ALLAY-LID-I: Efficacy and Safety of Amantadine Hydrochloride (HCl) ER Tablets to Treat Parkinson's Disease Patients With LID.

• Sponsor: Adamas Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02153645
• Collaborator: (none)
• Enrollment: 87
• Locations: 56
• Arms: 3
• Actual Duration (Months): 21.1
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study was terminated early due to slow enrollment with 87 of 162 planned subjects enrolled. The purpose of this multi-center, randomized, double-blind, parallel-group, 16 week study is to compare the efficacy and safety of two different dose levels of Amantadine Extended Release Tablets to placebo for the treatment of levodopa induced dyskinesia in patients with Parkinson's disease.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease; Levodopa Induced Dyskinesias (LID)	Drug: 240mg Amantadine HCl ER tablets; Drug: Placebo tablets; Drug: 320mg Amantadine HCl ER tablets	Phase 3

Detailed Description

This study was terminated early due to slow enrollment with 87 of 162 planned subjects enrolled. Amantadine has been used for many years as a treatment for Parkinson's disease. It has been reported in the literature to effectively treat the motor complications of levodopa, especially dyskinesia, but it must be given 2 to 4 times a day. The purpose of this multi-center, randomized, double-blind, parallel-group, 16 week study is to compare the efficacy and safety of two different dose levels of Amantadine Extended Release Tablets to placebo for the treatment of levodopa induced dyskinesia in patients with Parkinson's disease. The dose will be given once a day in the morning so that amantadine concentrations are maintained throughout the day for treating the levodopa induced dyskinesia, but will be lower during the night, potentially reducing the negative impact of amantadine on sleep.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Placebo-controlled, Double-blind, 16 Week Study to Evaluate the Efficacy and Safety of Amantadine HCl Extended Release Tablets in Parkinson's Disease Subjects With Levodopa-Induced Dyskinesias
• Actual Study Start Date: Aug 18, 2014
• Actual Primary Completion Date: May 20, 2016
• Actual Study Completion Date: May 20, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 240mg Amantadine HCl ER tablets Amantadine HCl ER Tablets 240mg daily for 12 weeks post two week titration phase.	Drug: 240mg Amantadine HCl ER tablets; Other Names: Osmolex ER 240 mg Tablet
Experimental: 320mg Amantadine HCl ER tablets Amantadine HCl ER Tablets 320mg daily for 12 weeks post a two week dose titration phase.	Drug: 320mg Amantadine HCl ER tablets; Other Names: Osmolex ER 320mg Tablet
Placebo Comparator: Placebo tablets Placebo Tablets matching Amantadine HCl ER Tablets taken daily for 16 weeks.	Drug: Placebo tablets

Outcome Measures

Primary Outcome Measures

1. Unified Dyskinesia Rating Scale [From baseline to Day 98]

   The Unified Dyskinesia Rating Scale is a validated tool for assessment of dyskinesia (involuntary movements) in Parkinson's Disease patients. Rating consists of the change from baseline to Day 98 of the sum of the 26 questions comprising the questionnaire. Each question in the questionnaire is rated on a 5 point scale from 0-4 where 0 is a better outcome. Questions assess: over the past week total hours with dyskinesia and total hours without dyskinesia; problems with speech, chewing and swallowing, eating, dressing, hygiene, handwriting, hobbies, balance, socializing, emotions, spasm or cramps, pain without dystonia (spasm or cramps) and pain from dystonia, the degree of impairment for each of 7 body parts, and the degree of disability in communication, drinking from a cup, dressing and ambulation. The minimum score is 0 (better) and the maximum score is 130 (worse).

