AD-4833/TOMM40_303 Extension Study of the Safety and Efficacy of Pioglitazone to Slow Cognitive Decline in Participants With Mild Cognitive Impairment Due to Alzheimer Disease

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02284906
• Collaborator: (none)
• Enrollment: 40
• Locations: 43
• Arms: 2
• Actual Duration (Months): 38.8
• Patients Per Site: 0.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40_301 study [NCT01931566] with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD).

Condition or Disease	Intervention/Treatment	Phase
Mild Cognitive Impairment Due to Alzheimer's Disease	Drug: Pioglitazone; Drug: Placebo	Phase 3

Detailed Description

The drug being tested in this study is called pioglitazone. This study is designed to further evaluate the safety and effectiveness of pioglitazone on cognitive function in participants who have completed the AD-4833/TOMM40_301. This study will look at the effectiveness of pioglitazone on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40_301 study with a diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD).

The study enrolled 40 participants, but is dependent on how many decide to continue treatment in an extension phase after completing the main (301) study. Participants will continue to receive the same study medication they received during the pivotal AD-4833/TOMM40_301 study, either:

• Pioglitazone 0.8 mg tablets or

• Placebo (this is a tablet that looks like the study drug but has no active ingredient).

All participants will be asked to take one tablet at the same time each day throughout the study.

This multi-centre trial, like its precedent pivotal trial, will be conducted worldwide. The overall time to participate in this study is minimum 2 years and a maximum of 7 years depending on when participants roll over from the 301 study. Participants will make approximately 2 visits per year to the clinic, and will be contacted by telephone 3 months after each treatment visit for a follow-up assessment, and 2 weeks after the final visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone (AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in Subjects Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild Cognitive Impairment Due to Alzheimer Disease
• Actual Study Start Date: Feb 12, 2015
• Actual Primary Completion Date: Jan 31, 2018
• Actual Study Completion Date: May 8, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pioglitazone 0.8 mg Pioglitazone 0.8 mg, tablets, orally, once, daily, for minimum of 2 years.	Drug: Pioglitazone; Pioglitazone tablets; Other Names: AD-4833
Placebo Comparator: Placebo Pioglitazone placebo-matching tablets, orally, once, daily, for minimum of 2 years.	Drug: Placebo; Pioglitazone placebo-matching tablets

Outcome Measures

Primary Outcome Measures

1. Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24 [Baseline and Month 24]

   Composite scores were derived from the test battery. Each test in the battery falls into 1 of the following cognitive domains: Episodic Memory (California Verbal Learning Test - 2nd Edition [CVLT-II], Brief Visuospatial Memory Test - Revised [BVMT-R]), Executive Function (Trail Making Part B, Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span Forward, Trail Making Part A), and Visuospatial (Clock Drawing, BVMT-Copy). Only the domains of episodic memory, executive function, language, and attention were used for the calculation of composite score (i.e., Clock Drawing, BVMT-Copy, and the Multilingual Naming Test (MINT), which do not allow generation of standard z scores, were only used for diagnostic purposes and were excluded from the calculation of the composite score). To form the composite, z-scores were calculated for each test, each z-score for the domain were averaged, and then all relevant domains were averaged to form the composite.

Secondary Outcome Measures

1. Time to Diagnosis of Alzheimer's Disease (AD) Dementia [Day 1 and every 6 months (up to maximum of 36 months)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) without ongoing serious adverse events (SAEs) from AD-4833/TOMM40_301.

2. Is male or female and is at least 65 years of age at the time of the Baseline Visit.

3. In the opinion of the investigator, is capable of understanding and complying with the protocol requirements.

4. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

5. Must be living independently or in nonmedical residential care.

6. Has a project partner able to separately consent on his/her own behalf and take part in the study (with the intent to do so as long as the participant is enrolled), providing information on the cognitive, functional, and behavioral status of the participant and assisting with observation of adverse events (AEs) and monitoring of study medication, if needed. Project partners participating in the pivotal AD-4833/TOMM40_301 study are encouraged to participate in this extension study in this capacity.

Exclusion Criteria:

1. Completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of AD dementia.

2. Has a current diagnosis of significant psychiatric illness, per Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (including but not limited to major depressive disorder, anxiety disorders) and is in an acute phase/episode, or the participant has a current diagnosis or history of schizophrenia or bipolar disorder.

3. Has a glycosylated hemoglobin (HbA1c) >8% at the extension study Baseline Visit or requires treatment with insulin, triple oral antidiabetic therapy or a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist.

