To Evaluate The Safety of SAR153191 (REGN88) and Tocilizumab Added to Other RA Drugs in Patients With RA Who Are Not Responding to or Intolerant of Anti-TNF Therapy (SARIL-RA-ASCERTAIN)

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01768572
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 202
• Locations: 78
• Arms: 3
• Duration (Months): 19
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Primary Objective:

To assess, in the same study, the safety of sarilumab and tocilizumab in participants with rheumatoid arthritis (RA) who were inadequate responders to or intolerant of tumor necrosis factor (TNF) antagonists.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: sarilumab SAR153191 (REGN88); Drug: tocilizumab; Drug: hydroxychloroquine; Drug: methotrexate; Drug: sulfasalazine; Drug: leflunomide; Drug: subcutaneous placebo; Drug: intravenous placebo	Phase 3

Detailed Description

Total study duration was up to 34 weeks: Screening up to 28 days, treatment phase of 24 weeks, and post-treatment follow-up of 6 weeks.

After completion of the treatment phase of this study, participants were eligible to enter a long term safety study (LTS11210) for active treatment with SAR153191 (REGN88).

Study Design

• Study Type: Interventional
• Actual Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Double-Dummy Study Assessing The Safety and Tolerability of Sarilumab and Tocilizumab In Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF Antagonists
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sarilumab 150 mg q2w Sarilumab 150 mg subcutaneous (SC) injection once every 2 weeks (q2w) and placebo intravenous (IV) infusion once every 4 weeks (q4w) was added to one or a combination of the nonbiologic disease modifying antirheumatic drug (DMARD), hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate.	Drug: sarilumab SAR153191 (REGN88); Pharmaceutical form: solution Route of administration: subcutaneous; Drug: hydroxychloroquine; Dispensed according to local practice.; Drug: methotrexate; Dispensed according to local practice.; Drug: sulfasalazine; Dispensed according to local practice.; Drug: leflunomide; Dispensed according to local practice.; Drug: intravenous placebo; Pharmaceutical form: solution Route of administration: intravenous
Experimental: Sarilumab 200 mg q2w Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD, hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate.	Drug: sarilumab SAR153191 (REGN88); Pharmaceutical form: solution Route of administration: subcutaneous; Drug: hydroxychloroquine; Dispensed according to local practice.; Drug: methotrexate; Dispensed according to local practice.; Drug: sulfasalazine; Dispensed according to local practice.; Drug: leflunomide; Dispensed according to local practice.; Drug: intravenous placebo; Pharmaceutical form: solution Route of administration: intravenous
Active Comparator: Tocilizumab q4w Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD, hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate.	Drug: tocilizumab; Pharmaceutical form: solution Route of administration: intravenous; Drug: hydroxychloroquine; Dispensed according to local practice.; Drug: methotrexate; Dispensed according to local practice.; Drug: sulfasalazine; Dispensed according to local practice.; Drug: leflunomide; Dispensed according to local practice.; Drug: subcutaneous placebo; Pharmaceutical form: solution Route of administration: subcutaneous

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Up to 211 days]

   Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. All adverse events that occurred from the first dose of the study drug administration up to 60 days after the end of treatment visit were considered as TEAEs. Serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. A summary of SAEs, all other non-serious AEs, regardless of causality, are reported in AE section.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

Diagnosis of RA was, according to the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2010 Rheumatoid Arthritis Classification Criteria with ≥ 3 months disease duration

ACR Class I-III functional status, was based on the 1991 revised criteria. Moderate-to-severely active RA. Anti-TNF therapy failures, was defined as participants with an inadequate clinical response was defined by the investigator, after being treated for at least 3 consecutive months, and/or intolerance to at least 1 TNF-antagonist, resulting in or requiring their discontinuation. TNF-antagonists were include, but were not limited to, etanercept, infliximab, adalimumab, golimumab and/or certolizumab pegol

Continuous treatment with one or a combination of non-biologic disease modifying antirheumatic drugs (DMARDs) for at least 12 consecutive weeks prior to screening and on a stable dose(s) for at least 6 consecutive weeks prior to screening:

• Methotrexate - 10 to 25 milligram/week orally or parenteral (or per local labelling requirements if the dose range differs)

• Leflunomide - 10 to 20 mg orally daily

• Sulfasalazine (SSZ) - 1000 to 3000 mg orally daily

• Hydroxychloroquine (HCQ) - 200 to 400 mg orally daily

Exclusion criteria:

Participants <18 years of age. Use of parenteral corticosteroids or intra-articular corticosteroids within 4 weeks prior to screening

Use of oral corticosteroids in a dose higher than prednisone 10 mg or equivalent per day, or a change in dosage within 4 weeks prior to screening

Past history of, or current, autoimmune or inflammatory systemic or localized joint disease(s) other than RA

History of juvenile idiopathic arthritis or arthritis onset prior to age 16. Severe systemic RA, including but not limited to vasculitis, pulmonary fibrosis, and/or Felty's syndrome

Participation in any clinical research study that evaluated an investigational drug or therapy within 5 half-lives or 60 days of the Screening Visit, whichever was longer

Participants with active tuberculosis or latent tuberculosis infection. Prior or current history of interstitial lung disease. Prior treatment with anti-interleukin (IL) -6 or anti-IL-6R therapies, including but not limited to tocilizumab or sarilumab

Treatment with anti-TNF agents, as follows:

• Etanercept: within 28 days prior to randomization

• Infliximab, adalimumab, golimumab, certolizumab pegol: within 42 days prior to randomization

Treatment with RA-directed biologic agents with non- TNF-α antagonist mechanisms without adequate washout as follows:

• Anakinra: within 28 days prior to randomization

• Abatacept: within 42 days prior to randomization

• Rituximab or other cell depleting agent: Within 6 months prior to randomization or until total lymphocyte count and CD 19+ lymphocyte count were normalized, or whichever was longer

Prior treatment with a janus kinase (JAK) inhibitor (eg, tofacitinib). Participants with a history of invasive opportunistic infection. Prior or current history of malignancy, including lymphoproliferative diseases, other than adequately-treated carcinoma in-situ of the cervix, nonmetastatic squamous cell or basal cell carcinoma of the skin, within 5 years prior to the randomization (baseline) visit