Secondary Outcome Measures

1. Mobility State Self-Assessment - Subject Diary Cards [Day 14 and Day 98 of treatment]

   Change from baseline in the number of awake hours without troublesome dyskinesia (involuntary movements). Every half hour the subject will indicate in the diary if the medication has ("ON") or has not ("OFF") produced benefits in terms of mobility, slowness and rigidity. Valid diaries of the 3 consecutive days prior to each visit will be averaged with respect to the number of awake hours without troublesome dyskinesia. The change from baseline in the number of waking hours that subjects report being "ON" without troublesome dyskinesias will be analyzed at analysis visits Day 14 and Day 98 of treatment. Higher scores mean a better outcome and the maximum value is 24 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed Investigational Review Board/Independent Ethics Review Committee (IRB/IEC) informed consent form.,

• Idiopathic Parkinson's disease per the United Kingdom (UK) Parkinson's Disease Society Brain Bank criteria.

• Male or female 30 to 85 years old.

• Levodopa induced, predictable peak-effect dyskinesia considered problematic and/or disabling.

• Screening serum creatinine level within normal range

• On stable doses of all oral anti-Parkinson's medication, including any levodopa preparation, for 30 days and be willing to remain on the same doses throughout the trial.

• The subject/caregiver must demonstrate the ability to complete an accurate home diary based on training and evaluation during the screening period.

Exclusion Criteria:

• Secondary parkinsonian syndrome, such as vascular, postinflammatory,drug-induced, neoplastic and post-traumatic parkinsonism or any atypical parkinsonian syndrome (e.g., Progressive Supranuclear Palsy, Multi-System Atrophy, etc.);

• Use of amantadine within 14 days before study start, or previously had an adverse event to amantadine

• Currently taking neuroleptics and atypical antipsychotic agents, acetylcholinesterase inhibitors, apomorphine, rimantadine, memantine and dextromethorphan and quinidine if used in combination for treating dyskinesia.

• History of neurosurgical intervention for treating Parkinson's s disease (i.e. pallidotomy or implanted with a deep brain stimulator).

• Any medical condition or past medical history that would increase the risk of exposure to Amantadine HCl Extended Release Tablets or interfere with safety and efficacy evaluations.

• History of cancer within 5 years of screening with following exceptions: adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer or in situ cervical cancer.

• History or current diagnosis of schizophrenia or bipolar disorder;

• Inadequately treated Major Depressive Disorder. Subjects on stable doses of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are eligible for the study.

• Is at imminent risk of suicide or had a suicide attempt within 6 months of screening

• History or current diagnosis of Impulse Control Disorder

• Calculated plasma creatinine clearance of <60 mL/min at screening

• History of or currently has any of the following clinically significant conditions, cardiovascular, respiratory, renal, hepatic, or gastrointestinal disease

• Any clinically significant vital sign, ECG, or laboratory abnormalities:

• A positive test for HIV antibody or history of HIV; hepatitis B surface antigen unless the positive test followed a recent (<28 days) vaccination for hepatitis B; hepatitis C antibody.

• A positive urine drug test.

• Pregnant or breastfeeding at screening or has a positive pregnancy test

• If a sexually active female, is not surgically sterile or at least 2 years post-menopausal, or does not agree to utilize an effective method of contraception from the screening visit to at least 4 weeks after the completion of study treatment.

• History of alcohol or narcotic substance abuse ≤1 year before screening.

• Has dementia or another psychiatric illness that prevents provision of informed consent.

• Has a known hypersensitivity to the study treatment(s), based on known allergies to drugs of the same class including rimantadine HCl and memantine HCl.

• Has participated in other studies involving investigational drugs or surgeries within the last 30 days or investigational biologics within the last 6 months prior to screening.

• Plans to undergo major elective surgery during the course of the study.

• Received administration of Live Attenuated Influenza Vaccine (LAIV) within 2 weeks.

