ASSERT: Assessment Study of Steroid Effect in Relapsing Multiple Sclerosis Subjects Treated With Glatiramer Acetate

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00203047
• Collaborator: (none)
• Enrollment: 414
• Arms: 2
• Duration (Months): 51.9

Study Details

Study Description

Brief Summary

This is a study evaluating the effect on brain volume of daily glatiramer acetate (GA) and add-on pulse steroids.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Remitting Multiple Sclerosis	Drug: Glatiramer Acetate; Drug: Placebo; Drug: Prednisone	Phase 4

Detailed Description

One interim analysis was planned for possible early termination due to proven efficacy when 75% of the preplanned 500 (approx. 375 patients) recruited patients completed the entire study duration or early discontinued.

In addition to the stopping rule already given for proven efficacy, the sponsor was also interested in examining the data for futility (i.e., absence of the desired treatment effect) with the view to terminating the trial if an "insufficient" effect of the treatment is seen.

The reasons why the need for futility arose were:

1. Recruitment difficulties

2. Increasing dropout rate

3. Budgetary constraints

The primary efficacy measure is defined as the percent change from baseline to termination (Month 36 or Early Termination) in normalized brain volume (Brain Atrophy) measured according to the SIENA (Structural Imaging Evaluation using Normalization of Atrophy) method. However, since not many patients had completed the entire study at the time of futility analysis, it was the sponsor's decision that the futility analysis be performed on patients with MRI scans at months 24 or 36 or at early termination visits - the latest available.

Based on the recalculation of study power (probability is unconditioned on the interim result and provide the real power of the study if designed anew), conditional power (based on the interim results) and risk assessment of a false negative, the Data Monitoring Committee agreed that the study should be terminated early.

Study Design

• Study Type: Interventional
• Actual Enrollment: 414 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-Centered, Randomized, Double-Blind, Placebo Controlled Study Assessing the Add-on Effect of Oral Steroids in Relapsing Remitting Multiple Sclerosis Subjects Treated With Glatiramer Acetate (GA)
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: GA + Placebo Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Drug: Glatiramer Acetate; 20mg glatiramer acetate (GA) administered by daily subcutaneous injections; Other Names: Copaxone ; Drug: Placebo; Placebo for prednisone given daily
Experimental: GA + Prednisone Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.	Drug: Glatiramer Acetate; 20mg glatiramer acetate (GA) administered by daily subcutaneous injections; Other Names: Copaxone ; Drug: Prednisone; Prednisone 1250 mg taken daily; Other Names: corticosteroid

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method [Day 0, latest scan at month 24, 36 or early termination visit]

   Results represent the database as of January 29, 2009. Brain volume was measured at baseline and at months 24, 36 and at early termination visits by magnetic resonance imaging (MRI). Brain atrophy was measured by comparing the change in brain volume from baseline to the latest scan at the three during study timeframes. SIENA is a fully automated method of analyzing longitudinal brain change. Adjusted (least square) mean values are presented.

Secondary Outcome Measures

1. Cumulative Number of Enhancing Lesions at Months 12, 24 and 36 [Months 12, 24, and 36]

   Results represent the database as of January 29, 2009. Enhancing lesions are lesions that show inflammation on an MRI and are assumed to be new lesions. The sum of enhancing lesions observed in MRIs taken at months 12, 24 and 36 are offered.

2. Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions [Day 0, Month 36 or the early termination visit]

   Results represent the database as of January 29, 2009. The difference in T2 brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. T2 lesions are hyperintense lesions meaning that they appear as bright spots on the MRI image. These tend to show the total number of lesions and disease burden.

3. Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions [Day 0, Month 36 or early termination visit]

   Results represent the database as of January 29, 2009. The difference in hypointense brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. Hypointense lesions display as dark areas on the MRI image, and represent areas of permanent axonal damage.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Clinically definite multiple sclerosis (CDMS) according to Poser (Ann. Neurol. 1983) or McDonald (Ann. Neurol. 2001)

2. Subjects eligible for GA treatment based on the investigator's clinical assessment and according to the current indication.

3. Subjects must have a relapsing remitting disease course.

4. Subjects must have had at least 1 documented relapse within the last year prior to study entry.

5. Subjects may be male or female. Women of childbearing potential must practice an acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, double-barrier method (condom or intrauterine device [IUD] with spermicide), or partner's vasectomy.

6. Subjects must be between the ages of 18 and 55 years inclusive.

7. Subjects must be ambulatory, with a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0 inclusive.

8. Subjects must be willing and able to give written informed consent prior to entering the study.

Exclusion Criteria:

1. Long-term glatiramer acetate users who have been on therapy within 6 months of the baseline magnetic resonance imaging (MRI). New glatiramer acetate users who have initiated therapy for more than 6 weeks prior to the baseline MRI.

2. Previous use of cladribine.

3. Previous use of mitoxantrone.

4. Use of digitalis at study entry.

5. Previous use of immunosuppressive agents (such as azathioprine, cyclophosphamide or mycophenolate mofetil) in the last 6 months prior to screening.

6. Use of experimental or investigational drugs, including intravenous (IV) immunoglobulin within 6 months prior to screening.

7. Use of interferon agents within 1 month prior to the baseline MRI.

8. Use of corticosteroids (IV, intramuscular [IM] and/or by mouth [PO]) within 30 days prior to the baseline MRI.

9. Chronic corticosteroid (IV, IM and/or PO) treatment (more than 30 consecutive days) in the 6 months prior to the screening visit.

10. Subjects with diabetes.

11. Previous total body irradiation or total lymphoid irradiation.

12. Pregnancy or breast feeding.

13. Significant medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or any condition which the investigator feels may interfere with participation in the study (e.g. alcohol or drug abuse).