4. Has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p gastric bypass surgery), endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.

5. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, pivotal, child, sibling) or may consent under duress.

6. Is required to take excluded medications.

7. Has a history of hypersensitivity or allergies to pioglitazone or related compounds.

8. Had any of the following values at the extension study Baseline Visit:

9. A serum total bilirubin value >15 x upper limit of normal (ULN).

10. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value

2 x ULN.

1. Unexplained microscopic/macroscopic hematuria on 2 repeat examinations within 2 weeks.

2. Has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy, or prevent the participant from adequately participating in the study or continue for the anticipated duration of the study.

3. Has received any investigational compound, with the exception of treatment during the AD-4833/TOMM40_301 study, within 30 days prior to Baseline or 5 half-lives prior to Baseline or is currently participating in another study that entails the administration of an investigational or marketed drug, supplement, or intervention including, but not limited to diet, exercise, lifestyle, or invasive procedure.

4. Has any cancer that has been in remission for less than 2 years from the extension study Baseline Visit. Participants with basal cell or stage I squamous cell carcinoma of the skin will be eligible. Participants with current diagnosis of bladder cancer are not eligible irrespective of the remission status.

5. Has a current diagnosis of macular edema, degeneration or any maculopathy.

6. Has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association class III-IV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85006
2		Sun City	Arizona	United States	85351
3		San Diego	California	United States	92103
4		Delray Beach	Florida	United States	33445
5		Fort Myers	Florida	United States	33912
6		Lake Worth	Florida	United States	33449
7		Melbourne	Florida	United States	32940
8		Merritt Island	Florida	United States	32952
9		Port Orange	Florida	United States	32127
10		Saint Petersburg	Florida	United States	33709
11		Weston	Florida	United States	33331
12		Atlanta	Georgia	United States	30329
13		Decatur	Georgia	United States	30033
14		Chicago	Illinois	United States	60640
15		Elk Grove Village	Illinois	United States	60007
16		Elk Grove	Illinois	United States	60007
17		Iowa City	Iowa	United States	52242
18		Saint Louis	Missouri	United States	63141
19		Las Vegas	Nevada	United States	89106
20		Marlton	New Jersey	United States	08053
21		New York	New York	United States	10019
22		Concord	North Carolina	United States	28025
23		Durham	North Carolina	United States	27705
24		Akron	Ohio	United States	44320
25		Charleston	South Carolina	United States	29401
26		Houston	Texas	United States	77030
27		Salt Lake City	Utah	United States	84107
28		Middleton	Wisconsin	United States	53562
29		North Ryde	New South Wales	Australia	2113
30		Southport	Queensland	Australia	4215
31		Heidelberg West	Victoria	Australia	3081
32		Nedlands	Western Australia	Australia	6009
33		Basel		Switzerland	CH-4012
34		Bristol	Avon	United Kingdom	BS16 1LE
35		Exeter	Devon	United Kingdom	EX2 5DW
36		Plymouth	Devon	United Kingdom	PL6 8DH
37		Hammersmith	Greater London	United Kingdom	W6 8RF
38		London	Greater London	United Kingdom	EC1M 6BQ
39		Manchester	Greater Manchester	United Kingdom	M13 9NQ
40		Blackpool	Lancashire	United Kingdom	FY2 0JH
41		Isleworth	Middlesex	United Kingdom	TW7 6FY
42		Glasgow	Strathclyde	United Kingdom	G20 0XA
43		Perth	Tayside Region	United Kingdom	PH2 7BH

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Statistical Analysis Plan - Sep 14, 2018
• Study Protocol - Jan 19, 2016

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02284906
• Other Study ID Numbers: AD-4833/TOMM40_303; U1111-1154-9637; 2013-004984-30
• First Posted: Nov 6, 2014
• Last Update Posted: Jul 2, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Alzheimer Disease; Cognitive Dysfunction; Pioglitazone

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 3 investigative sites in Australia, United Kingdom and United States from 12 Feb 2015 to 08 May 2018.
Pre-assignment Detail	Participants with who have completed the pivotal AD-4833/TOMM40_301 (NCT01931566) study with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) were enrolled to pioglitazone (0.8 mg sustained release tablet) or placebo.