• Cognitive impairment, as evidenced by a score <26 on the Montreal Cognitive Assessment (MoCA) at the screening visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States	85724
2		Fountain Valley	California	United States	92708
3		Irvine	California	United States	92697
4		Pasadena	California	United States	91105
5		Reseda	California	United States	91335
6		Ventura	California	United States	93001
7		Ventura	California	United States	93003
8		Boulder	Colorado	United States	80304
9		Hollywood	Florida	United States	33021
10		Miami	Florida	United States	33101
11		North Palm Beach	Florida	United States	33403
12		Tampa	Florida	United States	33612
13		Chicago	Illinois	United States	60612
14		Indianapolis	Indiana	United States	46202
15		Baton Rouge	Louisiana	United States	70810
16		Ann Arbor	Michigan	United States	48103
17		Ann Arbor	Michigan	United States	48109
18		Summit	New Jersey	United States	07901
19		Brooklyn	New York	United States	11203
20		Manhasset	New York	United States	11020
21		Patchogue	New York	United States	11772
22		Raleigh	North Carolina	United States	27612
23		Columbus	Ohio	United States	43221
24		Round Rock	Texas	United States	78681
25		Orem	Utah	United States	84058
26		Kirkland	Washington	United States	98034
27		London	Ontario	Canada
28		Ottawa	Ontario	Canada
29		Rennes	Ille-et-Vilaine	France
30		Amiens		France
31		Bron		France	69677
32		Clermont-Ferrand		France
33		Creteil		France
34		Lille		France
35		Marseille		France	13385
36		Montauban		France
37		Nimes		France
38		Paris		France
39		Poitiers		France
40		Toulouse		France
41		Haag	Bayern	Germany
42		Weissensee	Berlin	Germany
43		Erbach	Hessen	Germany
44		Achim	Niedersachsen	Germany
45		Bochum	Nordrhein-Westfalen	Germany
46		Berlin		Germany	13088
47		Berlin		Germany
48		Wurzburg		Germany	97080
49		Manresa	Barcelona	Spain
50		Sevilla	Barcelona	Spain
51		Alcorcón	Madrid	Spain
52		Castellana	Madrid	Spain
53		Barcelona		Spain	08036
54		Barcelona		Spain	08041
55		Barcelona		Spain
56		Pamplona		Spain	31008

Sponsors and Collaborators

• Adamas Pharmaceuticals, Inc.

Investigators

• Study Chair: Angela Dentiste, MBA, Osmotica Pharmaceutical US LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Adamas Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02153645
• Other Study ID Numbers: OS320-3005
• First Posted: Jun 3, 2014
• Last Update Posted: Feb 16, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Adamas Pharmaceuticals, Inc.: Parkinson's Disease; Levodopa Induced Dyskinesias (LID); Dyskinesias; Parkinsonism
• Additional relevant MeSH terms: Parkinson Disease; Dyskinesias; Amantadine

Study Results

Participant Flow

Arm/Group Title	240mg Amantadine Hydrochloride (HCl) ER Tablets	320mg Amantadine HCl ER Tablets	Placebo Tablets for Amantadine
Arm/Group Description	Amantadine HCl ER Tablets 240mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets	Amantadine HCl ER Tablets 320mg daily for 12 weeks post a two week dose titration phase. Amantadine ER Tablets	Placebo Tablets matching Amantadine HCl ER Tablets taken daily for 16 weeks. Placebo Tablets for Amantadine ER Tablets
Period Title: Overall Study
STARTED	30	29	28
COMPLETED	17	19	18
NOT COMPLETED	13	10	10

Baseline Characteristics

Arm/Group Title	240mg Amantadine HCl ER Tablets	320mg Amantadine HCl ER Tablets	Placebo Tablets for Amantadine	Total
Arm/Group Description	Amantadine HCl ER Tablets 240mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets	Amantadine HCl ER Tablets 320mg daily for 12 weeks post a two week dose titration phase. Amantadine ER Tablets	Placebo Tablets matching Amantadine HCl ER Tablets taken daily for 16 weeks. Placebo Tablets for Amantadine ER Tablets	Total of all reporting groups
Overall Participants	30	29	28	87
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	30 100%	29 100%	28 100%	87 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.6 (8.02)	63.3 (9.17)	66.1 (8.04)	66.1 (8.61)
Sex: Female, Male (Count of Participants)
Female	16 53.3%	10 34.5%	12 42.9%	38 43.7%
Male	14 46.7%	19 65.5%	16 57.1%	49 56.3%
Region of Enrollment (participants) [Number]
Canada	1 3.3%	0 0%	1 3.6%	2 2.3%
United States	7 23.3%	16 55.2%	8 28.6%	31 35.6%
France	8 26.7%	8 27.6%	10 35.7%	26 29.9%
Germany	6 20%	3 10.3%	3 10.7%	12 13.8%
Spain	8 26.7%	2 6.9%	6 21.4%	16 18.4%