14. Other diseases that can cause brain atrophy (ex. neurodegenerative disorder, cerebrovascular disease, history of alcohol abuse).

15. Bone density less than -2.5 standard deviations (SD) (osteoporosis).

16. A known history of sensitivity to mannitol.

17. Contraindication to, or known history of, sensitivity or severe reaction to steroids.

18. A known history of sensitivity to gadolinium.

19. Inability to successfully undergo MRI scanning.

20. Previous use of natalizumab.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Chair: Jean-Louis Stril, MD, Teva Neuroscience Canada

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT00203047
• Other Study ID Numbers: TNC GA MS 2004_01
• First Posted: Sep 20, 2005
• Last Update Posted: Jan 6, 2014
• Last Verified: Nov 1, 2013

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Multiple Sclerosis; brain atrophy; Glatiramer Acetate; Copaxone; Steroids; Prednisone
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Prednisone; Glatiramer Acetate; (T,G)-A-L

Study Results

Participant Flow

Arm/Group Title	GA + Placebo	GA + Prednisone
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.
Period Title: Overall Study
STARTED	204	210
In Database as of January 29, 2009	199	209
COMPLETED	13	7
NOT COMPLETED	191	203

Baseline Characteristics

Arm/Group Title	GA + Placebo	GA + Prednisone	Total
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.	Total of all reporting groups
Overall Participants	199	209	408
Age, Customized (participants) [Number]
<=29 years	32 16.1%	40 19.1%	72 17.6%
=30 and < 40 years	61 30.7%	68 32.5%	129 31.6%
=40 and < 50 years	70 35.2%	70 33.5%	140 34.3%
=50 and < 55 years	35 17.6%	29 13.9%	64 15.7%
>= 55 years	1 0.5%	2 1%	3 0.7%
Sex: Female, Male (Count of Participants)
Female	151 75.9%	157 75.1%	308 75.5%
Male	48 24.1%	52 24.9%	100 24.5%
Race/Ethnicity, Customized (participants) [Number]
Hispanic	10 5%	9 4.3%	19 4.7%
Asian / Oriental	1 0.5%	0 0%	1 0.2%
Black of African Heritage	13 6.5%	15 7.2%	28 6.9%
Caucasian	171 85.9%	179 85.6%	350 85.8%
Other	4 2%	6 2.9%	10 2.5%
Region of Enrollment (participants) [Number]
Australia	4 2%	1 0.5%	5 1.2%
Canada	16 8%	20 9.6%	36 8.8%
United States	179 89.9%	188 90%	367 90%
Time from First Multiple Sclerosis (MS) Symptom (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	89.8 (104.5)	76.7 (75.5)	83.1 (91.0)
Time from MS Diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	40.5 (71.4)	42.1 (62.9)	41.3 (67.1)
T1 Enhancing Lesions at Baseline (lesions) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [lesions]	1.05 (2.77)	1.86 (9.91)	1.43 (7.12)
T1 Hypointense Lesions Volume at Baseline (cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm^3]	0.94 (1.77)	0.84 (1.50)	0.89 (1.64)
T2 Lesions Volume at Baseline (cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm^3]	5.51 (7.17)	5.35 (7.97)	5.44 (7.55)

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method
Description	Results represent the database as of January 29, 2009. Brain volume was measured at baseline and at months 24, 36 and at early termination visits by magnetic resonance imaging (MRI). Brain atrophy was measured by comparing the change in brain volume from baseline to the latest scan at the three during study timeframes. SIENA is a fully automated method of analyzing longitudinal brain change. Adjusted (least square) mean values are presented.
Time Frame	Day 0, latest scan at month 24, 36 or early termination visit

Outcome Measure Data

Analysis Population Description

Treated population of participants who had both a baseline MRI and an MRI at least one of the three during study time frames. The latest MRI was used if more than one during study MRI was available.

Arm/Group Title	GA + Placebo	GA + Prednisone
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.
Measure Participants	105	84
Least Squares Mean (Standard Error) [percent change of baseline brain volume]	-0.46 (0.088)	-0.43 (0.106)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GA + Placebo, GA + Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8023
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11820976
	Estimation Comments

2. Secondary Outcome

Title	Cumulative Number of Enhancing Lesions at Months 12, 24 and 36
Description	Results represent the database as of January 29, 2009. Enhancing lesions are lesions that show inflammation on an MRI and are assumed to be new lesions. The sum of enhancing lesions observed in MRIs taken at months 12, 24 and 36 are offered.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

Treated population who had at least a 12 month MRI

Arm/Group Title	GA + Placebo	GA + Prednisone
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.
Measure Participants	155	143
Mean (Standard Deviation) [lesions]	0.69 (3.28)	0.76 (1.86)

3. Secondary Outcome

Title	Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions
Description	Results represent the database as of January 29, 2009. The difference in T2 brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. T2 lesions are hyperintense lesions meaning that they appear as bright spots on the MRI image. These tend to show the total number of lesions and disease burden.
Time Frame	Day 0, Month 36 or the early termination visit

Outcome Measure Data

Analysis Population Description

Treated population of participants with an MRI at the stated time frames.

Arm/Group Title	GA + Placebo	GA + Prednisone
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.
Measure Participants	58	51
Mean (Standard Deviation) [cm^3]	0.07 (3.21)	0.09 (2.93)

4. Secondary Outcome

Title	Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions
Description	Results represent the database as of January 29, 2009. The difference in hypointense brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. Hypointense lesions display as dark areas on the MRI image, and represent areas of permanent axonal damage.
Time Frame	Day 0, Month 36 or early termination visit

Outcome Measure Data

Analysis Population Description

Treated population of participants with an MRI at the stated time frames.