Arm/Group Title	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone
Arm/Group Description	Pioglitazone placebo-matching tablets, orally, once daily, for 10 months to participants assigned to low risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone placebo-matching tablets, orally, once daily, for minimum of 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone 0.8 mg tablets, orally, once daily for 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).
Period Title: Overall Study
STARTED	3	18	19
COMPLETED	0	0	0
NOT COMPLETED	3	18	19

Baseline Characteristics

Arm/Group Title	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone	Total
Arm/Group Description	Pioglitazone placebo-matching tablets, orally, once daily, for 10 months to participants assigned to low risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone placebo-matching tablets, orally, once daily, for minimum of 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone 0.8 mg tablets, orally, once daily for 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Total of all reporting groups
Overall Participants	3	18	19	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.7 (4.73)	78.9 (3.98)	78.1 (4.42)	78.2 (4.27)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 27.8%	10 52.6%	16 40%
Male	2 66.7%	13 72.2%	9 47.4%	24 60%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 33.3%	1 5.6%	1 5.3%	3 7.5%
Not Hispanic or Latino	2 66.7%	17 94.4%	18 94.7%	37 92.5%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	0 0%	0 0%	1 5.3%	1 2.5%
White	3 100%	18 100%	18 94.7%	39 97.5%
Race/Ethnicity, Customized (Count of Participants)
Non-Hispanic/Latino Caucasian	2 66.7%	17 94.4%	17 89.5%	36 90%
Hispanic/Latino and/or non-Caucasian	1 33.3%	1 5.6%	2 10.5%	4 10%
Region of Enrollment (Count of Participants)
United States	2 66.7%	11 61.1%	15 78.9%	28 70%
United Kingdom	1 33.3%	2 11.1%	2 10.5%	5 12.5%
Australia	0 0%	5 27.8%	2 10.5%	7 17.5%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.7 (4.16)	168.7 (10.85)	166.8 (11.73)	167.9 (10.81)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	78.20 (6.053)	76.00 (13.719)	72.11 (15.685)	74.32 (14.224)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.27 (3.412)	26.49 (2.769)	25.68 (3.653)	26.16 (3.218)
Smoking Classification (Count of Participants)
Participant Has Never Smoked	2 66.7%	7 38.9%	9 47.4%	18 45%
Participant is an Ex-smoker	1 33.3%	11 61.1%	10 52.6%	22 55%
Alcohol Classification (Count of Participants)
Participant Has Never Drunk	1 33.3%	3 16.7%	3 15.8%	7 17.5%
Participant is a Current Drinker	2 66.7%	15 83.3%	15 78.9%	32 80%
Participant is an Ex-drinker	0 0%	0 0%	1 5.3%	1 2.5%
Years of Education (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.0 (3.61)	14.8 (3.59)	14.9 (3.67)	14.9 (3.54)
Years Lived in Country/Region for 10 Years or More (Count of Participants)
Count of Participants [Participants]	3 100%	18 100%	19 100%	40 100%
Primary Language (Count of Participants)
English	2 66.7%	16 88.9%	19 100%	37 92.5%
Other	1 33.3%	2 11.1%	0 0%	3 7.5%
Ability to Communicate in Primary Language (Count of Participants)
Not At All	0 0%	1 5.6%	0 0%	1 2.5%
Very Well	3 100%	17 94.4%	19 100%	39 97.5%
If Participant Speaks Second Language, Ability to Very Well Communicate in Second Language (Count of Participants)
Count of Participants [Participants]	0 0%	1 5.6%	0 0%	1 2.5%
Does Participant Speak More Than Two Languages (Count of Participants)
Yes	0 0%	1 5.6%	0 0%	1 2.5%
No	3 100%	17 94.4%	19 100%	39 97.5%
Diabetic Status (Count of Participants)
Diabetic	0 0%	3 16.7%	3 15.8%	6 15%
Non-Diabetic	3 100%	15 83.3%	16 84.2%	34 85%
Baseline Statin Use (Count of Participants)
Yes	1 33.3%	9 50%	8 42.1%	18 45%
No	2 66.7%	9 50%	11 57.9%	22 55%

Outcome Measures

1. Primary Outcome

Title	Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24
Description	Composite scores were derived from the test battery. Each test in the battery falls into 1 of the following cognitive domains: Episodic Memory (California Verbal Learning Test - 2nd Edition [CVLT-II], Brief Visuospatial Memory Test - Revised [BVMT-R]), Executive Function (Trail Making Part B, Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span Forward, Trail Making Part A), and Visuospatial (Clock Drawing, BVMT-Copy). Only the domains of episodic memory, executive function, language, and attention were used for the calculation of composite score (i.e., Clock Drawing, BVMT-Copy, and the Multilingual Naming Test (MINT), which do not allow generation of standard z scores, were only used for diagnostic purposes and were excluded from the calculation of the composite score). To form the composite, z-scores were calculated for each test, each z-score for the domain were averaged, and then all relevant domains were averaged to form the composite.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

As the study was early terminated, there were limited number of enrolled participants and insufficient treatment duration, therefore, data was not collected for this outcome measure.