Outcome Measures

1. Primary Outcome

Title	Unified Dyskinesia Rating Scale
Description	The Unified Dyskinesia Rating Scale is a validated tool for assessment of dyskinesia (involuntary movements) in Parkinson's Disease patients. Rating consists of the change from baseline to Day 98 of the sum of the 26 questions comprising the questionnaire. Each question in the questionnaire is rated on a 5 point scale from 0-4 where 0 is a better outcome. Questions assess: over the past week total hours with dyskinesia and total hours without dyskinesia; problems with speech, chewing and swallowing, eating, dressing, hygiene, handwriting, hobbies, balance, socializing, emotions, spasm or cramps, pain without dystonia (spasm or cramps) and pain from dystonia, the degree of impairment for each of 7 body parts, and the degree of disability in communication, drinking from a cup, dressing and ambulation. The minimum score is 0 (better) and the maximum score is 130 (worse).
Time Frame	From baseline to Day 98

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	240 mg Amantadine HCl ER Tablets	320 mg Amantadine HCl ER Tablets	Placebo Amantadine HCl ER Tablets
Arm/Group Description	Amantadine HCl ER Tablets 240 mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets	Amantadine HCl ER Tablets 320 mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets	Amantadine HCl ER Placebo Tablets daily for 12 weeks post two week titration phase. Amantadine ER Tablets
Measure Participants	30	29	28
Visit 2 (Baseline)	46.2 (13.19)	39.2 (11.91)	38.7 (11.23)
Visit 7 (Day 98)/Stable Dose LOCF [1]	27.5 (19.13)	26.4 (13.17)	28.7 (13.70)
Change from Baseline (SD)	-18.8 (16.38)	-13.3 (13.73)	-9.6 (14.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	240 mg Amantadine HCl ER Tablets, 320 mg Amantadine HCl ER Tablets, Placebo Amantadine HCl ER Tablets
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.179
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.6
	Confidence Interval	(2-Sided) 95%; -13.9 to 2.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.90
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	320 mg Amantadine HCl ER Tablets
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.458
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -11.2 to 5.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.95
	Estimation Comments

2. Secondary Outcome

Title	Mobility State Self-Assessment - Subject Diary Cards
Description	Change from baseline in the number of awake hours without troublesome dyskinesia (involuntary movements). Every half hour the subject will indicate in the diary if the medication has ("ON") or has not ("OFF") produced benefits in terms of mobility, slowness and rigidity. Valid diaries of the 3 consecutive days prior to each visit will be averaged with respect to the number of awake hours without troublesome dyskinesia. The change from baseline in the number of waking hours that subjects report being "ON" without troublesome dyskinesias will be analyzed at analysis visits Day 14 and Day 98 of treatment. Higher scores mean a better outcome and the maximum value is 24 hours.
Time Frame	Day 14 and Day 98 of treatment

Outcome Measure Data

Analysis Population Description

The number analyzed was the number of subjects with values at each time point.

