A Study of Laquinimod in Participants With Systemic Lupus Erythematosus (SLE) Active Lupus Nephritis

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01085097
• Collaborator: (none)
• Enrollment: 46
• Locations: 30
• Arms: 3
• Actual Duration (Months): 25.8
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study aims to evaluate the safety and clinical effect of daily oral treatment with laquinimod capsules in active lupus nephritis participants. This study will assess Laquinimod doses of 0.5 milligrams (mg)/day and 1 mg/day in combination with standard of care treatment (mycophenolate mofetil [MMF] and corticosteroids). Laquinimod is a novel immunomodulating drug which is currently in advanced stages of development by Teva Pharmaceuticals Ltd. for Multiple Sclerosis.

Condition or Disease	Intervention/Treatment	Phase
Lupus Nephritis	Drug: Laquinimod; Drug: Mycophenolate Mofetil; Drug: Prednisolone/Prednisone; Drug: Placebo; Drug: Methylprednisolone	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety, Tolerability and Clinical Effect of Laquinimod in Active Lupus Nephritis Patients, in Combination With Standard of Care (Mycophenolate Mofetil and Steroids)
• Actual Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Oct 24, 2012
• Actual Study Completion Date: Oct 24, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants will receive 2 capsules of placebo matching to laquinimod orally once daily (QD) for 24 weeks, MMF 500 mg tablet orally twice daily (BID) for the first week then 1 gram (g) BID from Week 2 to Week 28, and MP 500 mg/day intravenously (IV) from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which is tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Drug: Mycophenolate Mofetil; Mycophenolate Mofetil (MMF) will be administered per dose and schedule specified in the arm description.; Drug: Prednisolone/Prednisone; Prednisolone/Prednisone will be administered per dose and schedule specified in the arm description.; Drug: Placebo; Placebo matching to laquinimod will be administered per schedule specified in the arm description.; Drug: Methylprednisolone; Methylprednisolone (MP) will be administered per dose and schedule specified in the arm description.
Experimental: Laquinimod 0.5 mg Participants will receive 1 capsule of laquinimod 0.5 mg and 1 capsule of placebo matching to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which is tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Drug: Laquinimod; Laquinimod will be administered per dose and schedule specified in the arm description.; Drug: Mycophenolate Mofetil; Mycophenolate Mofetil (MMF) will be administered per dose and schedule specified in the arm description.; Drug: Prednisolone/Prednisone; Prednisolone/Prednisone will be administered per dose and schedule specified in the arm description.; Drug: Placebo; Placebo matching to laquinimod will be administered per schedule specified in the arm description.; Drug: Methylprednisolone; Methylprednisolone (MP) will be administered per dose and schedule specified in the arm description.
Experimental: Laquinimod 1 mg Participants will receive 2 capsules of laquinimod 0.5 mg orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which is tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Drug: Laquinimod; Laquinimod will be administered per dose and schedule specified in the arm description.; Drug: Mycophenolate Mofetil; Mycophenolate Mofetil (MMF) will be administered per dose and schedule specified in the arm description.; Drug: Prednisolone/Prednisone; Prednisolone/Prednisone will be administered per dose and schedule specified in the arm description.; Drug: Methylprednisolone; Methylprednisolone (MP) will be administered per dose and schedule specified in the arm description.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) [Baseline up to Week 28]

   An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (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. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.

2. Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 [Baseline, Week 24]

   Estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants diagnosed with SLE

• Kidney biopsy within 12 months prior to baseline with a histological diagnosis of proliferative or membranous Lupus Nephritis (LN)

• Clinically active Lupus Nephritis as evident by urine protein-to-creatinine ratio (UPCR) of 1 or higher, for LN classes III, IV, or class V in combination with classes III or IV, or a UPCR of 2 or higher for LN class V, at screening or any time between screening and baseline.

