A Study of Hyaluronate Injectable Viscosupplement for Treatment of Osteoarthritis of the Knee

• Sponsor: Actavis Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02495857
• Collaborator: (none)
• Enrollment: 599
• Locations: 2
• Arms: 3
• Actual Duration (Months): 15.7
• Patients Per Site: 299.5
• Patients Per Site Per Month: 19.1

Study Details

Study Description

Brief Summary

The study is a prospective, multi-center, randomized, three-arm, parallel group, clinical study to evaluate the superiority of 3 weekly intra-articular (IA) doses of 2 mL of Investigational hyaluronate as compared to placebo injected into the target knee for the treatment of pain in subjects with Osteoarthritis (OA).The safety and effectiveness of the investigational product will also be compared with Euflexxa.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis	Device: Hyaluronate Injectable Viscosupplement; Device: Euflexxa IA injection; Device: Placebo	N/A

Detailed Description

The primary objective is to evaluate the safety and effectiveness of 3 weekly IA doses of 2 mL of hyaluronate viscosupplement as compared to placebo injected into the target knee for the treatment of pain in subjects with OA As secondary objectives, the study will evaluate the safety and effectiveness of 3 weekly IA doses of 2 mL of Viscosupplement as compared to Euflexxa injected into the target knee for the treatment of pain in subjects with OA. In addition, to assess the effect of Viscosupplement on pain, stiffness, and physical function of the target knee, as well as functional health and general well-being

Study Design

• Study Type: Interventional
• Actual Enrollment: 599 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Study of the Effectiveness and Safety of Hyaluronate Injectable Viscosupplement for Treatment of Osteoarthritis of the Knee
• Actual Study Start Date: Aug 15, 2015
• Actual Primary Completion Date: Dec 5, 2016
• Actual Study Completion Date: Dec 5, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hyaluronate Injectable Viscosupplement Hyaluronate Injectable Viscosupplement (1% sodium hyaluronate). IA injection to the knee once weekly for 3 weeks	Device: Hyaluronate Injectable Viscosupplement; Test product of a 1% sodium hyaluronate for injection; Other Names: 1% sodium hyaluronate
Active Comparator: Euflexxa IA injection Euflexxa IA injection to the knee once weekly for 3 weeks	Device: Euflexxa IA injection; Brand product of a 1% sodium hyaluronate for injection; Other Names: 1% sodium hyaluronate
Placebo Comparator: Placebo Placebo (normal saline). IA injection to the knee once weekly for 3 weeks	Device: Placebo; 0.9% sodium chloride, sterile; Other Names: Normal saline

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] [Baseline and 26 weeks]

   The primary effectiveness endpoint was the change from Baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) pain score in the target knee at Week 26.The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain.

Secondary Outcome Measures

1. Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 [26 weeks]

   The change from Baseline in the WOMAC pain score over time (baseline to Week 1, Week 6, Week 12 and Week 26) using Western Ontario and McMaster Universities Arthritis Index (WOMAC®)].The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain.

2. Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] [26 weeks]

   The change from baseline in the stiffness in the target knee at Week 26. The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of stiffness score was 0 to 100 mm with higher scores for worse stiffness.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Chronic OA of target knee confirmed by American College of Rheumatology Criteria

• Pain due to OA in target knee that had been present for at least 6 months, with a moderate to severe pain score of >50 mm recorded on a 100 mm Visual Analogue Scale (VAS) following a 50-foot walk

• Subject agrees to discontinue all pain medications for at least 7 days prior to start of study

• A bilateral standing anteroposterior x-ray confirming Grade 2 or 3 OA of the target knee

• Body mass index ≤40kg/m2

• Able and willing to use only acetaminophen as the analgesic (rescue) study medication under the following conditions:

• acetaminophen dose is not to exceed 4 grams (4000mg)/day

• if the subject has known chronic liver disease, the maximum dose of acetaminophen is not to exceed 2 grams (2000 mg)/day

• subject must be able and willing to discontinue acetaminophen at least 24 hours prior to all study-specific visits

• Ability to perform procedures required of the pain index evaluations (unassisted walking for a distance of 50 feet on a flat surface and going up and down stairs)