Arm/Group Title	GA + Placebo	GA + Prednisone
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.
Measure Participants	58	51
Mean (Standard Deviation) [cm^3]	0.43 (1.60)	0.17 (0.86)

Adverse Events

Time Frame	Day 1 through month 36
Arm/Group Title	GA + Placebo		GA + Prednisone
Arm/Group Description	Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.		Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.
All Cause Mortality
	GA + Placebo		GA + Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	GA + Placebo		GA + Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/199 (8%)		13/209 (6.2%)
Cardiac disorders
Myocardial infarction	1/199 (0.5%)		0/209 (0%)
Pericarditis	0/199 (0%)		1/209 (0.5%)
Ear and labyrinth disorders
Vertigo	0/199 (0%)		1/209 (0.5%)
Endocrine disorders
Autoimmune thyroiditis	1/199 (0.5%)		0/209 (0%)
Eye disorders
Blindness	1/199 (0.5%)		1/209 (0.5%)
Gastrointestinal disorders
Constipation	0/199 (0%)		1/209 (0.5%)
Nausea	0/199 (0%)		1/209 (0.5%)
Vomiting	0/199 (0%)		1/209 (0.5%)
General disorders
Death	0/199 (0%)		1/209 (0.5%)
Pyrexia	0/199 (0%)		2/209 (1%)
Chest pain	1/199 (0.5%)		1/209 (0.5%)
Hepatobiliary disorders
Cholecystitis	0/199 (0%)		1/209 (0.5%)
Immune system disorders
Anaphylactic reaction	0/199 (0%)		1/209 (0.5%)
Infections and infestations
Cellulitis	1/199 (0.5%)		0/209 (0%)
Mastoiditis	1/199 (0.5%)		0/209 (0%)
Otitis media	1/199 (0.5%)		0/209 (0%)
Influenza	0/199 (0%)		1/209 (0.5%)
Urosepsis	0/199 (0%)		1/209 (0.5%)
Staphylococcal infection	1/199 (0.5%)		0/209 (0%)
Urinary tract infection	0/199 (0%)		1/209 (0.5%)
Injury, poisoning and procedural complications
Brain contusion	1/199 (0.5%)		0/209 (0%)
Closed head injury	0/199 (0%)		1/209 (0.5%)
Subdural haematoma	1/199 (0.5%)		0/209 (0%)
Drug toxicity	0/199 (0%)		1/209 (0.5%)
Investigations
Heart rate increased	0/199 (0%)		1/209 (0.5%)
Metabolism and nutrition disorders
Dehydration	0/199 (0%)		2/209 (1%)
Musculoskeletal and connective tissue disorders
Muscle twitching	0/199 (0%)		1/209 (0.5%)
Muscular weakness	0/199 (0%)		1/209 (0.5%)
Musculoskeletal chest pain	0/199 (0%)		1/209 (0.5%)
Pain in extremity	1/199 (0.5%)		0/209 (0%)
Sensation of heaviness	0/199 (0%)		1/209 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/199 (0.5%)		0/209 (0%)
Breast cancer in situ	1/199 (0.5%)		0/209 (0%)
Lymphoma	1/199 (0.5%)		0/209 (0%)
Nervous system disorders
Aphasia	1/199 (0.5%)		0/209 (0%)
Syncope	0/199 (0%)		1/209 (0.5%)
Grand mal convulsion	1/199 (0.5%)		0/209 (0%)
Headache	0/199 (0%)		2/209 (1%)
Multiple sclerosis	2/199 (1%)		0/209 (0%)
Hypoaesthesia	0/199 (0%)		1/209 (0.5%)
Convulsion	0/199 (0%)		1/209 (0.5%)
Dysarthria	0/199 (0%)		1/209 (0.5%)
Tremor	0/199 (0%)		1/209 (0.5%)
Psychiatric disorders
Suicidal ideation	1/199 (0.5%)		1/209 (0.5%)
Renal and urinary disorders
Nephrolithiasis	1/199 (0.5%)		0/209 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/199 (0%)		1/209 (0.5%)
Other (Not Including Serious) Adverse Events
	GA + Placebo		GA + Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	131/199 (65.8%)		151/209 (72.2%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/199 (0.5%)		0/209 (0%)
Anaemia	2/199 (1%)		1/209 (0.5%)
Lymphadenopathy	1/199 (0.5%)		0/209 (0%)
Cardiac disorders
Palpitations	1/199 (0.5%)		5/209 (2.4%)
Tachycardia	0/199 (0%)		6/209 (2.9%)
Arrhythmia supraventricular	0/199 (0%)		1/209 (0.5%)
Congenital, familial and genetic disorders
Colour blindness	0/199 (0%)		1/209 (0.5%)
Ear and labyrinth disorders
Ear pain	0/199 (0%)		1/209 (0.5%)
Hearing impaired	0/199 (0%)		1/209 (0.5%)
