received deep s.c. placebo every 4 weeks (±3 days) for 16 weeks (DB phase). After completing the DB phase (or if they met criteria for ERO) the subjects entered the IOL phase during which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. During the LTOLE phase, subjects continued treatment with lanreotide Autogel 120 mg deep s.c. every 4 weeks until at least 2 years after the last subject completed the IOL phase or when marketing approval for the treatment of symptoms of carcinoid syndrome was obtained [whichever occurred first]).	Drug: Placebo; deep s.c. injection of placebo (0.9% saline solution) every 4 weeks (±3 days) for 16 weeks, then deep s.c. injection of lanreotide 120 mg, every 4 weeks (±3 days).

Outcome Measures

Primary Outcome Measures

1. Percentage of Days With Subcutaneous Octreotide as Rescue Medication [16-week DB phase]

   Use of s.c. octreotide required to control symptoms associated with carcinoid syndrome, measured as the percentage of days that s.c. octreotide was used as rescue medication, based on subject Interactive Voice Response System (IVRS) or Interactive Web Response System (IWRS) diary records.

Secondary Outcome Measures

1. Average Frequency of Diarrhoea Events (Per Day) Based on Subject Diary Records. [16-week DB phase]

2. Average Frequency of Flushing Events (Per Day) Based on Subject Diary Records. [16-week DB phase]

3. Percentage of Days of Use of Other Rescue Medication [16-week DB phase]

   Usage of other concomitant rescue medications for diarrhoea and/or flushing events, measured as the percentage of days that the medications were used as rescue medication based on subject IVRS/IWRS diary records. Subjects were required to record the use and dose of s.c. octreotide, if any, as well as the use of other concomitant rescue medications (e.g. loperamide 2 mg tabs, and/or tincture of opium).

4. Proportion of Subjects Who Rolled Over Into the IOL Phase Before Completing the DB Phase of the Study [16-week DB phase]

   Subjects who rolled over early were those who received less than four DB injections before receiving the first IOL injection.

5. Changes From Baseline in "Global Health Status/Quality of Life (QoL)" Score (Based on Items 29 and 30 of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ] C30) [Baseline and Week 12 of DB phase]

   Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment. Q29 and Q30 range from 1 (Very poor) to 7 (Excellent) with 1 being worst case and 7 the most favourable answer. Scores were derived according to the rules contained within the EORTC scoring manual. All of the scores range in score from 0 to 100. A high score for global health status/QoL represents high QoL. The principle for scoring the scale is: Estimate the average of the items (I1, I2, ..., In) that contribute to the scale; this is the raw score. Raw score = RS = (I1 + I2 +…+ In)/n. For global health status/QoL: Score = {(RS - 1)/range} x 100, where range is the difference between the maximum possible value of RS and the minimum possible value of RS.

6. Changes From Baseline in "Gastrointestinal (G.I). Symptoms" Subscore (Based on Items Q34, Q35, Q36, Q37 and Q38 of EORTC G.I. Neuroendocrine Tumour [NET] 21] [Baseline and Week 12 of DB phase]

   Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment. The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 to Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 to Q51 range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the scores were generated. All of the scores range in score from 0 to 100. A high score for a symptom scale represents a high level of symptomatology. The principle for scoring the scale is: Estimate the average of the items (I1, I2, ..., In) that contribute to the scale; this is the raw score. RS = (I1 + I2 +…+ In)/n. For symptom scales: Score = {(RS - 1)/range} x 100, where range is the difference between the maximum possible value of RS and the minimum possible value of RS.

7. Changes From Baseline in QoL in "Endocrine Symptoms" Subscore (Assessed Based on Items Q31, Q32 and Q33 Using EORTC QLQ-G.I.NET-21 Questionnaires) [Baseline and Week 12 of DB phase]

   Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment. The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 to Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 to Q51 range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the scores were generated. All of the scores range in score from 0 to 100. A high score for a symptom scale represents a high level of symptomatology. The principle for scoring the scale is: Estimate the average of the items (I1, I2, ..., In) that contribute to the scale; this is the raw score. RS = (I1 + I2 +…+ In)/n. For symptom scales: Score = {(RS - 1)/range} x 100, where range is the difference between the maximum possible value of RS and the minimum possible value of RS.

