ALBATROSS-3: Fasitibant Intra-articular Injection in Patients With Symptomatic Osteoarthritis of the Knee

• Sponsor: Menarini Group (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02205814
• Collaborator: (none)
• Enrollment: 436
• Locations: 25
• Arms: 4
• Duration (Months): 9
• Patients Per Site: 17.4
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

This study is designed as a double-blind, randomised, placebo-controlled, four parallel arm, dose-finding study, to be conducted in approximately 26 sites, to evaluate the efficacy, safety, tolerability, and pharmacokinetics of single intra-articular (IA) injections of fasitibant in patients with symptomatic osteoarthritis (OA) of the knee.

Approximately 400 male and female patients 40-80 years old, with BMI < 30 kg/m² and with a clinical diagnosis of symptomatic primary osteoarthritis of the knee will be randomised to a total of 4 treatment arms. Each arm includes a single intra-articular injection of one of three dosages of fasitibant (low, intermediate and high dose) OR placebo. The randomisation ratio will be 1:1:1:1.

The primary efficacy variable will be the change of the Western Ontario and McMaster Universities Visual Analogue Scale 3.1 A (WOMAC VA 3.1 A) (total pain) subscore from baseline up to 2 weeks after randomisation. Safety will be assessed by monitoring adverse events and clinical laboratory tests; local tolerability at the injection site will also be assessed. In addition, the population pharmacokinetics and the exposure-response relationship will be evaluated.

The individual experimental clinical phase will last up to maximal 15 weeks encompassing 7 planned visits at site, including screening, randomisation, 4 follow-up visits and the End of study visit.

Condition or Disease	Intervention/Treatment	Phase
Knee Osteoarthritis	Drug: Fasitibant- low dose; Drug: Fasitibant- intermediate dose; Drug: Fasitibant- high dose; Drug: Placebo comparator	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 436 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomised, Placebo-controlled, Four Parallel Arm, Dose-finding Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Single Intra-articular Injections of Fasitibant in Patients With Symptomatic Osteoarthritis of the Knee.
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fasitibant low dose Drug: solution for intra-articular injection	Drug: Fasitibant- low dose; Single intra-articular injection of low dose of fasitibant
Experimental: Fasitibant intermediate dose Drug: solution for intra-articular injection	Drug: Fasitibant- intermediate dose; Single intra-articular injection of intermediate dose of fasitibant
Experimental: Fasitibant high dose Drug: solution for intra-articular injection	Drug: Fasitibant- high dose; Single intra-articular injection of high dose of fasitibant
Placebo Comparator: PLACEBO Drug: solution for intra-articular injection	Drug: Placebo comparator; Single intra-articular injection of placebo

Outcome Measures

Primary Outcome Measures

1. Change in WOMAC A [from baseline up to 2 weeks after randomisation]

   The validated Western Ontario and McMaster University questionnaire (WOMAC) was used to measure total knee pain choosing its visual analogue scale version (VAS). The WOMAC VA 3.1 A subscore (WOMAC A) ranges from 0 to 500 mm (summing up five VAS 0-100 mm) with higher scores indicating more pain.

Secondary Outcome Measures

1. Change in WOMAC INDEX [from baseline up to 6 weeks after randomisation]

   The WOMAC VA 3.1 Index score (WOMAC INDEX) is the sum of WOMAC A (total pain), WOMAC B (stiffness) and WOMAC C (functional impairment) subscores. The WOMAC INDEX score ranges from 0 to 2400 mm, with higher scores indicating higher disease burden.

2. Responder Rate According to OMERACT-OARSI Criteria [from baseline up to 6 weeks after randomisation]

   Percentage of responders according to Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria (OMERACT-OARSI criteria). Patients with at least 50 % improvement in pain or in function scores are considered responders. Alternatively, patients are considered responders if they show at least 20% improvement in at least two of the following scores: pain, function and Patients's Global Assessment (PGA) scores.

3. Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate [from baseline up to 6 weeks after randomisation]

   Response based on change ≥ 20 % from baseline for EQ-5D-5L index value

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female patients aged 40 to 80 years with BMI < 30 kg/m²

• Patient with Kellgren-Lawrence Grade 2 to 3, symptomatic primary osteoarthritis at the index knee (ACR criteria), for which an IA treatment is indicated

• Pain of moderate to severe intensity, even if treated with chronic doses of non steroidal antinflammatory drugs

Exclusion Criteria:

• History of hypersensitivity/allergy to drugs including paracetamol and to disinfectants

• Any pharmacological treatment of concomitant disease(s) started or changed during 4 weeks prior to randomisation, or likely to be changed during the course of the study

• Use of systemic or topical corticosteroids > 10 mg prednisolone equivalent per day, or immunosuppressant drugs

• Current use of any pain or OA medication (e.g. NSAIDs, COX-2 inhibitors, analgesics, antidepressive agents), including topical treatments

• Viscosupplementation to the target knee administered < 4 months prior to randomisation and/or scheduled during the course of the study

• Evidence of clinically significant hepatic disease or of moderate or severe renal insufficiency

• Current use of any medications that are substrate of CYP3A4 and/or moderate or strong CYP3A4 inhibitors

• Patients with any clinically relevant or unstable disease, or malignant neoplasms that, in the opinion of the Investigator, may pose the patient at risk, or confound the efficacy and safety results of the study

• Patients with any clinically relevant abnormal safety laboratory test results, and/or abnormalities in vital signs, and/or ECG parameters

• Pregnant and breastfeeding women

• Any sign of significant immunodeficiency, systemic infection, knee infection or knee bursitis

• Patients with bleeding diathesis or on therapy with anticoagulants

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tucson Orthopaedic Institute	Tucson	Arizona	United States	85712
2	Colorado Orthopaedic Consultants	Englewood	Colorado	United States	80110
3	Avail Clinical Research, LLC	Deland	Florida	United States	32720
4	Radiant Research	Columbus	Ohio	United States	43212
5	Columbus Clinical Research	Columbus	Ohio	United States	43213
6	Blair Orthopaedic Associates	Altoona	Pennsylvania	United States	16602
7	Tekton Research	Austin	Texas	United States	78745
8	Physicians Research Options, LLC	Draper	Utah	United States	84020
9	Spokan Joint Replacement Center	Spokane	Washington	United States	99218
10	Revmatologie s.r.o.	Brno		Czech Republic	638 00
11	Institute of Rheumatology, Charles University Faculty Hospital	Prague		Czech Republic	128 50
12	MEDICAL PLUS s.r.o	Uherske Hradiste		Czech Republic	686 01
13	Synexus Clinical Research GmbH, Research Centre Berlin	Berlin		Germany	1262
14	Synexus Clinical Research GmbH, Research Centre Bochum	Bochum		Germany	44787
15	Synexus Clinical Research GmbH, Research Centre Frankfurt	Frankfurt		Germany	60596
16	Clinical Research Hamburg GmbH	Hamburg		Germany	22143
17	Synexus Clinical Research GmbH, Research Centre Leipzig	Leipzig		Germany	04103
18	AmBeNet GmbH	Leipzig		Germany	04107
19	Dipartimento di Medicina Interna - SOD di Reumatologia Azienda - Ospedaliero Universitaria Careggi	Firenze	Tuscany	Italy	50139
20	Azienda Ospedaliero-Universitaria S.Anna/ Unità Operativa Complessa e Sezione di Reumatologia/Dipartimento di Medicina Clinica e Sperimentale	Cona		Italy	44124
21	Ospedale Galateo U.O. di Reumatologia	Lecce		Italy	73016
22	Ospedale Fornaroli/Unità Complessa di Reumatologia	Magenta		Italy	20013
23	Ospedale Luigi Sacco, Azienda Ospedaliera, Polo Universitario/Unità Operativa Complessa di Reumatologia	Milano		Italy	20157
24	Azienda Ospedaliera di Perugia/Policlinico di Monteluce/Unità Operativa diagnosi e cura delle malattie reumatiche	Perugia		Italy	06122
25	Centro Ricerche Cliniche di Verona	Verona		Italy	37134

Sponsors and Collaborators

• Menarini Group

Investigators

• Study Chair: Karel Pavelka, Professor, Institute of Rheumatology, Charles University Faculty Hospital, Na Slupi 4, 128 50 Prague 2, Czech Republic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Menarini Group
• ClinicalTrials.gov Identifier: NCT02205814
• Other Study ID Numbers: BKOS-04; 2013-004999-35
• First Posted: Jul 31, 2014
• Last Update Posted: Nov 3, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Menarini Group: Osteoarthritis, Knee; Arthritis; WOMAC; Injections, intra-articular; Fasitibant; MEN 16132
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; (4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium

Study Results

Participant Flow

Recruitment Details	The first patient was screened on 28th April 2014. The first patient was randomised on 6th May 2014. The last patient completed the study on 6th January 2015. The study was conducted in 25 study sites in Czech Republic, Germany, Italy and US.
Pre-assignment Detail	A total of 645 patients entered a 2-week Screening period (including wash out); 209 of them were screen failed. One patient randomised to PLACEBO did not receive the study treatment (counted for ITT but not in safety population). Five patients received the study treatment without randomisation (not counted for ITT, but in safety population).

Arm/Group Title	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	PLACEBO
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant	Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo
Period Title: Overall Study
STARTED	110	110	108	108
COMPLETED	108	109	103	104
NOT COMPLETED	2	1	5	4

Baseline Characteristics

Arm/Group Title	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	PLACEBO	Total
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant	Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo	Total of all reporting groups
Overall Participants	108	108	107	108	431
Age (years) [Mean (Standard Deviation) ]
Age	65.3 (7.61)	63.2 (8.73)	64.7 (8.43)	64.4 (8.50)	64.4 (8.34)
Sex: Female, Male (Count of Participants)
Female	62 57.4%	71 65.7%	64 59.8%	66 61.1%	263 61%
Male	46 42.6%	37 34.3%	43 40.2%	42 38.9%	168 39%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 0.9%	0 0%	1 0.9%	2 1.9%	4 0.9%
Not Hispanic or Latino	107 99.1%	108 100%	106 99.1%	106 98.1%	427 99.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	27.1 (2.12)	26.5 (2.83)	27.1 (2.35)	27.0 (2.60)	26.9 (2.50)
WOMAC A (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	286.5 (40.4)	282.7 (40.08)	278.3 (38.11)	275.5 (39.81)	280.8 (39.61)
WOMAC INDEX (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1321.5 (278.88)	1275.4 (283.60)	1282.6 (274.50)	1293.5 (239.73)	1293.3 (269.35)
EQ VAS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	63.1 (20.54)	64.3 (17.21)	67.4 (18.18)	65.7 (19.47)	65.1 (18.89)

Outcome Measures

1. Primary Outcome

Title	Change in WOMAC A
Description	The validated Western Ontario and McMaster University questionnaire (WOMAC) was used to measure total knee pain choosing its visual analogue scale version (VAS). The WOMAC VA 3.1 A subscore (WOMAC A) ranges from 0 to 500 mm (summing up five VAS 0-100 mm) with higher scores indicating more pain.
Time Frame	from baseline up to 2 weeks after randomisation

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis was performed on the ITT-population (n=431).

Arm/Group Title	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	PLACEBO
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant	Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo
Measure Participants	108	108	107	108
Week 1 after randomisation	-91.8 (101.85)	-110.0 (99.48)	-109.8 (94.65)	-93.7 (94.15)
Week 2 after randomisation	-106.1 (101.88)	-131.5 (96.41)	-115.9 (104.61)	-117.2 (90.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fasitibant Low Dose, Fasitibant Intermediate Dose, Fasitibant High Dose, PLACEBO
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Fourhundred evaluable patients were supposed to provide approximately 80% power in rejecting the null hypothesis of equality between any dose of fasitibant and placebo based on previous results and an overall significance level of 5% (two-sided).
	Method	mixed linear model for repeated measures
	Comments

2. Secondary Outcome

Title	Change in WOMAC INDEX
Description	The WOMAC VA 3.1 Index score (WOMAC INDEX) is the sum of WOMAC A (total pain), WOMAC B (stiffness) and WOMAC C (functional impairment) subscores. The WOMAC INDEX score ranges from 0 to 2400 mm, with higher scores indicating higher disease burden.
Time Frame	from baseline up to 6 weeks after randomisation

Outcome Measure Data

Analysis Population Description

The secondary efficacy analysis was performed on the ITT population (n=431).