Vestibular disorder	1/199 (0.5%)		0/209 (0%)
Motion sickness	0/199 (0%)		1/209 (0.5%)
Tinnitis	0/199 (0%)		1/209 (0.5%)
Vertigo	2/199 (1%)		2/209 (1%)
Vertigo positional	1/199 (0.5%)		0/209 (0%)
Tympanic membrane perforation	0/199 (0%)		1/209 (0.5%)
Endocrine disorders
Hyperparathyroidism	0/199 (0%)		1/209 (0.5%)
Goitre	0/199 (0%)		1/209 (0.5%)
Thyroid disorder	0/199 (0%)		1/209 (0.5%)
Hyperthyroidism	1/199 (0.5%)		0/209 (0%)
Hypothyroidism	1/199 (0.5%)		0/209 (0%)
Eye disorders
Blindness	1/199 (0.5%)		0/209 (0%)
Cataract	1/199 (0.5%)		1/209 (0.5%)
Conjunctivitis	0/199 (0%)		2/209 (1%)
Dry eye	2/199 (1%)		1/209 (0.5%)
Lacrimation increased	1/199 (0.5%)		1/209 (0.5%)
Madarosis	0/199 (0%)		1/209 (0.5%)
Eye pain	0/199 (0%)		4/209 (1.9%)
Eye allergy	0/199 (0%)		1/209 (0.5%)
Eye irritation	1/199 (0.5%)		0/209 (0%)
Ocular hyperaemia	2/199 (1%)		0/209 (0%)
Asthenopia	1/199 (0.5%)		0/209 (0%)
Optic atrophy	1/199 (0.5%)		0/209 (0%)
Visual acuity reduced	0/199 (0%)		1/209 (0.5%)
Pupillary reflex impaired	0/199 (0%)		1/209 (0.5%)
Macular cyst	1/199 (0.5%)		0/209 (0%)
Diplopia	0/199 (0%)		1/209 (0.5%)
Vision blurred	1/199 (0.5%)		9/209 (4.3%)
Visual disturbance	0/199 (0%)		3/209 (1.4%)
Gastrointestinal disorders
Abdominal hernia	2/199 (1%)		0/209 (0%)
Toothache	2/199 (1%)		3/209 (1.4%)
Hiatus hernia	1/199 (0.5%)		0/209 (0%)
Diarrhoea	8/199 (4%)		14/209 (6.7%)
Dyspepsia	5/199 (2.5%)		16/209 (7.7%)
Epigastic discomfort	0/199 (0%)		2/209 (1%)
Eructation	0/199 (0%)		1/209 (0.5%)
Abdominal distension	0/199 (0%)		2/209 (1%)
Flatulence	0/199 (0%)		1/209 (0.5%)
Gastritis	2/199 (1%)		5/209 (2.4%)
Abdominal pain	3/199 (1.5%)		5/209 (2.4%)
Abdominal pain upper	2/199 (1%)		7/209 (3.3%)
Constipation	1/199 (0.5%)		3/209 (1.4%)
Gastrooesophageal reflux disease	2/199 (1%)		6/209 (2.9%)
Enteritis	1/199 (0.5%)		0/209 (0%)
Abdominal discomfort	1/199 (0.5%)		2/209 (1%)
Breath odour	0/199 (0%)		1/209 (0.5%)
Dysphagia	2/199 (1%)		3/209 (1.4%)
Faecal incontinence	1/199 (0.5%)		0/209 (0%)
Stomach discomfort	0/199 (0%)		1/209 (0.5%)
Gingivitis	1/199 (0.5%)		0/209 (0%)
Haemorrhoids	1/199 (0.5%)		2/209 (1%)
Nausea	15/199 (7.5%)		15/209 (7.2%)
Vomiting	6/199 (3%)		7/209 (3.3%)
Haematochezia	1/199 (0.5%)		0/209 (0%)
Reflux oesophagitis	0/199 (0%)		1/209 (0.5%)
Dry mouth	0/199 (0%)		2/209 (1%)
Hypoaesthesia oral	2/199 (1%)		0/209 (0%)
Peritoneal lesion	0/199 (0%)		1/209 (0.5%)
Mouth ulceration	0/199 (0%)		1/209 (0.5%)
Stomatitis	1/199 (0.5%)		1/209 (0.5%)
General disorders
Administration site reaction	0/199 (0%)		1/209 (0.5%)
Asthenia	1/199 (0.5%)		1/209 (0.5%)
Fatigue	13/199 (6.5%)		21/209 (10%)
Malaise	0/199 (0%)		6/209 (2.9%)
Chills	1/199 (0.5%)		5/209 (2.4%)
Peripheral coldness	1/199 (0.5%)		0/209 (0%)
Pyrexia	6/199 (3%)		5/209 (2.4%)
Gait disturbance	0/199 (0%)		2/209 (1%)
Chest discomfort	3/199 (1.5%)		5/209 (2.4%)
Energy increased	0/199 (0%)		1/209 (0.5%)
Feeling abnormal	0/199 (0%)		1/209 (0.5%)
Feeling jittery	1/199 (0.5%)		3/209 (1.4%)
Flushing	1/199 (0.5%)		1/209 (0.5%)
Hangover	0/199 (0%)		1/209 (0.5%)
Influenza like illness	0/199 (0%)		3/209 (1.4%)
Irritability	0/199 (0%)		2/209 (1%)
Swelling	0/199 (0%)		2/209 (1%)
Thirst	0/199 (0%)		1/209 (0.5%)
Inflammation	2/199 (1%)		0/209 (0%)
Infusion site reaction	1/199 (0.5%)		0/209 (0%)
Injection site bruising	1/199 (0.5%)		3/209 (1.4%)
Injection site erythema	9/199 (4.5%)		3/209 (1.4%)
Injection site haemorrhage	0/199 (0%)		1/209 (0.5%)
Injection site induration	3/199 (1.5%)		1/209 (0.5%)
Injection site mass	1/199 (0.5%)		0/209 (0%)
Injection site nodule	1/199 (0.5%)		0/209 (0%)