Exclusion Criteria:

• Participants with severe renal impairment or dialysis

• Participants with a clinically significant or unstable medical or surgical condition

• Women who are pregnant or nursing or who intend to be during the study period

• Women of child-bearing potential who do not practice an acceptable method of birth control NOTE: Other inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 1032	Phoenix	Arizona	United States	85012
2	Teva Investigational Site 1024	La Jolla	California	United States	92037-0943
3	Teva Investigational Site 1028	Los Angeles	California	United States	90048
4	Teva Investigational Site 1025	San Leandro	California	United States	94578
5	Teva Investigational Site 1031	Baltimore	Maryland	United States	21205
6	Teva Investigational Site 1021	Rochester	Minnesota	United States	55905
7	Teva Investigational Site 1022	Lake Success	New York	United States	11042
8	Teva Investigational Site 1018	Manhasset	New York	United States	11030
9	Teva Investigational Site 1019	New York	New York	United States	10016
10	Teva Investigational Site 1017	New York	New York	United States	10032
11	Teva Investigational Site 1020	Charlotte	North Carolina	United States	28210
12	Teva Investigational Site 1016	Columbus	Ohio	United States	43210
13	Teva Investigational Site 1030	Charleston	South Carolina	United States	29425
14	Teva Investigational Site 1026	Chattanooga	Tennessee	United States	37408
15	Teva Investigational Site 1115	Edmonton	Alberta	Canada	T6G 2B7
16	Teva Investigational Site 1114	Winnipeg	Manitoba	Canada	R3A 1M4
17	Teva Investigational Site 1113	Toronto	Ontario	Canada	M5T 2S8
18	Teva Investigational Site 3510	Lille		France	59057
19	Teva Investigational Site 3509	Paris		France	75013
20	Teva Investigational Site 5006	Kazan		Russian Federation	420064
21	Teva Investigational Site 5007	Kemerovo		Russian Federation	650029
22	Teva Investigational Site 5001	Moscow		Russian Federation	115522
23	Teva Investigational Site 5003	Moscow		Russian Federation	123182
24	Teva Investigational Site 5002	Moscow		Russian Federation	125284
25	Teva Investigational Site 5005	Yaroslavl		Russian Federation	150062
26	Teva Investigational Site 3413	Birmingham		United Kingdom	B15 2TH
27	Teva Investigational Site 3409	Cambridge		United Kingdom	CB2 0QQ
28	Teva Investigational Site 3412	Dudley		United Kingdom	DY1 2HQ
29	Teva Investigational Site 3410	London		United Kingdom	SE1 7EH
30	Teva Investigational Site 3411	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, M.D., Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01085097
• Other Study ID Numbers: LN-LAQ-201; 2010-018329-20
• First Posted: Mar 11, 2010
• Last Update Posted: Mar 9, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Systemic Lupus Erythematosus (SLE); Lupus Nephritis; Laquinimod
• Additional relevant MeSH terms: Nephritis; Lupus Nephritis; Lupus Erythematosus, Systemic; Mycophenolic Acid; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1 mg
Arm/Group Description	Participants received 2 capsules of placebo matched to laquinimod orally once daily (QD) for 24 weeks, mycophenolate mofetil (MMF) 500 milligrams (mg) tablet orally twice daily (BID) for the first week then 1 gram (g) BID from Week 2 to Week 28, and methylprednisolone (MP) 500 mg/day intravenously(IV) from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 1 capsule of laquinimod 0.5 mg and 1 capsule of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 2 capsules of laquinimod 0.5 mg orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.
Period Title: Overall Study
STARTED	15	16	15
Received at Least 1 Dose of Study Drug	15	16	15
COMPLETED	13	16	13
NOT COMPLETED	2	0	2