Prior or current history of other significant concomitant illness(es) that, according to Investigator's judgement, was adversely affect the participant's participation in the study.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 840152	Huntsville	Alabama	United States	35801
2	Investigational Site Number 840151	Colorado Springs	Colorado	United States	80903
3	Investigational Site Number 840153	Aventura	Florida	United States	33180
4	Investigational Site Number 840033	Fort Lauderdale	Florida	United States	33334
5	Investigational Site Number 840048	Miami	Florida	United States	33155
6	Investigational Site Number 840155	Palm Harbor	Florida	United States	34684
7	Investigational Site Number 840013	Wheaton	Maryland	United States	20902
8	Investigational Site Number 840154	Boston	Massachusetts	United States	02115
9	Investigational Site Number 840150	Lansing	Michigan	United States	48910
10	Investigational Site Number 840062	Reading	Pennsylvania	United States	19611
11	Investigational Site Number 840038	Austin	Texas	United States	78705
12	Investigational Site Number 840022	Dallas	Texas	United States	75235
13	Investigational Site Number 840156	Dallas	Texas	United States	75246
14	Investigational Site Number 840074	Mesquite	Texas	United States	75150
15	Investigational Site Number 032006	Caba		Argentina	C1015ABO
16	Investigational Site Number 032010	Ramos Mejia		Argentina	B1704ETD
17	Investigational Site Number 032013	Rosario		Argentina	S200PBJ
18	Investigational Site Number 032015	San Fernando		Argentina
19	Investigational Site Number 032004	San Miguel De Tucuman		Argentina	4000
20	Investigational Site Number 032005	Tucuman		Argentina	4000
21	Investigational Site Number 056010	Leuven		Belgium	3000
22	Investigational Site Number 076001	Curitiba		Brazil	80060-240
23	Investigational Site Number 076030	Sao Jose Do Rio Preto		Brazil	15090-000
24	Investigational Site Number 203009	Liberec		Czechia	46063
25	Investigational Site Number 203011	Praha 2		Czechia	12850
26	Investigational Site Number 203010	Praha 4		Czechia	140 00
27	Investigational Site Number 233010	Tallinn		Estonia	10138
28	Investigational Site Number 233002	Tallinn		Estonia	13419
29	Investigational Site Number 246001	Helsinki		Finland	00290
30	Investigational Site Number 246010	Riihimäki		Finland	11120
31	Investigational Site Number 348014	Budapest		Hungary	1027
32	Investigational Site Number 348022	Budapest		Hungary	1036
33	Investigational Site Number 348021	Esztergom		Hungary	2500
34	Investigational Site Number 348016	Kistarcsa		Hungary	2143
35	Investigational Site Number 348009	Szolnok		Hungary	5000
36	Investigational Site Number 348015	Szombathely		Hungary	9700
37	Investigational Site Number 376010	Haifa		Israel	31096
38	Investigational Site Number 376011	Tel Aviv		Israel	64239
39	Investigational Site Number 380002	Firenze		Italy	50141
40	Investigational Site Number 380005	Genova		Italy	16132
41	Investigational Site Number 484008	Durango		Mexico	34080
42	Investigational Site Number 484035	Leon		Mexico	37000
43	Investigational Site Number 484009	Merida		Mexico	97000
44	Investigational Site Number 484001	México, D.F.		Mexico	11850
45	Investigational Site Number 484036	Zapopan		Mexico	44280
46	Investigational Site Number 528010	Amsterdam		Netherlands	1056 AB
47	Investigational Site Number 528001	Leiden		Netherlands	2333 ZA
48	Investigational Site Number 578010	Kristiansand		Norway	4604
49	Investigational Site Number 578006	Tønsberg		Norway	3105
50	Investigational Site Number 616019	Bydgoszcz		Poland	85-168
51	Investigational Site Number 616054	Bytom		Poland	41-902
52	Investigational Site Number 616030	Lublin		Poland	20-090
53	Investigational Site Number 616031	Warszawa		Poland	01-518
54	Investigational Site Number 616017	Warszawa		Poland	02-653
55	Investigational Site Number 642006	Braila		Romania	810019
56	Investigational Site Number 642020	Bucharest		Romania	020125
57	Investigational Site Number 642010	Bucharest		Romania
58	Investigational Site Number 642021	Bucuresti		Romania	010584
59	Investigational Site Number 642001	Bucuresti		Romania	010976
60	Investigational Site Number 642022	Targoviste		Romania	130083
61	Investigational Site Number 643017	Kemerovo		Russian Federation	650066
62	Investigational Site Number 643020	Moscow		Russian Federation	115404
63	Investigational Site Number 643001	Moscow		Russian Federation	115522
64	Investigational Site Number 643002	Moscow		Russian Federation	117997
65	Investigational Site Number 643031	Moscow		Russian Federation	121374
66	Investigational Site Number 643030	Moscow		Russian Federation	125284
67	Investigational Site Number 643032	St-Petersburg		Russian Federation	191186
68	Investigational Site Number 724020	Barcelona		Spain	08035
69	Investigational Site Number 724021	Santander		Spain	39008
70	Investigational Site Number 724022	Sevilla		Spain	41010
71	Investigational Site Number 752004	Malmö		Sweden	205 02
72	Investigational Site Number 752002	Uppsala		Sweden	751 85
73	Investigational Site Number 826004	Doncaster		United Kingdom	DN2 5LT
74	Investigational Site Number 826006	Edinburgh		United Kingdom	EH4 2XU
75	Investigational Site Number 826001	Leeds		United Kingdom	LS7 4SA
76	Investigational Site Number 826002	London		United Kingdom	E11 1NR
77	Investigational Site Number 826005	Southampton		United Kingdom	SO16 6YD
78	Investigational Site Number 826025	Wigan		United Kingdom	WN6 9EP

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01768572
• Other Study ID Numbers: SFY13370; 2012-003536-23; U1111-1133-7839
• First Posted: Jan 15, 2013
• Last Update Posted: Jun 26, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Hydroxychloroquine; Sulfasalazine; Methotrexate; Leflunomide

Study Results

Participant Flow

Recruitment Details	The study was conducted at 78 centers in 19 countries. A total of 389 participants were screened between 25 March 2013 and 02 April 2014, 187 of whom were screen failures. Screen failures were mainly due to failure to meet inclusion and exclusion criteria.
Pre-assignment Detail	Randomization of participants were stratified by region and screening value of absolute neutrophil count. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in 1:1:2 (sarilumab 150 mg q2w: sarilumab 200 mg q2w: tocilizumab q4w). 202 participants were randomized.