8. Absolute Changes From Baseline in Biochemical Markers (Plasma Chromogranin A [CgA]) [Baseline and Week 12 of DB phase]

   Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment.

9. Absolute Changes From Baseline in Biochemical Markers (Urinary 5-hydroxyindoleacetic Acid [5-HIAA]) [Baseline and Week 12 of DB phase]

   Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Subjects were eligible for participation in the study if they met the following criteria:

1. At least 18 years of age at the time of first dosing.

2. Subjects must have given signed informed consent before any study related activities were conducted.

3. Subjects in the United States of America (USA) must have given written authorisation for the release of protected health information in compliance with the Health Insurance Portability and Accountability Act (HIPAA) regulations; subjects in other countries must have provided appropriate authorisation as needed by regulatory authorities in each country.

4. Subjects must have been willing to receive s.c. octreotide injections as rescue medication, as needed to control their symptoms, if any.

5. If female, the subject must not have been pregnant (confirmed by negative pregnancy test) and must have had the following documented via verbally given history:

• At least 1 year postmenopausal (natural cessation of menses), or

• Surgically sterile (if by tubal ligation, surgery must have been performed more than 3 months prior to entry into the study), or

• If the subject was of childbearing potential and sexually active, she must have been using an acceptable form of contraception (oral, injected, transdermal or implanted contraceptives, diaphragm or barrier method with spermicidal and/or intrauterine device); local methods such as condoms or sponges/vaginal tablets were not acceptable forms of contraception.

1. Subjects with a histopathologically confirmed diagnosis of carcinoid tumour or, a carcinoid tumour of unknown location with liver metastases (documented biopsy), and a history of carcinoid syndrome (flushing and/or diarrhoea) who were either naïve to treatment with a somatostatin analogue (SSTa) or responsive (according to the opinion of the principal investigator) to conventional doses of Sandostatin LAR® Depot (LAR; ≤30 mg every 4 weeks) or to daily doses of ≤600 μg of s.c. octreotide.

2. Confirmation of positive somatostatin receptor (SSTR) status by somatostatin receptor scintigraphy (SRS; up to 6 months prior to study entry at the Screening Visit).

3. Absence of tumour progression documented by two sequential computed tomography (CT) scans or two sequential magnetic resonance imaging (MRI) scans (≥3 months apart); the last CT or MRI scan must have been performed within 6 months of study entry (Screening Visit).

4. Subjects previously treated with LAR, must have received their last dose of LAR at least 4 weeks prior to first dose of study treatment (no later than at the Screening Visit).

5. Be able to communicate and cooperate with the principal investigator and the staff and willing to comply with the study instructions.

Subjects were excluded from entering the study for the following reasons:

1. History of known allergy or hypersensitivity to investigational drug or any components of its formulation, or octreotide.

2. History of carcinoid syndrome refractory to treatment with conventional doses of SSTa.

3. Treatment with any other investigational drug within 30 days prior to study entry (Screening Visit) and/or at any time during the subject's participation in the study.

4. Treatment with interferon, chemotherapy and/or radiotherapy (a radiolabelled SSTa) and/or tumour debulking <3 months prior to study entry (Screening Visit).

5. History of hepatic arterial embolisation, hepatic arterial chemoembolisation and/or selective internal radiation therapy (selective internal radiation [SIR] therapy [SIRT]; e.g. SIR Spheres) <6 months prior to study entry (Screening Visit).

6. Short bowel syndrome.

7. Uncontrolled diabetes and/or hypertension.

8. Severe renal impairment (glomerular filtration rate <30 mL/min/1.73 m2) and/or severe liver impairment as evidenced by serum total bilirubin >1.5 mg/dL associated with bile duct blockage or with alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5.0 upper limit of normal (ULN).

9. Diagnosis of cardiac disease New York Heart Association (NYHA) functional classification >Class I. (Subject has limitation of physical activity. Ordinary physical activity causes undue fatigue, palpitation, or dyspnoea).

10. Life expectancy less than 1 year.

11. Any malignancies except carcinoid tumour, basocellular carcinoma of the skin, in situ carcinoma of the cervix and ≥5 years disease free after curative cancer treatment.

12. Any serious medical condition that could jeopardise the safety of the subject and/or the efficacy assessments of the study.