Baseline Characteristics

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1 mg	Total
Arm/Group Description	Participants received 2 capsules of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 1 capsule of laquinimod 0.5 mg and 1 capsule of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 2 capsules of laquinimod 0.5 mg orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Total of all reporting groups
Overall Participants	15	16	15	46
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.4 (10.9)	35.3 (11.5)	32.7 (9.7)	33.8 (10.6)
Sex: Female, Male (Count of Participants)
Female	11 73.3%	10 62.5%	13 86.7%	34 73.9%
Male	4 26.7%	6 37.5%	2 13.3%	12 26.1%
Race/Ethnicity, Customized (Count of Participants)
Asian	2 13.3%	0 0%	1 6.7%	3 6.5%
Black or African American	3 20%	4 25%	1 6.7%	8 17.4%
White	7 46.7%	11 68.8%	9 60%	27 58.7%
Hispanic	2 13.3%	1 6.3%	4 26.7%	7 15.2%
Other	1 6.7%	0 0%	0 0%	1 2.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (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. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time Frame	Baseline up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomly assigned participants who received at least 1 dose of study drug. In this set, participants were assigned to the treatment actually received, regardless of the assigned treatment.

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1 mg
Arm/Group Description	Participants received 2 capsules of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 1 capsule of laquinimod 0.5 mg and 1 capsule of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 2 capsules of laquinimod 0.5 mg orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.
Measure Participants	15	16	15
Number [participants]	14 93.3%	15 93.8%	15 100%

2. Primary Outcome

Title	Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24
Description	Estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) analysis set included all randomized participants, excluding observations after treatment failure.

Arm/Group Title	Placebo	Laquinimod 0.5 mg	Laquinimod 1 mg
Arm/Group Description	Participants received 2 capsules of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 1 capsule of laquinimod 0.5 mg and 1 capsule of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.	Participants received 2 capsules of laquinimod 0.5 mg orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.
Measure Participants	15	16	15
Mean (Standard Deviation) [percent change]	12.1 (20.17)	18.0 (30.65)	24.3 (28.84)