Injection site pain	3/199 (1.5%)		6/209 (2.9%)
Injection site pruritus	5/199 (2.5%)		3/209 (1.4%)
Injection site reaction	8/199 (4%)		8/209 (3.8%)
Injection site swelling	2/199 (1%)		0/209 (0%)
Injection site urticaria	1/199 (0.5%)		0/209 (0%)
Cyst	1/199 (0.5%)		0/209 (0%)
Face oedema	0/199 (0%)		4/209 (1.9%)
Generalised oedema	0/199 (0%)		1/209 (0.5%)
Oedema	0/199 (0%)		4/209 (1.9%)
Oedema peripheral	3/199 (1.5%)		5/209 (2.4%)
Chest pain	0/199 (0%)		5/209 (2.4%)
Non-cardiac chest pain	0/199 (0%)		1/209 (0.5%)
Pain	2/199 (1%)		12/209 (5.7%)
Adverse drug reaction	1/199 (0.5%)		2/209 (1%)
Idiosyncratic drug reaction	0/199 (0%)		1/209 (0.5%)
Hepatobiliary disorders
Cholelithiasis	0/199 (0%)		1/209 (0.5%)
Hepatic cirrhosis	0/199 (0%)		1/209 (0.5%)
Hepatic steatosis	0/199 (0%)		1/209 (0.5%)
Immune system disorders
Allergy to animal	0/199 (0%)		1/209 (0.5%)
Hypersensitivity	1/199 (0.5%)		1/209 (0.5%)
Drug hypersensitivity	1/199 (0.5%)		3/209 (1.4%)
Food allergy	1/199 (0.5%)		1/209 (0.5%)
Seasonal allergy	0/199 (0%)		3/209 (1.4%)
Infections and infestations
Gastric infection	0/199 (0%)		1/209 (0.5%)
Gastroenteritis	2/199 (1%)		1/209 (0.5%)
Bacteriuria	1/199 (0.5%)		0/209 (0%)
Cellulitis	0/199 (0%)		1/209 (0.5%)
Vaginitis bacterial	2/199 (1%)		0/209 (0%)
Candidiasis	0/199 (0%)		1/209 (0.5%)
Oral candidiasis	2/199 (1%)		3/209 (1.4%)
Coxsackie viral infection	0/199 (0%)		1/209 (0.5%)
Tooth abscess	3/199 (1.5%)		3/209 (1.4%)
Tooth infection	2/199 (1%)		2/209 (1%)
Ear infection	1/199 (0.5%)		0/209 (0%)
Otitis externa	0/199 (0%)		1/209 (0.5%)
Otitis media	1/199 (0.5%)		1/209 (0.5%)
Conjunctivitis infective	2/199 (1%)		0/209 (0%)
Eye infection	4/199 (2%)		2/209 (1%)
Vaginal infection	0/199 (0%)		2/209 (1%)
Fungal infection	2/199 (1%)		3/209 (1.4%)
Onychomycosis	2/199 (1%)		0/209 (0%)
Oral fungal infection	0/199 (0%)		1/209 (0.5%)
Vulvovaginal mycotic infection	0/199 (0%)		4/209 (1.9%)
Herpes simplex	3/199 (1.5%)		2/209 (1%)
Herpes simplex ophthalmic	1/199 (0.5%)		0/209 (0%)
Herpes virus infection	0/199 (0%)		1/209 (0.5%)
Herpes zoster	1/199 (0.5%)		1/209 (0.5%)
Localised infection	1/199 (0.5%)		0/209 (0%)
Influenza	5/199 (2.5%)		6/209 (2.9%)
Bronchitis	13/199 (6.5%)		5/209 (2.4%)
Bronchitis acute	1/199 (0.5%)		2/209 (1%)
Bronchitis chronic	0/199 (0%)		1/209 (0.5%)
Lower respiratory tract infection	2/199 (1%)		0/209 (0%)
Pneumonia	0/199 (0%)		1/209 (0.5%)
Mycoplasma infection	1/199 (0.5%)		0/209 (0%)
Eczema infected	1/199 (0.5%)		0/209 (0%)
Skin infection	1/199 (0.5%)		0/209 (0%)
Staphylococcal infection	0/199 (0%)		4/209 (1.9%)
Pharyngitis streptococcal	2/199 (1%)		1/209 (0.5%)
Tinea infection	0/199 (0%)		1/209 (0.5%)
Acute sinusitis	1/199 (0.5%)		0/209 (0%)
Chronic sinusitis	0/199 (0%)		1/209 (0.5%)
Nasopharyngitis	19/199 (9.5%)		22/209 (10.5%)
Pharyngitis	1/199 (0.5%)		0/209 (0%)
Sinusitis	10/199 (5%)		16/209 (7.7%)
Upper respiratory tract infection	12/199 (6%)		25/209 (12%)
Cystitis	0/199 (0%)		1/209 (0.5%)
Pyelonephritis	1/199 (0.5%)		0/209 (0%)
Urinary tract infection	15/199 (7.5%)		23/209 (11%)
Bronchitis viral	1/199 (0.5%)		1/209 (0.5%)
Gastroenteritis viral	3/199 (1.5%)		3/209 (1.4%)
Viral pharyngitis	0/199 (0%)		2/209 (1%)
Viral sinusitis	0/199 (0%)		1/209 (0.5%)
Injury, poisoning and procedural complications
Caustic injury	0/199 (0%)		1/209 (0.5%)
Joint dislocation	0/199 (0%)		1/209 (0.5%)
Injection site reaction	1/199 (0.5%)		0/209 (0%)
Injection site urticaria	1/199 (0.5%)		0/209 (0%)
Joint injury	0/199 (0%)		1/209 (0.5%)
Joint sprain	1/199 (0.5%)		5/209 (2.4%)