Arm/Group Title	240 mg Amantadine HCl ER Tablets	320 mg Amantadine HCl ER Tablets	Placebo Amantadine HCl ER Tablets
Arm/Group Description	Amantadine HCl ER Tablets 240 mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets	Amantadine HCl ER Tablets 320 mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets	Amantadine HCl ER Placebo Tablets daily for 12 weeks post two week titration phase. Amantadine ER Tablets
Measure Participants	30	29	28
Visit 2 (Baseline)	3.5 (2.02)	3.3 (2.63)	4.3 (2.59)
Visit 7 (Day 98)/Stable Dose LOCF [1]	4.1 (2.48)	2.8 (2.24)	3.8 (2.36)
Change from Baseline (SD)	0.8 (2.92)	-0.5 (2.18)	0.1 (2.78)

Adverse Events

Time Frame	Three months
Arm/Group Title	240mg Amantadine HCl ER Tablets		320mg Amantadine HCl ER Tablets		Placebo Tablets for Amantadine
Arm/Group Description	Amantadine HCl ER Tablets 240mg daily for 12 weeks post two week titration phase. Amantadine ER Tablets		Amantadine HCl ER Tablets 320mg daily for 12 weeks post a two week dose titration phase. Amantadine ER Tablets		Placebo Tablets matching Amantadine HCl ER Tablets taken daily for 16 weeks. Placebo Tablets for Amantadine ER Tablets
All Cause Mortality
	240mg Amantadine HCl ER Tablets		320mg Amantadine HCl ER Tablets		Placebo Tablets for Amantadine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		0/29 (0%)		0/28 (0%)
Serious Adverse Events
	240mg Amantadine HCl ER Tablets		320mg Amantadine HCl ER Tablets		Placebo Tablets for Amantadine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/30 (10%)		1/29 (3.4%)		2/28 (7.1%)
Blood and lymphatic system disorders
syncope	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
traumatic haemothroax	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Cardiac disorders
arrhythmia supraventricular	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Gastrointestinal disorders
megacolon multi-organ failure	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Musculoskeletal and connective tissue disorders
arthralgia osteonecrosis	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Psychiatric disorders
impulse-control disorder	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	240mg Amantadine HCl ER Tablets		320mg Amantadine HCl ER Tablets		Placebo Tablets for Amantadine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/30 (66.7%)		24/29 (82.8%)		15/28 (53.6%)
Blood and lymphatic system disorders
Anaemia	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Cardiac disorders
Angina pectoris	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Arrhythmia supraventricular	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Extrasystoles	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Eye disorders
Cataract	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Diplopia	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Dry Eye	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Vision Blurred	1/30 (3.3%)	1	1/29 (3.4%)	1	0/28 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Constipation	1/30 (3.3%)	1	2/29 (6.9%)	2	0/28 (0%)	0
Diarrhea	0/30 (0%)	0	1/29 (3.4%)	1	1/28 (3.6%)	1
Dry Mouth	1/30 (3.3%)	1	3/29 (10.3%)	3	0/28 (0%)	0
Megacolon	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Nausea	0/30 (0%)	0	1/29 (3.4%)	1	2/28 (7.1%)	2
Oral Pain	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Toothache	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Vomiting	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
General disorders
Asthenia	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Fatigue	1/30 (3.3%)	1	1/29 (3.4%)	1	1/28 (3.6%)	1
Gait disturbance	1/30 (3.3%)	1	0/29 (0%)	0	1/28 (3.6%)	1
General physical health deterioration	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Multi-organ failure	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Oedema	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Oedema peripheral	2/30 (6.7%)	2	4/29 (13.8%)	4	0/28 (0%)	0
Peripheral swelling	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Infections and infestations
Ear infection	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Nasopharyngitis	1/30 (3.3%)	1	4/29 (13.8%)	4	0/28 (0%)	0
Onychomycosis	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Orchitis	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Skin infection	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Stoma site infection	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Urinary tract infection	2/30 (6.7%)	2	1/29 (3.4%)	1	2/28 (7.1%)	2
Viral infection	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Injury, poisoning and procedural complications
Fall	1/30 (3.3%)	1	1/29 (3.4%)	1	1/28 (3.6%)	1
Procedural pain	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Rib fracture	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Traumatic haemothorax	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Investigations