Adverse Events

Time Frame	Baseline up to Week 28
Adverse Event Reporting Description	Safety analysis set included all randomly assigned participants who received at least 1 dose of study drug. In this set, participants were assigned to the treatment actually received, regardless of the assigned treatment.
Arm/Group Title	Placebo		Laquinimod 0.5 mg		Laquinimod 1 mg
Arm/Group Description	Participants received 2 capsules of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.		Participants received 1 capsule of laquinimod 0.5 mg and 1 capsule of placebo matched to laquinimod orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.		Participants received 2 capsules of laquinimod 0.5 mg orally QD for 24 weeks, MMF 500 mg tablet orally BID for the first week then 1 g BID from Week 2 to Week 28, and MP 500 mg/day IV from Days 1 through 3, followed by oral prednisolone/prednisone (initial dose 40 mg/day which was tapered to 10 mg/day or less by the end of Week 20, on a fixed steroid-tapering regimen) from Day 4 through Week 28.
All Cause Mortality
	Placebo		Laquinimod 0.5 mg		Laquinimod 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/16 (0%)		1/15 (6.7%)
Serious Adverse Events
	Placebo		Laquinimod 0.5 mg		Laquinimod 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)		4/16 (25%)		4/15 (26.7%)
Blood and lymphatic system disorders
Anaemia	1/15 (6.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Disseminated Intravascular Coagulation	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Leukopenia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Thrombocytopenia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Cardiac disorders
Atrial Fibrillation	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Cardio-Respiratory Arrest	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Gastrointestinal disorders
Gastroduodenitis	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
General disorders
Generalised Oedema	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Infections and infestations
Cellulitis	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Herpes Zoster	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Pneumonia	1/15 (6.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Sepsis	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Tracheobronchitis	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Metabolism and nutrition disorders
Fluid Overload	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
Systemic Lupus Erythematosus	1/15 (6.7%)	1	1/16 (6.3%)	1	0/15 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Renal and urinary disorders
Renal Failure Acute	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Pleuritic Pain	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Pulmonary Embolism	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Skin and subcutaneous tissue disorders
Skin Necrosis	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Vascular disorders
Deep Vein Thrombosis	1/15 (6.7%)	1	1/16 (6.3%)	1	0/15 (0%)	0
Thrombophlebitis Superficial	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Laquinimod 0.5 mg		Laquinimod 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)		13/16 (81.3%)		15/15 (100%)
Blood and lymphatic system disorders
Anaemia	1/15 (6.7%)	1	0/16 (0%)	0	2/15 (13.3%)	2
Lymphadenopathy	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Lymphopenia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Thrombocytopenia	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Cardiac disorders
Sinus Tachycardia	0/15 (0%)	0	0/16 (0%)	0	2/15 (13.3%)	2
Ear and labyrinth disorders
Ear Pain	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Middle Ear Effusion	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Endocrine disorders
Cushing's Syndrome	0/15 (0%)	0	1/16 (6.3%)	1	1/15 (6.7%)	1
Eye disorders
Conjunctivitis	0/15 (0%)	0	2/16 (12.5%)	3	1/15 (6.7%)	1
Dry Eye	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Visual Impairment	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Gastrointestinal disorders
Abdominal Pain	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Abdominal Pain Lower	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Abdominal Pain Upper	0/15 (0%)	0	2/16 (12.5%)	3	0/15 (0%)	0
Constipation	1/15 (6.7%)	1	0/16 (0%)	0	2/15 (13.3%)	2
Diarrhoea	1/15 (6.7%)	1	2/16 (12.5%)	2	3/15 (20%)	3
Dyspepsia	1/15 (6.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Dysphagia	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Flatulence	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Gastritis	1/15 (6.7%)	1	1/16 (6.3%)	1	0/15 (0%)	0
Gastrooesophageal Reflux Disease	0/15 (0%)	0	1/16 (6.3%)	1	1/15 (6.7%)	1
Gingival Recession	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Haemorrhoids	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Inguinal Hernia	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Irritable Bowel Syndrome	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Nausea	3/15 (20%)	3	2/16 (12.5%)	2	2/15 (13.3%)	2
Vomiting	2/15 (13.3%)	2	2/16 (12.5%)	2	0/15 (0%)	0
General disorders
Asthenia	2/15 (13.3%)	3	0/16 (0%)	0	0/15 (0%)	0
Chills	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Fatigue	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Generalised Oedema	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Non-Cardiac Chest Pain	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Oedema	0/15 (0%)	0	1/16 (6.3%)	2	0/15 (0%)	0
Oedema Peripheral	4/15 (26.7%)	6	2/16 (12.5%)	2	2/15 (13.3%)	2
Pyrexia	2/15 (13.3%)	2	0/16 (0%)	0	0/15 (0%)	0
Infections and infestations
Bronchitis	1/15 (6.7%)	1	2/16 (12.5%)	2	1/15 (6.7%)	1
Cystitis	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Escherichia Urinary Tract Infection	0/15 (0%)	0	0/16 (0%)	0	2/15 (13.3%)	5
Folliculitis	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Herpes Zoster	2/15 (13.3%)	3	0/16 (0%)	0	3/15 (20%)	3