Rotator cuff syndrome	0/199 (0%)		1/209 (0.5%)
Ankle fracture	1/199 (0.5%)		0/209 (0%)
Foot fracture	1/199 (0.5%)		2/209 (1%)
Muscle strain	1/199 (0.5%)		2/209 (1%)
Arthropod bite	0/199 (0%)		1/209 (0.5%)
Excoriation	0/199 (0%)		1/209 (0.5%)
Fall	2/199 (1%)		7/209 (3.3%)
Accidental needle stick	1/199 (0.5%)		0/209 (0%)
Procedural pain	2/199 (1%)		0/209 (0%)
Back injury	0/199 (0%)		1/209 (0.5%)
Head injury	0/199 (0%)		1/209 (0.5%)
Tooth fracture	1/199 (0.5%)		1/209 (0.5%)
Contusion	3/199 (1.5%)		1/209 (0.5%)
Skin laceration	0/199 (0%)		2/209 (1%)
Rib fracture	0/199 (0%)		1/209 (0.5%)
Humerus fracture	1/199 (0.5%)		0/209 (0%)
Ulna fracture	1/199 (0.5%)		0/209 (0%)
Investigations
Blood glucose increased	1/199 (0.5%)		2/209 (1%)
Cardiac murmur	1/199 (0.5%)		0/209 (0%)
Blood cholesterol increased	4/199 (2%)		3/209 (1.4%)
Heart rate decreased	0/199 (0%)		1/209 (0.5%)
Heart rate increased	0/199 (0%)		1/209 (0.5%)
Alanine aminotransferase increased	1/199 (0.5%)		0/209 (0%)
Blood uric acid increased	1/199 (0.5%)		0/209 (0%)
Urine ketone body present	1/199 (0.5%)		0/209 (0%)
Blood potassium increased	1/199 (0.5%)		0/209 (0%)
Body temperature fluctuations	1/199 (0.5%)		0/209 (0%)
Breath sounds abnormal	1/199 (0.5%)		0/209 (0%)
Weight increased	3/199 (1.5%)		7/209 (3.3%)
Blood thyroid stimulating hormone decreased	1/199 (0.5%)		1/209 (0.5%)
Blood thyroid stimulating hormone increased	0/199 (0%)		2/209 (1%)
Protein total increased	1/199 (0.5%)		0/209 (0%)
Blood testosterone decreased	1/199 (0.5%)		0/209 (0%)
Blood triglycerides increased	0/199 (0%)		1/209 (0.5%)
Protein urine	1/199 (0.5%)		0/209 (0%)
Urine analysis abnormal	0/199 (0%)		1/209 (0.5%)
Urine leukocyte esterase positive	1/199 (0.5%)		0/209 (0%)
White blood cells urine positive	1/199 (0.5%)		1/209 (0.5%)
Blood pressure increased	0/199 (0%)		1/209 (0.5%)
Herpes simplex serology positive	1/199 (0.5%)		0/209 (0%)
Vitamin D decreased	0/199 (0%)		1/209 (0.5%)
White blood cell count increased	1/199 (0.5%)		1/209 (0.5%)
Metabolism and nutrition disorders
Anorexia	0/199 (0%)		1/209 (0.5%)
Appetite disorder	0/199 (0%)		1/209 (0.5%)
Decreased appetite	1/199 (0.5%)		3/209 (1.4%)
Increased appetite	1/199 (0.5%)		2/209 (1%)
Hypercalcaemia	0/199 (0%)		1/209 (0.5%)
Diabetes mellitus	0/199 (0%)		1/209 (0.5%)
Diabetes mellitus non-insulin-dependent	0/199 (0%)		1/209 (0.5%)
Hypercholesterolaemia	2/199 (1%)		2/209 (1%)
Vitamin D deficiency	1/199 (0.5%)		4/209 (1.9%)
Hyperglycaemia	1/199 (0.5%)		1/209 (0.5%)
Hyperlipidaemia	0/199 (0%)		1/209 (0.5%)
Dyslipidaemia	0/199 (0%)		1/209 (0.5%)
Hypokalaemia	1/199 (0.5%)		0/209 (0%)
Gout	1/199 (0.5%)		1/209 (0.5%)
Fluid retention	0/199 (0%)		6/209 (2.9%)
Oedema	0/199 (0%)		1/209 (0.5%)
Musculoskeletal and connective tissue disorders
Arthritis	1/199 (0.5%)		1/209 (0.5%)
Bone cyst	0/199 (0%)		1/209 (0.5%)
Osteonecrosis	1/199 (0.5%)		0/209 (0%)
Bone pain	1/199 (0.5%)		2/209 (1%)
Pain in jaw	0/199 (0%)		1/209 (0.5%)
Intervertebral disc protrusion	0/199 (0%)		1/209 (0.5%)
Joint contracture	1/199 (0.5%)		0/209 (0%)
Periarthritis	1/199 (0.5%)		0/209 (0%)
Arthralgia	8/199 (4%)		11/209 (5.3%)
Joint stiffness	0/199 (0%)		2/209 (1%)
Joint swelling	0/199 (0%)		2/209 (1%)
Loose body in joint	1/199 (0.5%)		0/209 (0%)
Plantar fasciitis	0/199 (0%)		1/209 (0.5%)
Osteopenia	0/199 (0%)		4/209 (1.9%)
Osteoporosis	1/199 (0.5%)		0/209 (0%)
Myalgia	2/199 (1%)		9/209 (4.3%)
Muscle spasms	9/199 (4.5%)		9/209 (4.3%)
Muscle tightness	0/199 (0%)		1/209 (0.5%)
Muscle twitching	2/199 (1%)		0/209 (0%)
Myokymia	0/199 (0%)		1/209 (0.5%)
Muscular weakness	2/199 (1%)		6/209 (2.9%)