Arm/Group Title	Sarilumab 150 mg q2w	Sarilumab 200 mg q2w	Tocilizumab q4w
Arm/Group Description	Sarilumab 150 mg subcutaneous (SC) injection once every 2 weeks (q2w) and placebo intravenous (IV) infusion once every 4 weeks (q4w) was added to one or a combination of the nonbiologic disease modifying antirheumatic drug (DMARD) for 24 weeks.	Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.	Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD for 24 weeks. Dose for tocilizumab could be up-titrated to 8 mg/kg or down-titrated to 4 mg/kg based on clinical response as per Investigator's discretion.
Period Title: Overall Study
STARTED	49	51	102
COMPLETED	40	39	96
NOT COMPLETED	9	12	6

Baseline Characteristics

Arm/Group Title	Sarilumab 150 mg q2w	Sarilumab 200 mg q2w	Tocilizumab q4w	Total
Arm/Group Description	Sarilumab 150 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.	Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.	Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD for 24 weeks. Dose for tocilizumab could be up-titrated to 8 mg/kg or down-titrated to 4 mg/kg based on clinical response as per Investigator's discretion.	Total of all reporting groups
Overall Participants	49	51	102	202
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.8 (12.1)	51.7 (13.1)	50.4 (13.0)	51.8 (12.8)
Sex: Female, Male (Count of Participants)
Female	41 83.7%	39 76.5%	82 80.4%	162 80.2%
Male	8 16.3%	12 23.5%	20 19.6%	40 19.8%
Duration of rheumatoid arthritis (RA) since diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.59 (8.24)	10.45 (7.57)	10.84 (8.91)	11.41 (8.48)
RA functional class (participants) [Number]
I	10 20.4%	4 7.8%	16 15.7%	30 14.9%
II	25 51%	33 64.7%	62 60.8%	120 59.4%
III	14 28.6%	14 27.5%	24 23.5%	52 25.7%
IV	0 0%	0 0%	0 0%	0 0%
Health Assessment Questionnaire Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.63 (0.66)	1.71 (0.60)	1.78 (0.63)	1.72 (0.63)
Disease Activity Score for 28 Joints- C-reactive protein (DAS28-CRP) (score on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on scale]	5.85 (0.92)	5.88 (0.97)	5.91 (1.01)	5.89 (0.97)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. All adverse events that occurred from the first dose of the study drug administration up to 60 days after the end of treatment visit were considered as TEAEs. Serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. A summary of SAEs, all other non-serious AEs, regardless of causality, are reported in AE section.
Time Frame	Up to 211 days

Outcome Measure Data

Analysis Population Description

The safety population consisted of all randomized participants who received at least 1 dose or a partial dose of study drug analyzed according to the treatment actually received.

Arm/Group Title	Sarilumab 150 mg q2w	Sarilumab 200 mg q2w	Tocilizumab q4w
Arm/Group Description	Sarilumab 150 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.	Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.	Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD for 24 weeks. Dose for tocilizumab could be up-titrated to 8 mg/kg or down-titrated to 4 mg/kg based on clinical response as per Investigator's discretion.
Measure Participants	49	51	102
Any TEAE	33 67.3%	36 70.6%	68 66.7%
Any treatment-emergent SAE	1 2%	3 5.9%	7 6.9%
Any TEAE leading to death	0 0%	0 0%	1 1%
Any TEAE leading to discontinuation	6 12.2%	8 15.7%	4 3.9%