• Agrees to use a highly effective contraception

• Able and willing to complete effectiveness and safety questionnaires and able to read and understand study instructions

Exclusion Criteria:

• Any major injury to the target knee within the 12 months prior to the Screening and Enrollment Visit

• Any surgery to the target knee within the 12 months prior to the Screening and Enrollment Visit,

• Articular procedures such as transplants or ligament reconstruction to the target knee within 12 months prior to Screening and Enrollment Visit

• Inflammatory arthropathies such as rheumatoid arthritis, lupus arthropathy, or psoriatic arthritis

• Gout or calcium pyrophosphate diseases of the target knee that have flared within the 6 months prior to the Screening and Enrollment Visit

• X-ray findings of acute fractures, severe loss of bone density, avascular necrosis, and/or severe bone or joint deformity in the target knee

• Osteonecrosis of either knee

• Clinical signs and symptoms of active knee infection or crystal disease of the target knee

• Fibromyalgia, pes anserine bursitis, lumbar radiculopathy, and/or neurogenic or vascular claudication

• Significant anterior knee pain due to diagnosed isolated patella-femoral syndrome or chondromalacia in the target knee

• Significant target knee joint, infection or skin disorder infection within the 6 months prior to study enrollment

• Symptomatic OA of the hips, spine, or ankle, that interferes with the evaluation of the target knee

• Known hypersensitivity to acetaminophen or any of the study medications or their components

• Women of childbearing potential who are pregnant, nursing, or planning to become pregnant

• History of recurrent severe allergic or immune mediated reactions or other immune disorders

• Vascular insufficiency of lower limbs or peripheral neuropathy severe enough to interfere with the study evaluation

• Intra-arterial corticosteroid (investigational or marketed) in any joint within 3 months of Screening and Enrollment Visit

• Current treatment, or treatment within the 2 years prior to the Screening and Enrollment Visit, for any malignancy

• Active liver disease based on liver profile of aspartate aminotransferase, alanine aminotransferase, and conjugated bilirubin >2 times the upper limit of normal

• Renal insufficiency based on serum creatinine >2.0mg/dL

• Any intercurrent chronic disease or condition that might interfere with the completion of the study

• Current alcoholism and/or any known current addiction to pain medications

• Participation in any experimental device study within 6 months prior to the Screening and Enrollment Visit, or participation in an experimental drug study within 1 month prior to the Screening and Enrollment Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mehra	San Diego	California	United States	92103
2	Bretton	Albuquerque	New Mexico	United States	87102

Sponsors and Collaborators

• Actavis Inc.

Investigators

• Study Director: Henry Lay, PhD, Actavis Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actavis Inc.
• ClinicalTrials.gov Identifier: NCT02495857
• Other Study ID Numbers: AV01.2015-0863
• First Posted: Jul 13, 2015
• Last Update Posted: Jun 23, 2020
• Last Verified: Jun 1, 2020

• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Hyaluronic Acid; Viscosupplements

Study Results

Participant Flow

Recruitment Details	The populations for this study included the Safety Population, the modified Intent-to-Treat (mITT) population, and the Per-Protocol (PP) Population.

Arm/Group Title	Hyaluronate Injectable Viscosupplement	Euflexxa IA Injection	Placebo Solution
Arm/Group Description	Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2mL to the knee once weekly for 3 weeks.
Period Title: Overall Study
STARTED	200	200	199
COMPLETED	178	184	181
NOT COMPLETED	22	16	18

Baseline Characteristics

Arm/Group Title	Generic Hyaluronate Injectable, 1%	Euflexxa Injection 1%	Vehicle Solution	Total
Arm/Group Description	Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2mL to the knee once weekly for 3 weeks.	Total of all reporting groups
Overall Participants	200	200	199	599
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.2 (9.45)	63.3 (9.36)	62.0 (10.04)	62.8 (9.62)
Sex: Female, Male (Count of Participants)
Female	79 39.5%	83 41.5%	89 44.7%	251 41.9%
Male	121 60.5%	117 58.5%	110 55.3%	348 58.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	70 35%	54 27%	54 27.1%	178 29.7%
Not Hispanic or Latino	130 65%	146 73%	145 72.9%	421 70.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.5%	2 1%	0 0%	3 0.5%
Asian	13 6.5%	10 5%	8 4%	31 5.2%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	0 0%	1 0.2%
Black or African American	20 10%	27 13.5%	31 15.6%	78 13%
White	163 81.5%	161 80.5%	160 80.4%	484 80.8%
More than one race	1 0.5%	0 0%	0 0%	1 0.2%
Unknown or Not Reported	1 0.5%	0 0%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)]
Description	The primary effectiveness endpoint was the change from Baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) pain score in the target knee at Week 26.The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain.
Time Frame	Baseline and 26 weeks