13. Subject is being treated with a proton pump inhibitor (PPI) and has been at a stable dose (no change in dose or frequency of administration) for less than 4 weeks at study entry (Screening Visit).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Greater Los Angeles Health Care System	Los Angeles	California	United States	90073
2	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095
3	Stanford Cancer Center	Stanford	California	United States	94305
4	Cedars Sinai Outpatient Cancer Center	West Hollywood	California	United States	90048
5	Kentuckiana Cancer Institute	Louisville	Kentucky	United States	40202
6	Louisiana State University Health Science Center	Kenner	Louisiana	United States	70065
7	University of Michigan	Ann Arbor	Michigan	United States	48109
8	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
9	University of New Mexico Cancer Care Center	Albuquerque	New Mexico	United States	97239
10	Providence Portland Medical Center	Portland	Oregon	United States	97213
11	Oregon Health Science University	Portland	Oregon	United States	97239
12	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
13	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
14	UPMC Liver Cancer Center	Pittsburgh	Pennsylvania	United States	15213
15	Eastern Virginia Medical School	Norfolk	Virginia	United States	23510
16	Froedtert & Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
17	Biocancer - Centro de Pesquisa e Tratamento do Câncer	Belo Horizonte		Brazil
18	Hospital LifeCenter	Belo Horizonte		Brazil
19	Oxion Medicina Oncológica	Belo Horizonte		Brazil
20	Hospital Universitário de Brasilia	Brasilia		Brazil
21	Hospital Erasto Gaertner	Curitiba		Brazil
22	Irmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre		Brazil
23	Hospital de Base de São José do Rio Preto	São José do Rio Preto		Brazil
24	VFN Onkologicka klinika	Prague		Czechia	12808
25	Sir Gangaram Hospital	Delhi		India
26	Indo-American Cancer Institute & Research Centre	Hyderabad		India
27	Omega Hospitals	Hyderabad		India
28	Santokaba Durlabhji Memorial Hospital and Research Institute	Jaipur		India	302015
29	Bhagwan Mahaveer cancer hospital and research centre	Jaipur		India
30	Shatabdi Super Speciality hospital	Mumbai		India	422005
31	Tata Memorial Hospital	Mumbai		India
32	Paul Stradins Clinical University Hospital	Riga		Latvia	1002
33	Klinika Endokrynologii, Diabetologii i Leczenia Izotopami	Wrocław		Poland	50-367
34	Non-Federal Institution of Healthcare "Central Clinical Hospital # 1 of the LLC "Russian Railways (RZD)"	Moscow		Russian Federation
35	Russian Academy of Medical Sciences "Russian Oncological Research Centre named after N.N. Blokhin RAMS"	Moscow		Russian Federation
36	Federal Institution of Healthcare "Leningradsky Regional Oncological Dispensary"	Saint-Petersburg		Russian Federation
37	Clinic of Endocrinology, diabetes and metabolic diseases, Clinical Center of Serbia	Belgrade		Serbia	11000
38	Oncology Institute of Vojvodina, Sremska Kamenica	Sremska Kamenica		Serbia	21 204
39	Rondebosch Oncology Unit	Cape Town		South Africa	7700
40	Groote Schuur Hospital	Cape Town		South Africa
41	Westridge Medical Centre	Durban		South Africa
42	GVI Oncology Clinical Trial Unit	Port Elizabeth		South Africa	7570
43	Erciyes University Medical Faculty	Kayseri		Turkey	38039
44	Cherkassy Regional Oncology Dispensary	Cherkassy		Ukraine
45	Chernivtsi Regional Oncology Center	Chernivtsi		Ukraine	58013
46	Oncology and Medical Radiology Chair of Dnepropetrovsk State Medical Academy	Dnepropetrovsk		Ukraine
47	Regional Anticancer Center, Department of oncoproctology	Donetsk		Ukraine
48	Municipal Clinical Hospital #2, Proctology department	Kharkiv		Ukraine
49	Kyiv City Oncological Hospital, Thoracic department	Kyiv		Ukraine
50	Medical Centre "Mriya"	Kyiv		Ukraine
51	National Cancer Institute	Kyiv		Ukraine
52	Odessa Regional Clinical Hospital	Odessa		Ukraine	65117
53	Uzhgorods'ka Tsentral'na Mis'ka Klinichna Likarnya, Mis'kyy Onkologichnyy Tsentr	Uzhgorod		Ukraine
54	Vinnytsya Regional Clinical Oncological Center, Vinnytsya State Medical University	Vinnytsya		Ukraine