Nasopharyngitis	1/15 (6.7%)	1	1/16 (6.3%)	1	1/15 (6.7%)	1
Oral Candidiasis	1/15 (6.7%)	2	0/16 (0%)	0	0/15 (0%)	0
Oral Fungal Infection	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Sinusitis	2/15 (13.3%)	2	2/16 (12.5%)	3	0/15 (0%)	0
Subcutaneous Abscess	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Tinea Pedis	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Upper Respiratory Tract Infection	3/15 (20%)	3	1/16 (6.3%)	1	0/15 (0%)	0
Urinary Tract Infection	0/15 (0%)	0	4/16 (25%)	5	2/15 (13.3%)	2
Urinary Tract Infection Bacterial	1/15 (6.7%)	2	0/16 (0%)	0	1/15 (6.7%)	1
Varicella	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Concussion	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Contusion	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Excoriation	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Fall	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Muscle Strain	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Procedural Pain	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Investigations
Bacterial Test Positive	1/15 (6.7%)	1	1/16 (6.3%)	1	0/15 (0%)	0
Blood Albumin Increased	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Blood Glucose Increased	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Blood Urea Increased	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
C-Reactive Protein Increased	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Haemoglobin Decreased	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Weight Decreased	2/15 (13.3%)	2	3/16 (18.8%)	3	0/15 (0%)	0
Weight Increased	3/15 (20%)	3	3/16 (18.8%)	3	0/15 (0%)	0
Metabolism and nutrition disorders
Hyperlipidaemia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Macroamylasaemia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Vitamin B12 Deficiency	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/15 (13.3%)	3	2/16 (12.5%)	3	1/15 (6.7%)	1
Back Pain	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Bone Pain	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Joint Lock	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Joint Swelling	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Muscle Spasms	3/15 (20%)	4	3/16 (18.8%)	5	1/15 (6.7%)	1
Musculoskeletal Chest Pain	0/15 (0%)	0	1/16 (6.3%)	1	1/15 (6.7%)	1
Musculoskeletal Pain	1/15 (6.7%)	2	0/16 (0%)	0	0/15 (0%)	0
Myalgia	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Neck Pain	0/15 (0%)	0	1/16 (6.3%)	1	1/15 (6.7%)	1
Osteonecrosis	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Pain In Extremity	1/15 (6.7%)	1	2/16 (12.5%)	3	0/15 (0%)	0
Pain In Jaw	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Synovial Cyst	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Systemic Lupus Erythematosus	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic Naevus	1/15 (6.7%)	2	0/16 (0%)	0	0/15 (0%)	0
Skin Papilloma	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Nervous system disorders
Ageusia	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Burning Sensation	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Dizziness	1/15 (6.7%)	1	1/16 (6.3%)	2	0/15 (0%)	0
Headache	1/15 (6.7%)	1	4/16 (25%)	6	0/15 (0%)	0
Hypoaesthesia	0/15 (0%)	0	1/16 (6.3%)	1	1/15 (6.7%)	1
Migraine	0/15 (0%)	0	1/16 (6.3%)	4	0/15 (0%)	0
Paraesthesia	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Sinus Headache	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Tremor	1/15 (6.7%)	1	1/16 (6.3%)	1	0/15 (0%)	0
Psychiatric disorders
Affect Lability	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Anxiety	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Depressed Mood	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Insomnia	0/15 (0%)	0	3/16 (18.8%)	3	2/15 (13.3%)	2
Renal and urinary disorders
Dysuria	1/15 (6.7%)	1	1/16 (6.3%)	3	0/15 (0%)	0
Reproductive system and breast disorders
Haematospermia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Menorrhagia	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Polymenorrhoea	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Uterine Haemorrhage	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Vaginal Discharge	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Vaginal Haemorrhage	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/15 (6.7%)	1	1/16 (6.3%)	1	2/15 (13.3%)	3
Dyspnoea	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Dyspnoea Exertional	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Epistaxis	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Increased Upper Airway Secretion	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Oropharyngeal Pain	2/15 (13.3%)	2	0/16 (0%)	0	0/15 (0%)	0
Productive Cough	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Rhinorrhoea	1/15 (6.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Rhonchi	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Sinus Congestion	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	2/15 (13.3%)	2	0/16 (0%)	0	2/15 (13.3%)	2
Dry Skin	2/15 (13.3%)	2	0/16 (0%)	0	0/15 (0%)	0
Intertrigo	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Papule	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Pruritus	1/15 (6.7%)	2	1/16 (6.3%)	1	0/15 (0%)	0
Rash	2/15 (13.3%)	2	0/16 (0%)	0	0/15 (0%)	0
Rash Erythematous	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Rash Papular	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Skin Exfoliation	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Skin Ulcer	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Surgical and medical procedures
Vasectomy	0/15 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Vascular disorders
Flushing	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Hot Flush	1/15 (6.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Hypertension	1/15 (6.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Hypotension	0/15 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.