Outcome Measure Data

Analysis Population Description

Intention-To-Treat (ITT) Population

Arm/Group Title	Generic Hyaluronate Injectable, 1%	Euflexxa Injection 1%	Vehicle Solution
Arm/Group Description	Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2mL to the knee once weekly for 3 weeks.
Measure Participants	200	200	199
Mean (Standard Deviation) [Percentage of change from baseline]	-51.43 (41.012)	-54.49 (37.042)	-36.86 (52.826)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Hyaluronate Injectable, 1%, Vehicle Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	36.18
	Confidence Interval	(2-Sided) 95%; 10.25 to 62.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26
Description	The change from Baseline in the WOMAC pain score over time (baseline to Week 1, Week 6, Week 12 and Week 26) using Western Ontario and McMaster Universities Arthritis Index (WOMAC®)].The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Intention-To-Treat (ITT) Population

Arm/Group Title	Generic Hyaluronate Injectable, 1%	Euflexxa Injection 1%	Vehicle Solution
Arm/Group Description	Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2mL to the knee once weekly for 3 weeks.
Measure Participants	200	200	199
Week 1	-14.10 (30.568)	-15.13 (27.341)	-15.08 (32.680)
Week 6	-46.28 (41.042)	-49.91 (35.543)	-33.96 (68.782)
Week 12	-51.96 (40.894)	-52.47 (35.749)	-39.16 (58.080)
Week 26	-51.43 (41.012)	-54.49 (37.042)	-36.86 (52.826)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Hyaluronate Injectable, 1%, Euflexxa Injection 1%
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	36.19
	Confidence Interval	(2-Sided) 95%; 10.25 to 62.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)]
Description	The change from baseline in the stiffness in the target knee at Week 26. The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of stiffness score was 0 to 100 mm with higher scores for worse stiffness.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