Sponsors and Collaborators

• Ipsen

Investigators

• Study Director: Ipsen Medical Director, Ipsen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT00774930
• Other Study ID Numbers: 2-55-52030-730; TR321; 2010-019066-92
• First Posted: Oct 17, 2008
• Last Update Posted: Nov 5, 2020
• Last Verified: Nov 1, 2020

• Keywords provided by Ipsen: Carcinoid tumor; Somatuline Depot; Lanreotide Autogel; Neuroendocrine tumor; NET; Diarrhea; Flushing; Carcinoid tumour; Neuroendocrine tumour; Diarrhoea
• Additional relevant MeSH terms: Carcinoid Tumor; Malignant Carcinoid Syndrome; Syndrome; Serotonin Syndrome; Lanreotide; Somatostatin

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from multiple sites across countries from May 2009. The study was completed in December 2015.
Pre-assignment Detail	A total of 153 subjects were screened; 115 were randomized and 38 failed screening.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase). Subjects then received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks in the initial open label (IOL) phase and further deep s.c. injections with lanreotide Autogel every 4 weeks in the long term open label extension (LTOLE) phase.	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase). Subjects then received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks in the IOL phase and further deep s.c. injections with lanreotide Autogel every 4 weeks in the LTOLE phase.
Period Title: DB Phase
STARTED	59	56
COMPLETED	45	34
NOT COMPLETED	14	22
Period Title: DB Phase
STARTED	56	46
COMPLETED	43	37
NOT COMPLETED	13	9
Period Title: DB Phase
STARTED	32	25
COMPLETED	17	8
NOT COMPLETED	15	17

Baseline Characteristics

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo	Total
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase). Subjects then received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks in the IOL phase and further deep s.c. injections with lanreotide Autogel every 4 weeks in the LTOLE phase. Intent-to-treat (ITT) population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group). Subjects from the ITT population were analysed under the randomised treatment group.	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase). Subjects then received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks in the IOL phase and further deep s.c. injections with lanreotide Autogel every 4 weeks in the LTOLE phase.	Total of all reporting groups
Overall Participants	59	56	115
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (10.6)	59.3 (11.6)	58.6 (11.1)
Sex: Female, Male (Count of Participants)
Female	32 54.2%	35 62.5%	67 58.3%
Male	27 45.8%	21 37.5%	48 41.7%
Race/Ethnicity, Customized (participants) [Number]
Asian	6 10.2%	3 5.4%	9 7.8%
Black/African American	2 3.4%	3 5.4%	5 4.3%
White	44 74.6%	44 78.6%	88 76.5%
Multi race	7 11.9%	6 10.7%	13 11.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Days With Subcutaneous Octreotide as Rescue Medication
Description	Use of s.c. octreotide required to control symptoms associated with carcinoid syndrome, measured as the percentage of days that s.c. octreotide was used as rescue medication, based on subject Interactive Voice Response System (IVRS) or Interactive Web Response System (IWRS) diary records.
Time Frame	16-week DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group). Subjects from the ITT population were analysed under the randomised treatment group.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	59	56
Least Squares Mean (95% Confidence Interval) [Percentage of days]	33.72	48.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lanreotide Autogel (Somatuline Depot) 120 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0165
	Comments
	Method	ANCOVA
	Comments	This analysis does not include any imputation for the early roll over subjects

2. Secondary Outcome

Title	Average Frequency of Diarrhoea Events (Per Day) Based on Subject Diary Records.
Time Frame	16-week DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group). Subjects from the ITT population were analysed under the randomised treatment group.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	59	56
Mean (Standard Deviation) [Number of events per day]	1.56 (1.83)	1.35 (1.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lanreotide Autogel (Somatuline Depot) 120 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2544
	Comments
	Method	ANCOVA
	Comments	ANCOVA included treatment group and 2 stratification variables at randomisation as factors and average frequency of diarrhoea per day during Screening