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Day 211) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent that is AEs that developed/worsened that occurred during 'TEAE period' (first dose of study drug to last dose of study drug+60 days, last contact date, or the date of death, whichever came first). Analysis was performed on safety population.
Arm/Group Title	Sarilumab 150 mg q2w		Sarilumab 200 mg q2w		Tocilizumab q4w
Arm/Group Description	Sarilumab 150 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.		Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks.		Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD for 24 weeks. Dose for tocilizumab could be up-titrated to 8 mg/kg or down-titrated to 4 mg/kg based on clinical response as per Investigator's discretion.
All Cause Mortality
	Sarilumab 150 mg q2w		Sarilumab 200 mg q2w		Tocilizumab q4w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sarilumab 150 mg q2w		Sarilumab 200 mg q2w		Tocilizumab q4w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/49 (2%)		3/51 (5.9%)		7/102 (6.9%)
Blood and lymphatic system disorders
Neutropenia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Cardiac disorders
Atrial fibrillation	0/49 (0%)		1/51 (2%)		0/102 (0%)
Infections and infestations
Erysipelas	0/49 (0%)		0/51 (0%)		1/102 (1%)
Septic shock	0/49 (0%)		0/51 (0%)		1/102 (1%)
Urinary tract infection	0/49 (0%)		1/51 (2%)		0/102 (0%)
Investigations
Transaminases increased	0/49 (0%)		1/51 (2%)		0/102 (0%)
Musculoskeletal and connective tissue disorders
Osteochondrosis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Pseudarthrosis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Nervous system disorders
Tremor	0/49 (0%)		0/51 (0%)		1/102 (1%)
Renal and urinary disorders
Renal failure acute	0/49 (0%)		0/51 (0%)		1/102 (1%)
Respiratory, thoracic and mediastinal disorders
Idiopathic pulmonary fibrosis	1/49 (2%)		0/51 (0%)		0/102 (0%)
Pulmonary embolism	1/49 (2%)		0/51 (0%)		0/102 (0%)
Vascular disorders
Deep vein thrombosis	1/49 (2%)		0/51 (0%)		0/102 (0%)
Other (Not Including Serious) Adverse Events
	Sarilumab 150 mg q2w		Sarilumab 200 mg q2w		Tocilizumab q4w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/49 (67.3%)		36/51 (70.6%)		66/102 (64.7%)
Blood and lymphatic system disorders
Anaemia of chronic disease	0/49 (0%)		0/51 (0%)		1/102 (1%)
Iron deficiency anaemia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Leukocytosis	0/49 (0%)		1/51 (2%)		0/102 (0%)
Leukopenia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Lymphadenopathy	0/49 (0%)		0/51 (0%)		1/102 (1%)
Lymphopenia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Neutropenia	6/49 (12.2%)		8/51 (15.7%)		3/102 (2.9%)
Neutrophilia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Normochromic normocytic anaemia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Thrombocytopenia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Cardiac disorders
Cardiac failure chronic	1/49 (2%)		0/51 (0%)		0/102 (0%)
Ear and labyrinth disorders
Vertigo	1/49 (2%)		1/51 (2%)		0/102 (0%)
Eye disorders
Dark circles under eyes	0/49 (0%)		0/51 (0%)		1/102 (1%)
Ocular hyperaemia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Ulcerative keratitis	1/49 (2%)		0/51 (0%)		0/102 (0%)
Gastrointestinal disorders
Abdominal pain	0/49 (0%)		1/51 (2%)		0/102 (0%)
Abdominal pain upper	0/49 (0%)		0/51 (0%)		1/102 (1%)
Diarrhoea	2/49 (4.1%)		0/51 (0%)		1/102 (1%)
Dyspepsia	0/49 (0%)		2/51 (3.9%)		0/102 (0%)