Intention-To-Treat (ITT) Population

Arm/Group Title	Generic Hyaluronate Injectable, 1%	Euflexxa Injection 1%	Vehicle Solution
Arm/Group Description	Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.	Patients received intra-articular (IA) injection of 2mL to the knee once weekly for 3 weeks.
Measure Participants	200	200	199
Mean (Standard Deviation) [percentage of change from baseline]	-47.37 (45.275)	-47.25 (63.020)	-35.77 (63.103)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Hyaluronate Injectable, 1%, Euflexxa Injection 1%
	Comments
	Type of Statistical Test	Equivalence
	Comments	From baseline to week 26 visit, change in the WOMAC stiffness score was evaluated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.63
	Confidence Interval	(2-Sided) 95%; -13.61 to 8.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Data was collected for 26 weeks.
Arm/Group Title	Generic Hyaluronate Injectable, 1%		Euflexxa Injection 1%		Vehicle Solution
Arm/Group Description	Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.		Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.		Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks.
All Cause Mortality
	Generic Hyaluronate Injectable, 1%		Euflexxa Injection 1%		Vehicle Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/199 (0%)		0/199 (0%)		0/197 (0%)
Serious Adverse Events
	Generic Hyaluronate Injectable, 1%		Euflexxa Injection 1%		Vehicle Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/199 (2.5%)		2/199 (1%)		3/197 (1.5%)
Cardiac disorders
Atrioventricular block complete	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Cardiac arrest	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Cardiac failure congestive	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Cardiomyopathy	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Ear and labyrinth disorders
Vertigo	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Gastrointestinal disorders
Enteritis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Gastritis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Gastrointestinal haemorrhage	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Intestinal ischaemia	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Hepatobiliary disorders
Cholelithiasis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Osteoarthritis	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Prostate cancer	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Renal and urinary disorders
Nephrolithiasis	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Other (Not Including Serious) Adverse Events
	Generic Hyaluronate Injectable, 1%		Euflexxa Injection 1%		Vehicle Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/199 (38.2%)		82/199 (41.2%)		76/197 (38.6%)
Blood and lymphatic system disorders
Lymphadenopathy	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Cardiac disorders
Atrioventricular block complete	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Cardiac arrest	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Cardiac failure congestive	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Cardiomyopathy	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Ear and labyrinth disorders
Vertigo	1/199 (0.5%)		0/199 (0%)		1/197 (0.5%)
Meniere's disease	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Eye disorders
Cataract	1/199 (0.5%)		2/199 (1%)		0/197 (0%)
Conjunctivitis allergic	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Eyelid cyst	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Gastrointestinal disorders
Diarrhoea	2/199 (1%)		2/199 (1%)		0/197 (0%)
Nausea	2/199 (1%)		0/199 (0%)		1/197 (0.5%)
Abdominal pain upper	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Abdominal tenderness	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Anal fissure	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Colitis	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Colitis ulcerative	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Dry mouth	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Dyspepsia	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Enteritis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Gastritis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Gastrointestinal haemorrhage	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Gastrooesophageal reflux disease	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Intestinal ischaemia	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Pancreatitis acute	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Vomiting	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
General disorders
Injection site joint pain	5/199 (2.5%)		1/199 (0.5%)		12/197 (6.1%)
Injection site joint effusion	1/199 (0.5%)		4/199 (2%)		3/197 (1.5%)
Injection site joint swelling	1/199 (0.5%)		2/199 (1%)		3/197 (1.5%)
Injection site pain	2/199 (1%)		2/199 (1%)		1/197 (0.5%)
Oedema peripheral	2/199 (1%)		1/199 (0.5%)		2/197 (1%)
Injection site erythema	0/199 (0%)		2/199 (1%)		0/197 (0%)
Injection site warmth	0/199 (0%)		2/199 (1%)		0/197 (0%)
Pain	1/199 (0.5%)		0/199 (0%)		1/197 (0.5%)
Asthenia	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Fatigue	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Injection site bruising	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Injection site haemorrhage	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Injection site reaction	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Injection site swelling	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Mass	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Pyrexia	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Swelling	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Tenderness	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Hepatobiliary disorders
Cholelithiasis	0/199 (0%)		1/199 (0.5%)		1/197 (0.5%)
Cholecystitis chronic	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Immune system disorders
Hypersensitivity	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Seasonal allergy	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Infections and infestations
Upper respiratory tract infection	7/199 (3.5%)		7/199 (3.5%)		3/197 (1.5%)
Nasopharyngitis	5/199 (2.5%)		3/199 (1.5%)		8/197 (4.1%)
Bronchitis	5/199 (2.5%)		1/199 (0.5%)		0/197 (0%)
Urinary tract infection	2/199 (1%)		2/199 (1%)		2/197 (1%)
Sinusitis	0/199 (0%)		3/199 (1.5%)		1/197 (0.5%)
Diverticulitis	1/199 (0.5%)		1/199 (0.5%)		0/197 (0%)
Ear infection	0/199 (0%)		2/199 (1%)		0/197 (0%)
Herpes zoster	2/199 (1%)		0/199 (0%)		0/197 (0%)
Influenza	0/199 (0%)		1/199 (0.5%)		1/197 (0.5%)
Pharyngitis	1/199 (0.5%)		1/199 (0.5%)		0/197 (0%)