3. Secondary Outcome

Title	Average Frequency of Flushing Events (Per Day) Based on Subject Diary Records.
Time Frame	16-week DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group). Subjects from the ITT population were analysed under the randomised treatment group.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	59	56
Mean (Standard Deviation) [Number of events per day]	0.92 (1.45)	1.75 (2.26)

4. Secondary Outcome

Title	Percentage of Days of Use of Other Rescue Medication
Description	Usage of other concomitant rescue medications for diarrhoea and/or flushing events, measured as the percentage of days that the medications were used as rescue medication based on subject IVRS/IWRS diary records. Subjects were required to record the use and dose of s.c. octreotide, if any, as well as the use of other concomitant rescue medications (e.g. loperamide 2 mg tabs, and/or tincture of opium).
Time Frame	16-week DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group). Subjects from the ITT population were analysed under the randomised treatment group.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	59	56
Mean (Standard Deviation) [Percentage of days]	8.86 (19.34)	6.25 (17.48)

5. Secondary Outcome

Title	Proportion of Subjects Who Rolled Over Into the IOL Phase Before Completing the DB Phase of the Study
Description	Subjects who rolled over early were those who received less than four DB injections before receiving the first IOL injection.
Time Frame	16-week DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group). Subjects from the ITT population were analysed under the randomised treatment group.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	59	56
Number [Percentage of subjects]	18.6	21.4

6. Secondary Outcome

Title	Changes From Baseline in "Global Health Status/Quality of Life (QoL)" Score (Based on Items 29 and 30 of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ] C30)
Description	Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment. Q29 and Q30 range from 1 (Very poor) to 7 (Excellent) with 1 being worst case and 7 the most favourable answer. Scores were derived according to the rules contained within the EORTC scoring manual. All of the scores range in score from 0 to 100. A high score for global health status/QoL represents high QoL. The principle for scoring the scale is: Estimate the average of the items (I1, I2, ..., In) that contribute to the scale; this is the raw score. Raw score = RS = (I1 + I2 +…+ In)/n. For global health status/QoL: Score = {(RS - 1)/range} x 100, where range is the difference between the maximum possible value of RS and the minimum possible value of RS.
Time Frame	Baseline and Week 12 of DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group); n=number of subjects taken into account for the analysis. Only the observed data are used in the calculation. The missing data are excluded from the analysis.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	48	34
Mean (Standard Deviation) [Units on a scale]	4.17 (14.18)	-1.72 (18.21)

7. Secondary Outcome

Title	Changes From Baseline in "Gastrointestinal (G.I). Symptoms" Subscore (Based on Items Q34, Q35, Q36, Q37 and Q38 of EORTC G.I. Neuroendocrine Tumour [NET] 21]
Description	Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment. The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 to Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 to Q51 range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the scores were generated. All of the scores range in score from 0 to 100. A high score for a symptom scale represents a high level of symptomatology. The principle for scoring the scale is: Estimate the average of the items (I1, I2, ..., In) that contribute to the scale; this is the raw score. RS = (I1 + I2 +…+ In)/n. For symptom scales: Score = {(RS - 1)/range} x 100, where range is the difference between the maximum possible value of RS and the minimum possible value of RS.
Time Frame	Baseline and Week 12 of DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group); n=number of subjects taken into account for the analysis. Only the observed data are used in the calculation. The missing data are excluded from the analysis.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	48	33
Mean (Standard Deviation) [Units on a scale]	-4.06 (12.80)	0.10 (13.83)

8. Secondary Outcome

Title	Changes From Baseline in QoL in "Endocrine Symptoms" Subscore (Assessed Based on Items Q31, Q32 and Q33 Using EORTC QLQ-G.I.NET-21 Questionnaires)
Description	Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment. The QLQ-G.I.NET21 questionnaire contains 21 single items (Q31 to Q51) which are supplemental items to the EORTC QLQ-C30 questionnaire. Q31 to Q51 range from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). Based on these items the scores were generated. All of the scores range in score from 0 to 100. A high score for a symptom scale represents a high level of symptomatology. The principle for scoring the scale is: Estimate the average of the items (I1, I2, ..., In) that contribute to the scale; this is the raw score. RS = (I1 + I2 +…+ In)/n. For symptom scales: Score = {(RS - 1)/range} x 100, where range is the difference between the maximum possible value of RS and the minimum possible value of RS.
Time Frame	Baseline and Week 12 of DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group); n=number of subjects taken into account for the analysis. Only the observed data are used in the calculation. The missing data are excluded from the analysis.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	48	33
Mean (Standard Deviation) [Units on a scale]	-6.83 (18.98)	-2.69 (22.23)