Arm/Group Title	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone 0.8 mg
Arm/Group Description	Pioglitazone placebo-matching tablets, orally, once daily, for 10 months to participants assigned to low risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone placebo-matching tablets, orally, once daily, for minimum of 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone 0.8 mg tablets, orally, once daily for 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).
Measure Participants	0	0	0

2. Secondary Outcome

Title	Time to Diagnosis of Alzheimer's Disease (AD) Dementia
Time Frame	Day 1 and every 6 months (up to maximum of 36 months)

Outcome Measure Data

Analysis Population Description

As the study was early terminated, there were limited number of enrolled participants and insufficient treatment duration, therefore, data was not collected for this outcome measure.

Arm/Group Title	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone 0.8 mg
Arm/Group Description	Pioglitazone placebo-matching tablets, orally, once daily, for 10 months to participants assigned to low risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone placebo-matching tablets, orally, once daily, for minimum of 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).	Pioglitazone 0.8 mg tablets, orally, once daily for 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).
Measure Participants	0	0	0

Adverse Events

Time Frame	Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Low Risk Placebo		High Risk Placebo		High Risk Pioglitazone
Arm/Group Description	Pioglitazone placebo-matching tablets, orally, once daily, for 10 months to participants assigned to low risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).		Pioglitazone placebo-matching tablets, orally, once daily, for minimum of 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).		Pioglitazone 0.8 mg tablets, orally, once daily for 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40_301).
All Cause Mortality
	Low Risk Placebo		High Risk Placebo		High Risk Pioglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/18 (0%)		0/19 (0%)
Serious Adverse Events
	Low Risk Placebo		High Risk Placebo		High Risk Pioglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		4/18 (22.2%)		3/19 (15.8%)
Cardiac disorders
Cardiac failure congestive	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Myocardial infarction	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Eye disorders
Retinal artery occlusion	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
General disorders
Non-cardiac chest pain	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Hip fracture	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Laceration	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer metastatic	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Low Risk Placebo		High Risk Placebo		High Risk Pioglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		10/18 (55.6%)		12/19 (63.2%)
Eye disorders
Cataract	0/3 (0%)		0/18 (0%)		2/19 (10.5%)
Gastrointestinal disorders
Abdominal pain upper	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Diarrhoea	1/3 (33.3%)		0/18 (0%)		0/19 (0%)
Haemorrhoids	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Large intestine polyp	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Pancreatic cyst	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
General disorders
Gait disturbance	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Hepatobiliary disorders
Hepatic mass	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Immune system disorders
Seasonal allergy	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Infections and infestations
Upper respiratory tract infection	0/3 (0%)		2/18 (11.1%)		4/19 (21.1%)
Urinary tract infection	0/3 (0%)		2/18 (11.1%)		1/19 (5.3%)
Injury, poisoning and procedural complications
Fall	0/3 (0%)		1/18 (5.6%)		2/19 (10.5%)
Contusion	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Skin abrasion	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Metabolism and nutrition disorders
Hyponatraemia	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)		0/18 (0%)		2/19 (10.5%)
Back pain	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Bursitis	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Muscle spasms	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Musculoskeletal pain	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Rotator cuff syndrome	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	0/3 (0%)		2/18 (11.1%)		0/19 (0%)
Benign neoplasm of skin	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Malignant melanoma	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Nervous system disorders
Cerebral infarction	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Dementia Alzheimer's type	1/3 (33.3%)		0/18 (0%)		0/19 (0%)
Syncope	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Psychiatric disorders
Depression	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Renal and urinary disorders
Haematuria	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Urinary retention	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Oropharyngeal pain	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Rhinorrhoea	0/3 (0%)		1/18 (5.6%)		0/19 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Skin lesion	0/3 (0%)		0/18 (0%)		1/19 (5.3%)
Vascular disorders
Hypotension	0/3 (0%)		0/18 (0%)		1/19 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.