Acute sinusitis	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Bacterial infection	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Cellulitis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Cystitis	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Epididymitis	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Eye infection	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Fungal infection	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Gastroenteritis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Injection site infection	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Oophoritis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Otitis media	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Parotitis	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Rhinitis	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Tooth abscess	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Viral infection	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Viral upper respiratory tract infection	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Injury, poisoning and procedural complications
Muscle strain	2/199 (1%)		1/199 (0.5%)		1/197 (0.5%)
Ligament sprain	1/199 (0.5%)		1/199 (0.5%)		0/197 (0%)
Skin abrasion	0/199 (0%)		1/199 (0.5%)		1/197 (0.5%)
Arthropod sting	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Contusion	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Fibula fracture	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Intervertebral disc injury	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Joint injury	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Laceration	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Limb injury	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Meniscus injury	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Muscle injury	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Muscle rupture	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Procedural pain	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Soft tissue injury	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Wrist fracture	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Investigations
Blood pressure increased	1/199 (0.5%)		1/199 (0.5%)		0/197 (0%)
Blood glucose increased	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Cardiac murmur	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Heart rate irregular	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Metabolism and nutrition disorders
Vitamin D deficiency	1/199 (0.5%)		1/199 (0.5%)		0/197 (0%)
Hyperlipidaemia	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Type 2 diabetes mellitus	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	19/199 (9.5%)		26/199 (13.1%)		24/197 (12.2%)
Joint swelling	5/199 (2.5%)		3/199 (1.5%)		7/197 (3.6%)
Joint crepitation	5/199 (2.5%)		3/199 (1.5%)		4/197 (2%)
Joint effusion	4/199 (2%)		2/199 (1%)		4/197 (2%)
Back pain	2/199 (1%)		3/199 (1.5%)		3/197 (1.5%)
Musculoskeletal pain	1/199 (0.5%)		1/199 (0.5%)		2/197 (1%)
Osteoarthritis	3/199 (1.5%)		1/199 (0.5%)		0/197 (0%)
Pain in extremity	0/199 (0%)		3/199 (1.5%)		1/197 (0.5%)
Exostosis	1/199 (0.5%)		2/199 (1%)		0/197 (0%)
Joint stiffness	1/199 (0.5%)		1/199 (0.5%)		1/197 (0.5%)
Joint range of motion decreased	0/199 (0%)		1/199 (0.5%)		1/197 (0.5%)
Plantar fascitis	1/199 (0.5%)		0/199 (0%)		1/197 (0.5%)
Bone pain	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Bursitis	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Haemarthrosis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Joint instability	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Joint warmth	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Muscle spasms	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Muscle tightness	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Musculoskeletal chest pain	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Myalgia	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Neck pain	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Rotator cuff syndrome	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Spinal pain	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Tendonitis	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma	0/199 (0%)		2/199 (1%)		1/197 (0.5%)
Adenocarcinoma of colon	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Intraductal papilloma of breast	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Pancreatic neoplasm	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Prostate cancer	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Nervous system disorders
Headache	3/199 (1.5%)		3/199 (1.5%)		5/197 (2.5%)
Presyncope	1/199 (0.5%)		0/199 (0%)		2/197 (1%)
Sciatica	2/199 (1%)		1/199 (0.5%)		0/197 (0%)
Sinus headache	1/199 (0.5%)		0/199 (0%)		1/197 (0.5%)
Balance disorder	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Cerebral small vessel ischaemic disease	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Dizziness	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Memory impairment	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Paraesthesia	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Vertebrobasilar insufficiency	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Psychiatric disorders
Depression	0/199 (0%)		0/199 (0%)		2/197 (1%)
Anxiety	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Insomnia	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Renal and urinary disorders
Nephrolithiasis	1/199 (0.5%)		0/199 (0%)		1/197 (0.5%)
Pollakiuria	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Renal pain	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/199 (1.5%)		2/199 (1%)		0/197 (0%)
Nasal congestion	1/199 (0.5%)		1/199 (0.5%)		1/197 (0.5%)
Dyspnoea	1/199 (0.5%)		1/199 (0.5%)		0/197 (0%)
Atelectasis	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Chronic obstructive pulmonary disease	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Oropharyngeal pain	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Respiratory disorder	1/199 (0.5%)		0/199 (0%)		0/197 (0%)
Rhinitis allergic	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Skin and subcutaneous tissue disorders
Erythema	0/199 (0%)		0/199 (0%)		2/197 (1%)
Actinic keratosis	0/199 (0%)		1/199 (0.5%)		0/197 (0%)
Dermatitis contact	0/199 (0%)		0/199 (0%)		1/197 (0.5%)
Vascular disorders
Hypertension	1/199 (0.5%)		0/199 (0%)		0/197 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The results of the study may be published or presented by the Investigator(s) after the review by, and in consultation and agreement with the Sponsor, and such that confidential or proprietary information is not disclosed.