9. Secondary Outcome

Title	Absolute Changes From Baseline in Biochemical Markers (Plasma Chromogranin A [CgA])
Description	Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment.
Time Frame	Baseline and Week 12 of DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group); n=number of subjects taken into account for the analysis. Only the observed data are used in the calculation. The missing data are excluded from the analysis.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	41	28
Mean (Standard Deviation) [μg/L]	1125.8 (12579.4)	801.5 (2294.0)

10. Secondary Outcome

Title	Absolute Changes From Baseline in Biochemical Markers (Urinary 5-hydroxyindoleacetic Acid [5-HIAA])
Description	Baseline is defined as the last non-missing observation obtained prior to the initiation of study treatment.
Time Frame	Baseline and Week 12 of DB phase

Outcome Measure Data

Analysis Population Description

ITT population: All randomised subjects (regardless of whether the subjects received or adhered to the allocated treatment group); n=number of subjects taken into account for the analysis. Only the observed data are used in the calculation. The missing data are excluded from the analysis.

Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg	Placebo
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase).	Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase).
Measure Participants	39	27
Mean (Standard Deviation) [μmol/day]	-201.4 (1009.9)	36.3 (142.3)

Adverse Events

Time Frame	Adverse events (AEs) were collected from the time the subject signed informed consent to the exit visit (up to 16 weeks of DB phase, 32 weeks of IOL phase and every 4 subsequent weeks in the LTOLE phase until at least 2 years after the last subject completed the IOL phase or when marketing approval for the treatment of symptoms of carcinoid syndrome was obtained [whichever occurred first]).
Adverse Event Reporting Description	Safety population: All randomised subjects who received at least 1 injection of study treatment; subjects were analysed under the actual treatment received. For placebo group (DB phase) n=57 as 1 subject was randomised to lanreotide Autogel but erroneously received placebo. Treatment-emergent AEs (TEAEs) reported in the IOL or LTOLE phases are AEs that were either not present or were of moderate or severe intensity prior to the first dose of lanreotide Autogel during that phase.
Arm/Group Title	Lanreotide Autogel (Somatuline Depot) 120 mg (DB Phase)		Placebo (DB Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (IOL Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (LTOLE Phase)
Arm/Group Description	Deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (±3 days) for 16 weeks (DB phase). Subjects then received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks in the IOL phase and further deep s.c. injections with lanreotide Autogel every 4 weeks in the LTOLE phase.		Deep s.c. injections of placebo every 4 weeks (±3 days) for 16 weeks (DB phase). Subjects then received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks in the IOL phase and further deep s.c. injections with lanreotide Autogel every 4 weeks in the LTOLE phase.		All 101 subjects in the IOL phase received deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks for 32 weeks (56 and 45 of these subjects received treatment with lanreotide Autogel and placebo, respectively, during the DB phase).		All 57 subjects in the LTOLE phase received further deep s.c. injections of lanreotide Autogel 120 mg every 4 weeks (32 and 25 of these subjects received treatment with lanreotide Autogel and placebo, respectively, during the DB phase).
All Cause Mortality
	Lanreotide Autogel (Somatuline Depot) 120 mg (DB Phase)		Placebo (DB Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (IOL Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (LTOLE Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lanreotide Autogel (Somatuline Depot) 120 mg (DB Phase)		Placebo (DB Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (IOL Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (LTOLE Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/58 (3.4%)		5/57 (8.8%)		8/101 (7.9%)		15/57 (26.3%)