Arm/Group Title	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	PLACEBO
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant	Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo
Measure Participants	108	108	107	108
Week 1 after randomisation	-396.0 (464.24)	-460.5 (469.68)	-445.2 (424.07)	-413.2 (452.04)
Week 2 after randomisation	-448.0 (477.95)	-563.0 (456.71)	-488.7 (480.39)	-517.7 (440.75)
week 4 after randomisation	-516.4 (513.70)	-628.4 (500.17)	-493.4 (513.94)	-562.3 (487.25)
Week 6 after randomisation	-566.3 (525.63)	-653.8 (516.31)	-547.6 (522.37)	-581.3 (503.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fasitibant Low Dose, Fasitibant Intermediate Dose, Fasitibant High Dose, PLACEBO
	Comments	All secondary efficacy variables were analysed on the ITT population only. Multiplicity was adjusted using the Hochberg procedure. The continuous secondary efficacy variables were analysed over time and were treated in the same way as the primary efficacy variable with respective output.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Fourhundred evaluable patients were supposed to provide approximately 80% power in rejecting the null hypothesis of equality between any dose of fasitibant and placebo based on previous results and an overall significance level of 5% (two-sided).
	Method	mixed linear model for repeated measures
	Comments

3. Secondary Outcome

Title	Responder Rate According to OMERACT-OARSI Criteria
Description	Percentage of responders according to Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria (OMERACT-OARSI criteria). Patients with at least 50 % improvement in pain or in function scores are considered responders. Alternatively, patients are considered responders if they show at least 20% improvement in at least two of the following scores: pain, function and Patients's Global Assessment (PGA) scores.
Time Frame	from baseline up to 6 weeks after randomisation

Outcome Measure Data

Analysis Population Description

The secondary efficacy variables were analysed in the ITT population (n=431).

Arm/Group Title	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	PLACEBO
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant	Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo
Measure Participants	108	108	107	108
Week 1 after randomisation	51.9	56.5	63.6	55.6
Week 2 after randomisation	59.3	72.2	62.6	68.5
Week 4 after randomisation	65.7	72.2	65.4	66.7
Week 6 after randomisation	71.3	74.1	67.3	67.6

4. Secondary Outcome

Title	Euro Quality of Life Questionnaire (EQ-5D-5L) Responder Rate
Description	Response based on change ≥ 20 % from baseline for EQ-5D-5L index value
Time Frame	from baseline up to 6 weeks after randomisation

Outcome Measure Data

Analysis Population Description

The secondary efficacy analysis was performed on the ITT-population (n=431).

Arm/Group Title	Fasitibant Low Dose	Fasitibant Intermediate Dose	Fasitibant High Dose	PLACEBO
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant	Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant	Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo
Measure Participants	108	108	107	108
Week 2 after randomisation	18.5	18.5	20.6	24.1
Week 6 after randomisation	23.1	27.8	25.2	21.3