Bacterial test positive	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Blood cholesterol increased	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Blood glucose increased	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Blood pressure orthostatic	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Haemoglobin urine present	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Neutrophil count increased	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Oxygen saturation decreased	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Protein urine present	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Urine ketone body present	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Urine leukocyte esterase positive	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Weight decreased	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
White blood cell count increased	1/30 (3.3%)	1	0/29 (0%)	0	1/28 (3.6%)	1
Metabolism and nutrition disorders
Decreased appetite	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/30 (3.3%)	1	2/29 (6.9%)	2	0/28 (0%)	0
back pain	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Mobility decreased	1/30 (3.3%)	1	0/29 (0%)	0	1/28 (3.6%)	1
Muscle rigidity	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Muscle spasms	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Muscular weakness	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Musculoskeletal stiffness	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Neck pain	1/30 (3.3%)	1	1/29 (3.4%)	1	0/28 (0%)	0
Osteoarthritis	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Osteonecrosis	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Pain in extremity	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Tendonitis	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Nervous system disorders
Akinesia	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Balance disorder	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Carpal tunnel syndorme	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Cognitive disorder	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Dizziness	1/30 (3.3%)	1	3/29 (10.3%)	3	0/28 (0%)	0
Dyskinesia	3/30 (10%)	3	1/29 (3.4%)	1	3/28 (10.7%)	3
Dystonia	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Freezing phenomenon	1/30 (3.3%)	1	1/29 (3.4%)	1	0/28 (0%)	0
Headache	2/30 (6.7%)	2	0/29 (0%)	0	2/28 (7.1%)	2
Hypoaesthesia	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
On and off phenomenon	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Sciatica	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Somnolence	2/30 (6.7%)	2	0/29 (0%)	0	2/28 (7.1%)	2
Syncope	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Tension headache	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Tremor	1/30 (3.3%)	1	1/29 (3.4%)	1	0/28 (0%)	0
Psychiatric disorders
Abnormal dreams	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Anxiety	0/30 (0%)	0	2/29 (6.9%)	2	0/28 (0%)	0
Confusional state	2/30 (6.7%)	2	1/29 (3.4%)	1	0/28 (0%)	0
Depressed mood	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Depression	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Hallucination	0/30 (0%)	0	4/29 (13.8%)	4	1/28 (3.6%)	1
Hallucination, auditory	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Hallucination, visual	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Hypersexuality	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Illusion	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Impulse-control disorder	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Insomnia	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Nightmare	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Obsessive-compulsive disorder	2/30 (6.7%)	2	0/29 (0%)	0	0/28 (0%)	0
Restlessness	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Sleep attacks	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Renal and urinary disorders
Dysuria	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Pollakiuria	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Renal Failure	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Urinary retention	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Reproductive system and breast disorders
Prostatism	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Prostatomegaly	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Dyspnoea exertional	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Pulmonary Mass	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Erythema	0/30 (0%)	0	1/29 (3.4%)	1	0/28 (0%)	0
Nail dystrophy	0/30 (0%)	0	0/29 (0%)	0	1/28 (3.6%)	1
Social circumstances
Gambling	1/30 (3.3%)	1	0/29 (0%)	0	0/28 (0%)	0
Vascular disorders
Hypertension	1/30 (3.3%)	1	3/29 (10.3%)	3	0/28 (0%)	0
Hypotension	2/30 (6.7%)	2	0/29 (0%)	0	1/28 (3.6%)	1
Orthostatic hypotension	0/30 (0%)	0	2/29 (6.9%)	2	2/28 (7.1%)	2

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Investigator shall allow SPONSOR 60 days to review any manuscript and 30 days to review any poster presentation, abstract or any other written or oral material which discloses the Study Results. SPONSOR may request in writing an additional 60 days for review. SPONSOR may remove all Confidential Information from any publications or presentations, or if deemed not sufficient to protect its Intellectual Property Rights, then SPONSOR may embargo the publication or presentation.