Cardiac disorders
Pericardial effusion	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	3	0/57 (0%)	0
Ear and labyrinth disorders
Deafness permanent	1/58 (1.7%)	1	0/57 (0%)	0	0/101 (0%)	0	0/57 (0%)	0
Gastrointestinal disorders
Small intestinal obstruction	1/58 (1.7%)	3	0/57 (0%)	0	3/101 (3%)	4	0/57 (0%)	0
Vomiting	0/58 (0%)	0	1/57 (1.8%)	2	0/101 (0%)	0	1/57 (1.8%)	1
Abdominal pain	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	1/57 (1.8%)	1
Diarrhoea	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	0/57 (0%)	0
Intestinal obstruction	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	0/57 (0%)	0
Subileus	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
General disorders
Disease progression	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Death	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
General physical health deterioration	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Pyrexia	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Infections and infestations
Urinary tract infection	1/58 (1.7%)	1	1/57 (1.8%)	1	0/101 (0%)	0	1/57 (1.8%)	1
Kidney infection	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	1/57 (1.8%)	1
Lower respiratory tract infection	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Urosepsis	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	1/57 (1.8%)	1
Sepsis	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	2/57 (3.5%)	2
Pyelonephritis	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Pyelonephritis acute	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Infection	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Injury, poisoning and procedural complications
Femur fracture	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Patella fracture	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Metabolism and nutrition disorders
Hyperglycaemia	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Glucose tolerance impaired	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	2
Musculoskeletal and connective tissue disorders
Back pain	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	0/57 (0%)	0
Pain in extremity	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	1/58 (1.7%)	1	0/57 (0%)	0	0/101 (0%)	0	0/57 (0%)	0
Metastases to central nervous system	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	0/57 (0%)	0
Metastases to liver	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Metastases to pleura	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Metastases to spine	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Tumour necrosis	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	2
Malignant neoplasm progression	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	2/57 (3.5%)	2
Pancreatic carcinoma	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Nervous system disorders
Cerebral ischaemia	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	0/57 (0%)	0
Hydrocephalus	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	0/57 (0%)	0
Dizziness	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Sciatica	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Syncope	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Psychiatric disorders
Mental status changes	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Renal and urinary disorders
Ureteric stenosis	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	1/57 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	0/57 (0%)	0
Pneumonia aspiration	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Pneumothorax	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	1/57 (1.8%)	1
Other (Not Including Serious) Adverse Events