Back pain	3/199 (1.5%)		4/209 (1.9%)
Dupuytren's contracture	1/199 (0.5%)		0/209 (0%)
Musculoskeletal chest pain	0/199 (0%)		2/209 (1%)
Musculoskeletal stiffness	2/199 (1%)		1/209 (0.5%)
Neck pain	4/199 (2%)		4/209 (1.9%)
Pain in extremity	7/199 (3.5%)		11/209 (5.3%)
Shoulder pain	2/199 (1%)		3/209 (1.4%)
Osteoarthritis	1/199 (0.5%)		0/209 (0%)
Axillary mass	0/199 (0%)		1/209 (0.5%)
Groin pain	0/199 (0%)		1/209 (0.5%)
Cervical spinal stenosis	1/199 (0.5%)		0/209 (0%)
Tendonitis	1/199 (0.5%)		3/209 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cyst	0/199 (0%)		2/209 (1%)
Teratoma	0/199 (0%)		1/209 (0.5%)
Lip neoplasm	1/199 (0.5%)		0/209 (0%)
Abdominal neoplasm	0/199 (0%)		1/209 (0.5%)
Ovarian cyst	0/199 (0%)		1/209 (0.5%)
Uterine leiomyoma	0/199 (0%)		1/209 (0.5%)
Nervous system disorders
Carotid artery aneurysm	0/199 (0%)		1/209 (0.5%)
Balance disorder	1/199 (0.5%)		4/209 (1.9%)
Coordination abnormal	0/199 (0%)		2/209 (1%)
Nystagmus	2/199 (1%)		1/209 (0.5%)
Lethargy	1/199 (0.5%)		1/209 (0.5%)
Loss of consciousness	2/199 (1%)		1/209 (0.5%)
Somnolence	2/199 (1%)		1/209 (0.5%)
Syncope vasovagal	0/199 (0%)		2/209 (1%)
Circadian rhythm sleep disorder	1/199 (0.5%)		0/209 (0%)
Hyperkinesia	0/199 (0%)		1/209 (0.5%)
Psychomotor hyperactivity	1/199 (0.5%)		2/209 (1%)
Headache	14/199 (7%)		31/209 (14.8%)
Sinus headache	1/199 (0.5%)		1/209 (0.5%)
Sciatica	0/199 (0%)		1/209 (0.5%)
Amnesia	1/199 (0.5%)		2/209 (1%)
Memory impairment	0/199 (0%)		1/209 (0.5%)
Cognitive disorder	0/199 (0%)		2/209 (1%)
Disturbance in attention	0/199 (0%)		6/209 (2.9%)
Migraine	6/199 (3%)		2/209 (1%)
Multiple sclerosis	2/199 (1%)		0/209 (0%)
Hypertonia	0/199 (0%)		1/209 (0.5%)
Dizziness	11/199 (5.5%)		12/209 (5.7%)
Myoclonus	2/199 (1%)		0/209 (0%)
Muscle spasticity	4/199 (2%)		1/209 (0.5%)
Optic neuritis	0/199 (0%)		1/209 (0.5%)
Burning sensation	1/199 (0.5%)		0/209 (0%)
Dysaesthesia	1/199 (0.5%)		1/209 (0.5%)
Hypoaesthesia	6/199 (3%)		7/209 (3.3%)
Hypoaesthesia oral	0/199 (0%)		1/209 (0.5%)
Lhermitte's sign	0/199 (0%)		1/209 (0.5%)
Paraesthesia	6/199 (3%)		9/209 (4.3%)
Diplegia	1/199 (0.5%)		0/209 (0%)
Hemiparesis	0/199 (0%)		1/209 (0.5%)
Convulsion	0/199 (0%)		2/209 (1%)
Dysgeusia	2/199 (1%)		6/209 (2.9%)
Loss of proprioception	0/199 (0%)		1/209 (0.5%)
Neuralgia	3/199 (1.5%)		0/209 (0%)
Restless leg syndrome	1/199 (0.5%)		1/209 (0.5%)
Sensory disturbance	0/199 (0%)		1/209 (0.5%)
Radicular pain	0/199 (0%)		1/209 (0.5%)
Tremor	5/199 (2.5%)		6/209 (2.9%)
Pregnancy, puerperium and perinatal conditions
Abortion	0/199 (0%)		1/209 (0.5%)
Unintended pregnancy	0/199 (0%)		1/209 (0.5%)
Pregnancy	1/199 (0.5%)		0/209 (0%)
Psychiatric disorders
Adjustment disorder with depressed mood	1/199 (0.5%)		0/209 (0%)
Affect lability	2/199 (1%)		4/209 (1.9%)
Agitation	0/199 (0%)		3/209 (1.4%)
Anxiety	4/199 (2%)		9/209 (4.3%)
Nervousness	0/199 (0%)		1/209 (0.5%)
Stress	1/199 (0.5%)		0/209 (0%)
Tension	0/199 (0%)		1/209 (0.5%)
Attention deficit/hyperactivity disorder	0/199 (0%)		1/209 (0.5%)
Aggression	0/199 (0%)		1/209 (0.5%)
Irritability	1/199 (0.5%)		0/209 (0%)
Disorientation	1/199 (0.5%)		0/209 (0%)
Depression	10/199 (5%)		9/209 (4.3%)
Insomnia	22/199 (11.1%)		44/209 (21.1%)
Anger	0/199 (0%)		1/209 (0.5%)
Mood altered	0/199 (0%)		3/209 (1.4%)
Mood swings	1/199 (0.5%)		3/209 (1.4%)
Restlessness	0/199 (0%)		2/209 (1%)
Depressed mood	2/199 (1%)		2/209 (1%)
Panic disorder	0/199 (0%)		1/209 (0.5%)
Panic attack	0/199 (0%)		2/209 (1%)
Abnormal dreams	1/199 (0.5%)		0/209 (0%)
Nightmare	0/199 (0%)		2/209 (1%)