Gastric ulcer	0/49 (0%)		0/51 (0%)		1/102 (1%)
Gastritis	1/49 (2%)		1/51 (2%)		0/102 (0%)
Gastrointestinal disorder	0/49 (0%)		1/51 (2%)		0/102 (0%)
Gastrooesophageal reflux disease	0/49 (0%)		1/51 (2%)		0/102 (0%)
Haematochezia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Irritable bowel syndrome	1/49 (2%)		0/51 (0%)		0/102 (0%)
Loose tooth	0/49 (0%)		1/51 (2%)		1/102 (1%)
Mouth ulceration	0/49 (0%)		2/51 (3.9%)		3/102 (2.9%)
Nausea	1/49 (2%)		1/51 (2%)		7/102 (6.9%)
Stomatitis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Vomiting	0/49 (0%)		2/51 (3.9%)		0/102 (0%)
General disorders
Chills	0/49 (0%)		0/51 (0%)		1/102 (1%)
Device dislocation	0/49 (0%)		0/51 (0%)		1/102 (1%)
Fatigue	1/49 (2%)		0/51 (0%)		1/102 (1%)
Injection site erythema	4/49 (8.2%)		4/51 (7.8%)		1/102 (1%)
Injection site macule	1/49 (2%)		0/51 (0%)		0/102 (0%)
Injection site nodule	0/49 (0%)		0/51 (0%)		1/102 (1%)
Injection site pain	0/49 (0%)		0/51 (0%)		1/102 (1%)
Injection site papule	0/49 (0%)		0/51 (0%)		1/102 (1%)
Injection site pruritus	2/49 (4.1%)		1/51 (2%)		1/102 (1%)
Injection site rash	0/49 (0%)		1/51 (2%)		0/102 (0%)
Malaise	1/49 (2%)		0/51 (0%)		2/102 (2%)
Nodule	0/49 (0%)		0/51 (0%)		1/102 (1%)
Non-cardiac chest pain	0/49 (0%)		0/51 (0%)		1/102 (1%)
Pain	0/49 (0%)		0/51 (0%)		1/102 (1%)
Hepatobiliary disorders
Hypertransaminasaemia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Immune system disorders
Seasonal allergy	0/49 (0%)		0/51 (0%)		2/102 (2%)
Infections and infestations
Acute sinusitis	0/49 (0%)		1/51 (2%)		0/102 (0%)
Bronchitis	1/49 (2%)		0/51 (0%)		1/102 (1%)
Bronchitis viral	1/49 (2%)		0/51 (0%)		0/102 (0%)
Cellulitis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Conjunctivitis	2/49 (4.1%)		0/51 (0%)		0/102 (0%)
Cystitis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Gastroenteritis	3/49 (6.1%)		0/51 (0%)		1/102 (1%)
Herpes simplex	1/49 (2%)		0/51 (0%)		0/102 (0%)
Influenza	0/49 (0%)		1/51 (2%)		0/102 (0%)
Lower respiratory tract infection	1/49 (2%)		0/51 (0%)		0/102 (0%)
Nasopharyngitis	6/49 (12.2%)		3/51 (5.9%)		4/102 (3.9%)
Onychomycosis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Oral herpes	2/49 (4.1%)		0/51 (0%)		2/102 (2%)
Otitis media	0/49 (0%)		1/51 (2%)		0/102 (0%)
Paronychia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Periodontitis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Pharyngotonsillitis	1/49 (2%)		1/51 (2%)		1/102 (1%)
Pneumonia	2/49 (4.1%)		0/51 (0%)		0/102 (0%)
Pyuria	0/49 (0%)		0/51 (0%)		1/102 (1%)
Rhinitis	1/49 (2%)		0/51 (0%)		1/102 (1%)
Sinusitis	0/49 (0%)		0/51 (0%)		2/102 (2%)
Skin infection	0/49 (0%)		1/51 (2%)		0/102 (0%)
Tinea pedis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Tinea versicolour	0/49 (0%)		0/51 (0%)		1/102 (1%)
Tooth infection	1/49 (2%)		0/51 (0%)		1/102 (1%)
Tracheitis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Upper respiratory tract infection	2/49 (4.1%)		1/51 (2%)		7/102 (6.9%)
Urinary tract infection	4/49 (8.2%)		1/51 (2%)		6/102 (5.9%)
Viral upper respiratory tract infection	0/49 (0%)		0/51 (0%)		1/102 (1%)
Vulvovaginitis trichomonal	1/49 (2%)		0/51 (0%)		0/102 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/49 (2%)		3/51 (5.9%)		9/102 (8.8%)
Ankle fracture	1/49 (2%)		0/51 (0%)		0/102 (0%)
Contusion	0/49 (0%)		0/51 (0%)		1/102 (1%)
Fall	1/49 (2%)		1/51 (2%)		2/102 (2%)
Infusion related reaction	0/49 (0%)		1/51 (2%)		1/102 (1%)
Joint injury	0/49 (0%)		1/51 (2%)		0/102 (0%)
Muscle strain	0/49 (0%)		0/51 (0%)		1/102 (1%)