Adverse Events

Time Frame	For all patients receiving the study treatment (safety population, N=435), adverse event data were collected over a period of maximal 15 weeks.
Adverse Event Reporting Description	An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Arm/Group Title	Fasitibant Low Dose		Fasitibant Intermediate Dose		Fasitibant High Dose		PLACEBO
Arm/Group Description	Drug: solution for intra-articular injection Fasitibant- low dose: Single intra-articular injection of low dose of fasitibant		Drug: solution for intra-articular injection Fasitibant- intermediate dose: Single intra-articular injection of intermediate dose of fasitibant		Drug: solution for intra-articular injection Fasitibant- high dose: Single intra-articular injection of high dose of fasitibant		Drug: solution for intra-articular injection Placebo comparator: Single intra-articular injection of placebo
All Cause Mortality
	Fasitibant Low Dose		Fasitibant Intermediate Dose		Fasitibant High Dose		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Fasitibant Low Dose		Fasitibant Intermediate Dose		Fasitibant High Dose		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/110 (1.8%)		2/110 (1.8%)		2/108 (1.9%)		4/107 (3.7%)
Gastrointestinal disorders
Inguinal hernia	0/110 (0%)	0	0/110 (0%)	0	1/108 (0.9%)	1	0/107 (0%)	0
Infections and infestations
Urinary tract infection	0/110 (0%)	0	0/110 (0%)	0	1/108 (0.9%)	1	0/107 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	0/110 (0%)	0	0/110 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1
Humerus fracture	0/110 (0%)	0	1/110 (0.9%)	1	0/108 (0%)	0	0/107 (0%)	0
Thoracic vertebral fracture	0/110 (0%)	0	1/110 (0.9%)	1	0/108 (0%)	0	0/107 (0%)	0
Investigations
Hepatic enzyme increased	0/110 (0%)	0	0/110 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1
Metabolism and nutrition disorders
Hypercalcaemia	0/110 (0%)	0	0/110 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/110 (0%)	0	0/110 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer female	1/110 (0.9%)	1	0/110 (0%)	0	0/108 (0%)	0	0/107 (0%)	0
Respiratory, thoracic and mediastinal disorders
Laryngeal oedema	1/110 (0.9%)	1	0/110 (0%)	0	0/108 (0%)	0	0/107 (0%)	0
Surgical and medical procedures
Hernia repair	0/110 (0%)	0	0/110 (0%)	0	1/108 (0.9%)	1	0/107 (0%)	0
Knee arthroplasty	0/110 (0%)	0	0/110 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1
Malignant breast lump removal	1/110 (0.9%)	1	0/110 (0%)	0	0/108 (0%)	0	0/107 (0%)	0
Other (Not Including Serious) Adverse Events
	Fasitibant Low Dose		Fasitibant Intermediate Dose		Fasitibant High Dose		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/110 (25.5%)		46/110 (41.8%)		36/108 (33.3%)		44/107 (41.1%)
Gastrointestinal disorders
Diarrhea	1/110 (0.9%)	1	1/110 (0.9%)	1	2/108 (1.9%)	2	3/107 (2.8%)	3
Toothache	1/110 (0.9%)	1	1/110 (0.9%)	2	1/108 (0.9%)	1	2/107 (1.9%)	3
Abdominal pain	0/110 (0%)	0	2/110 (1.8%)	2	0/108 (0%)	0	2/107 (1.9%)	2
General disorders
Injection site haematoma	0/110 (0%)	0	2/110 (1.8%)	2	0/108 (0%)	0	1/107 (0.9%)	1
Infections and infestations
Nasopharyngitis	4/110 (3.6%)	4	17/110 (15.5%)	18	11/108 (10.2%)	11	13/107 (12.1%)	13
Gastroenteritis	0/110 (0%)	0	2/110 (1.8%)	2	0/108 (0%)	0	0/107 (0%)	0
Rhinitis	2/110 (1.8%)	2	1/110 (0.9%)	1	2/108 (1.9%)	2	0/107 (0%)	0
Urinary tract infection	3/110 (2.7%)	3	1/110 (0.9%)	1	2/108 (1.9%)	2	3/107 (2.8%)	3
Injury, poisoning and procedural complications
Contusion	2/110 (1.8%)	2	0/110 (0%)	0	0/108 (0%)	0	1/107 (0.9%)	1
Ligament sprain	0/110 (0%)	0	2/110 (1.8%)	2	0/108 (0%)	0	0/107 (0%)	0
Investigations
Gamma-glutamyltransferase increased	0/110 (0%)	0	0/110 (0%)	0	2/108 (1.9%)	2	0/107 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	4/110 (3.6%)	6	7/110 (6.4%)	7	5/108 (4.6%)	6	8/107 (7.5%)	8
Back pain	2/110 (1.8%)	2	4/110 (3.6%)	5	5/108 (4.6%)	5	6/107 (5.6%)	6
Joint swelling	1/110 (0.9%)	1	1/110 (0.9%)	1	1/108 (0.9%)	1	2/107 (1.9%)	2
Muscle spasms	1/110 (0.9%)	1	0/110 (0%)	0	2/108 (1.9%)	2	1/107 (0.9%)	1
Musculoskeletal pain	0/110 (0%)	0	2/110 (1.8%)	2	0/108 (0%)	0	0/107 (0%)	0
Pain in extremity	2/110 (1.8%)	2	0/110 (0%)	0	1/108 (0.9%)	1	0/107 (0%)	0
Nervous system disorders
Headache	3/110 (2.7%)	4	3/110 (2.7%)	4	1/108 (0.9%)	1	2/107 (1.9%)	2
Vascular disorders
Hypertension	2/110 (1.8%)	2	0/110 (0%)	0	1/108 (0.9%)	1	0/107 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Prior to submitting the results of this study for publication or presentation, the Investigator will allow the sponsor at least 30 days time to review and comment upon the publication manuscript. It is agreed, that the results of the study will not be submitted for presentation, abstract, poster exhibition, or publication by the investigator until the sponsor has reviewed/commented and agreed to any publication.