Illusion	0/199 (0%)		1/209 (0.5%)
Claustrophobia	1/199 (0.5%)		0/209 (0%)
Speech disorder	0/199 (0%)		1/209 (0.5%)
Bruxism	0/199 (0%)		1/209 (0.5%)
Suicidal ideation	0/199 (0%)		3/209 (1.4%)
Renal and urinary disorders
Dysuria	1/199 (0.5%)		1/209 (0.5%)
Micturition urgency	1/199 (0.5%)		1/209 (0.5%)
Pollakiuria	1/199 (0.5%)		6/209 (2.9%)
Stress incontinence	0/199 (0%)		1/209 (0.5%)
Urinary incontinence	2/199 (1%)		1/209 (0.5%)
Urinary retention	2/199 (1%)		2/209 (1%)
Neurogenic bladder	1/199 (0.5%)		0/209 (0%)
Nephrolithiasis	1/199 (0.5%)		1/209 (0.5%)
Haematuria	2/199 (1%)		1/209 (0.5%)
Proteinuria	1/199 (0.5%)		0/209 (0%)
Nocturia	0/199 (0%)		1/209 (0.5%)
Reproductive system and breast disorders
Breast disorder	1/199 (0.5%)		0/209 (0%)
Breast pain	0/199 (0%)		1/209 (0.5%)
Erectile dysfunction	0/199 (0%)		1/209 (0.5%)
Hot flush	0/199 (0%)		1/209 (0.5%)
Menstrual disorder	0/199 (0%)		1/209 (0.5%)
Menstruation irregular	0/199 (0%)		2/209 (1%)
Amenorrhoea	0/199 (0%)		1/209 (0.5%)
Menorrhagia	0/199 (0%)		2/209 (1%)
Metrorrhagia	0/199 (0%)		1/209 (0.5%)
Ovarian cyst	0/199 (0%)		1/209 (0.5%)
Ovarian mass	1/199 (0.5%)		0/209 (0%)
Benign prostatic hyperplasia	0/199 (0%)		1/209 (0.5%)
Sexual dysfunction	1/199 (0.5%)		0/209 (0%)
Uterine haemorrhage	0/199 (0%)		1/209 (0.5%)
Uterine mass	0/199 (0%)		1/209 (0.5%)
Genital pruritus female	1/199 (0.5%)		0/209 (0%)
Vaginal ulceration	1/199 (0.5%)		0/209 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/199 (1.5%)		10/209 (4.8%)
Asthma	0/199 (0%)		1/209 (0.5%)
Cough	4/199 (2%)		7/209 (3.3%)
Laryngeal erythema	0/199 (0%)		1/209 (0.5%)
Hiccups	0/199 (0%)		2/209 (1%)
Nasal congestion	5/199 (2.5%)		2/209 (1%)
Epistaxis	3/199 (1.5%)		2/209 (1%)
Sinus congestion	2/199 (1%)		2/209 (1%)
Pharyngeal erythema	0/199 (0%)		1/209 (0.5%)
Pleurisy	0/199 (0%)		1/209 (0.5%)
Pulmonary congestion	1/199 (0.5%)		1/209 (0.5%)
Aspiration	0/199 (0%)		1/209 (0.5%)
Dysphonia	2/199 (1%)		2/209 (1%)
Pharyngolaryngeal pain	7/199 (3.5%)		9/209 (4.3%)
Rhinorrhoea	2/199 (1%)		0/209 (0%)
Sinus headache	1/199 (0.5%)		0/209 (0%)
Skin and subcutaneous tissue disorders
Acne	0/199 (0%)		8/209 (3.8%)
Alopecia	3/199 (1.5%)		1/209 (0.5%)
Hyperhidrosis	0/199 (0%)		2/209 (1%)
Night sweats	0/199 (0%)		1/209 (0.5%)
Dry skin	1/199 (0.5%)		2/209 (1%)
Hypoaesthesia facial	1/199 (0.5%)		1/209 (0.5%)
Skin warm	0/199 (0%)		1/209 (0.5%)
Swelling face	1/199 (0.5%)		6/209 (2.9%)
Dermatitis contact	1/199 (0.5%)		0/209 (0%)
Erythema	1/199 (0.5%)		2/209 (1%)
Lipoatrophy	3/199 (1.5%)		0/209 (0%)
Ingrowing nail	1/199 (0.5%)		0/209 (0%)
Rash papular	1/199 (0.5%)		0/209 (0%)
Pruritus	5/199 (2.5%)		0/209 (0%)
Pruritus generalised	2/199 (1%)		0/209 (0%)
Rash pruritic	0/199 (0%)		1/209 (0.5%)
Psoriasis	1/199 (0.5%)		0/209 (0%)
Ecchymosis	0/199 (0%)		1/209 (0.5%)
Rash	4/199 (2%)		12/209 (5.7%)
Subcutaneous nodule	1/199 (0.5%)		0/209 (0%)
Scar	1/199 (0.5%)		1/209 (0.5%)
Urticaria	4/199 (2%)		2/209 (1%)
Social circumstances
Alcohol use	0/199 (0%)		1/209 (0.5%)
Surgical and medical procedures
Tooth extraction	2/199 (1%)		1/209 (0.5%)
Inguinal hernia repair	1/199 (0.5%)		0/209 (0%)
Thyroid operation	1/199 (0.5%)		0/209 (0%)
Uterine dilation and curettage	0/199 (0%)		1/209 (0.5%)
Uterine prolapse repair	1/199 (0.5%)		0/209 (0%)
Vascular disorders
Aortic arteriosclerosis	0/199 (0%)		1/209 (0.5%)
Haematoma	1/199 (0.5%)		0/209 (0%)
Flushing	3/199 (1.5%)		15/209 (7.2%)
Hot flush	0/199 (0%)		1/209 (0.5%)
Femoral arterial stenosis	1/199 (0.5%)		0/209 (0%)
Hypertension	4/199 (2%)		5/209 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.