	Lanreotide Autogel (Somatuline Depot) 120 mg (DB Phase)		Placebo (DB Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (IOL Phase)		Lanreotide Autogel (Somatuline Depot) 120 mg (LTOLE Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/58 (53.4%)		34/57 (59.6%)		71/101 (70.3%)		46/57 (80.7%)
Blood and lymphatic system disorders
Anaemia	0/58 (0%)	0	0/57 (0%)	0	4/101 (4%)	4	6/57 (10.5%)	7
Gastrointestinal disorders
Nausea	5/58 (8.6%)	5	5/57 (8.8%)	5	8/101 (7.9%)	9	4/57 (7%)	5
Vomiting	4/58 (6.9%)	6	2/57 (3.5%)	2	6/101 (5.9%)	6	5/57 (8.8%)	8
Abdominal pain	5/58 (8.6%)	5	7/57 (12.3%)	7	11/101 (10.9%)	14	13/57 (22.8%)	25
Abdominal pain upper	1/58 (1.7%)	1	1/57 (1.8%)	1	4/101 (4%)	4	7/57 (12.3%)	9
Constipation	2/58 (3.4%)	2	2/57 (3.5%)	2	4/101 (4%)	5	5/57 (8.8%)	5
Diarrhoea	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	8/57 (14%)	10
Flatulence	3/58 (5.2%)	3	1/57 (1.8%)	2	3/101 (3%)	3	0/57 (0%)	0
General disorders
Fatigue	2/58 (3.4%)	2	4/57 (7%)	4	10/101 (9.9%)	10	9/57 (15.8%)	14
Oedema peripheral	0/58 (0%)	0	3/57 (5.3%)	3	3/101 (3%)	3	3/57 (5.3%)	3
Pyrexia	1/58 (1.7%)	1	1/57 (1.8%)	1	1/101 (1%)	1	5/57 (8.8%)	6
Influenza like illness	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	3/57 (5.3%)	4
Disease progression	0/58 (0%)	0	0/57 (0%)	0	0/101 (0%)	0	5/57 (8.8%)	5
Asthenia	2/58 (3.4%)	2	1/57 (1.8%)	1	2/101 (2%)	2	6/57 (10.5%)	9
Hepatobiliary disorders
Cholelithiasis	0/58 (0%)	0	1/57 (1.8%)	1	5/101 (5%)	5	4/57 (7%)	5
Infections and infestations
Nasopharyngitis	2/58 (3.4%)	2	2/57 (3.5%)	2	1/101 (1%)	1	7/57 (12.3%)	7
Upper respiratory tract infection	0/58 (0%)	0	2/57 (3.5%)	2	3/101 (3%)	3	3/57 (5.3%)	3
Investigations
Weight decreased	1/58 (1.7%)	1	0/57 (0%)	0	9/101 (8.9%)	9	0/57 (0%)	0
Blood creatine phosphokinase increased	0/58 (0%)	0	1/57 (1.8%)	1	2/101 (2%)	2	3/57 (5.3%)	3
Blood triglycerides increased	0/58 (0%)	0	0/57 (0%)	0	2/101 (2%)	2	4/57 (7%)	5
Gamma-glutamyltransferase increased	0/58 (0%)	0	0/57 (0%)	0	2/101 (2%)	2	5/57 (8.8%)	12
Aspartate aminotransferase increased	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	3/57 (5.3%)	4
Metabolism and nutrition disorders
Hypoglycaemia	2/58 (3.4%)	2	1/57 (1.8%)	1	0/101 (0%)	0	3/57 (5.3%)	7
Decreased appetite	1/58 (1.7%)	1	1/57 (1.8%)	1	7/101 (6.9%)	8	5/57 (8.8%)	5
Hypertriglyceridaemia	1/58 (1.7%)	1	1/57 (1.8%)	1	2/101 (2%)	2	3/57 (5.3%)	4
Gout	0/58 (0%)	0	1/57 (1.8%)	1	0/101 (0%)	0	3/57 (5.3%)	4
Hyperglycaemia	0/58 (0%)	0	1/57 (1.8%)	1	4/101 (4%)	9	7/57 (12.3%)	12
Musculoskeletal and connective tissue disorders
Muscle spasms	3/58 (5.2%)	3	0/57 (0%)	0	6/101 (5.9%)	6	1/57 (1.8%)	1
Back pain	1/58 (1.7%)	1	4/57 (7%)	4	5/101 (5%)	5	8/57 (14%)	10
Arthralgia	0/58 (0%)	0	1/57 (1.8%)	1	7/101 (6.9%)	8	6/57 (10.5%)	9
Musculoskeletal pain	0/58 (0%)	0	1/57 (1.8%)	1	1/101 (1%)	1	4/57 (7%)	4
Pain in extremity	0/58 (0%)	0	1/57 (1.8%)	1	3/101 (3%)	3	4/57 (7%)	4
Intervertebral disc protrusion	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	3/57 (5.3%)	3
Nervous system disorders
Headache	7/58 (12.1%)	7	3/57 (5.3%)	3	10/101 (9.9%)	15	5/57 (8.8%)	7
Dizziness	4/58 (6.9%)	4	0/57 (0%)	0	5/101 (5%)	5	2/57 (3.5%)	2
Psychiatric disorders
Anxiety	0/58 (0%)	0	1/57 (1.8%)	1	3/101 (3%)	3	3/57 (5.3%)	3
Respiratory, thoracic and mediastinal disorders
Cough	2/58 (3.4%)	2	1/57 (1.8%)	1	3/101 (3%)	3	3/57 (5.3%)	3
Dyspnoea	0/58 (0%)	0	4/57 (7%)	4	6/101 (5.9%)	6	2/57 (3.5%)	2
Vascular disorders
Hypertension	0/58 (0%)	0	1/57 (1.8%)	1	9/101 (8.9%)	10	5/57 (8.8%)	5
Flushing	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	3/57 (5.3%)	3
Hot flush	0/58 (0%)	0	0/57 (0%)	0	1/101 (1%)	1	3/57 (5.3%)	3

Limitations/Caveats

None specified.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

With permission from the Sponsor, each investigator may have published or reported data from their own subjects. The study data in aggregate are the property of the Sponsor and may not be published without permission of the Sponsor. The Sponsor is the final arbitrator of issues relating to the publication or presentation of the aggregate data.