Overdose	1/49 (2%)		0/51 (0%)		1/102 (1%)
Post-traumatic pain	0/49 (0%)		0/51 (0%)		1/102 (1%)
Road traffic accident	0/49 (0%)		0/51 (0%)		1/102 (1%)
Traumatic haematoma	0/49 (0%)		0/51 (0%)		1/102 (1%)
Investigations
Alanine aminotransferase increased	1/49 (2%)		2/51 (3.9%)		5/102 (4.9%)
Blood cholesterol increased	0/49 (0%)		1/51 (2%)		1/102 (1%)
Blood pressure increased	1/49 (2%)		0/51 (0%)		0/102 (0%)
Glomerular filtration rate increased	0/49 (0%)		0/51 (0%)		1/102 (1%)
Liver function test abnormal	0/49 (0%)		0/51 (0%)		1/102 (1%)
Neutrophil count decreased	0/49 (0%)		1/51 (2%)		3/102 (2.9%)
Neutrophil count increased	0/49 (0%)		1/51 (2%)		0/102 (0%)
Transaminases increased	1/49 (2%)		0/51 (0%)		1/102 (1%)
Metabolism and nutrition disorders
Dyslipidaemia	0/49 (0%)		1/51 (2%)		4/102 (3.9%)
Food craving	0/49 (0%)		0/51 (0%)		1/102 (1%)
Hypercholesterolaemia	2/49 (4.1%)		1/51 (2%)		6/102 (5.9%)
Hypertriglyceridaemia	0/49 (0%)		0/51 (0%)		2/102 (2%)
Hypoglycaemia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Hypokalaemia	0/49 (0%)		1/51 (2%)		1/102 (1%)
Vitamin D deficiency	1/49 (2%)		0/51 (0%)		0/102 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Back pain	0/49 (0%)		2/51 (3.9%)		3/102 (2.9%)
Hand deformity	1/49 (2%)		0/51 (0%)		0/102 (0%)
Muscle haemorrhage	0/49 (0%)		0/51 (0%)		1/102 (1%)
Muscle spasms	0/49 (0%)		0/51 (0%)		1/102 (1%)
Musculoskeletal chest pain	1/49 (2%)		0/51 (0%)		1/102 (1%)
Myalgia	0/49 (0%)		0/51 (0%)		2/102 (2%)
Osteoarthritis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Pain in extremity	0/49 (0%)		0/51 (0%)		2/102 (2%)
Rheumatoid arthritis	1/49 (2%)		0/51 (0%)		6/102 (5.9%)
Rheumatoid nodule	0/49 (0%)		0/51 (0%)		1/102 (1%)
Spinal osteoarthritis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Spinal pain	0/49 (0%)		1/51 (2%)		0/102 (0%)
Synovial cyst	0/49 (0%)		1/51 (2%)		0/102 (0%)
Nervous system disorders
Carpal tunnel syndrome	0/49 (0%)		1/51 (2%)		1/102 (1%)
Cerebral ischaemia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Dizziness	1/49 (2%)		3/51 (5.9%)		4/102 (3.9%)
Dysgeusia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Headache	1/49 (2%)		0/51 (0%)		5/102 (4.9%)
Hypoaesthesia	1/49 (2%)		0/51 (0%)		0/102 (0%)
Paraesthesia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Sciatica	1/49 (2%)		0/51 (0%)		1/102 (1%)
Renal and urinary disorders
Calculus urinary	0/49 (0%)		0/51 (0%)		1/102 (1%)
Haematuria	1/49 (2%)		0/51 (0%)		0/102 (0%)
Hydronephrosis	0/49 (0%)		0/51 (0%)		1/102 (1%)
Reproductive system and breast disorders
Menstruation irregular	0/49 (0%)		1/51 (2%)		0/102 (0%)
Ovarian cyst	0/49 (0%)		0/51 (0%)		1/102 (1%)
Respiratory, thoracic and mediastinal disorders
Bronchiectasis	1/49 (2%)		0/51 (0%)		0/102 (0%)
Cough	1/49 (2%)		0/51 (0%)		1/102 (1%)
Dyspnoea	1/49 (2%)		0/51 (0%)		0/102 (0%)
Nasal ulcer	0/49 (0%)		0/51 (0%)		1/102 (1%)
Oropharyngeal pain	0/49 (0%)		0/51 (0%)		3/102 (2.9%)
Skin and subcutaneous tissue disorders
Alopecia	0/49 (0%)		0/51 (0%)		1/102 (1%)
Dermatitis allergic	0/49 (0%)		0/51 (0%)		1/102 (1%)
Erythema	1/49 (2%)		0/51 (0%)		1/102 (1%)
Pruritus	0/49 (0%)		0/51 (0%)		1/102 (1%)
Pruritus generalised	0/49 (0%)		1/51 (2%)		0/102 (0%)
Rash	1/49 (2%)		0/51 (0%)		2/102 (2%)
Rash pruritic	0/49 (0%)		1/51 (2%)		0/102 (0%)
Skin ulcer	0/49 (0%)		0/51 (0%)		1/102 (1%)
Urticaria	0/49 (0%)		0/51 (0%)		1/102 (1%)
Vascular disorders
Hypertension	0/49 (0%)		2/51 (3.9%)		4/102 (3.9%)
Vascular fragility	0/49 (0%)		1/51 (2%)		0/102 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.