IXAZOMIB Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01850524
• Collaborator: (none)
• Enrollment: 705
• Locations: 148
• Arms: 2
• Actual Duration (Months): 109.4
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to provide continued access to ixazomib and/or lenalidomide to participants who are continuing to have clinical benefit and to continue collecting relevant safety data to monitor safety in participants with Newly Diagnosed Multiple Myeloma (NDMM) who are not eligible for stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Ixazomib; Drug: Placebo; Drug: Dexamethasone; Drug: Lenalidomide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 705 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma
• Actual Study Start Date: May 17, 2013
• Actual Primary Completion Date: Dec 2, 2019
• Actual Study Completion Date: Jun 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: IXAZOMIB IXAZOMIB 4.0 mg capsules orally once on Days 1,8,15 and lenalidomide 25 mg capsules orally on days 1-21 and dexamethasone 40 mg tablets orally on Days 1,8, 15 and 22, during every 28-day cycle for the first 18 cycles. After Cycle 18 dexamethasone was discontinued and participants continued to receive ixazomib capsule and lenalidomide at reduced doses until progressive disease or unacceptable toxicity, whichever comes first, up to data cut-off date 2 December 2019.	Drug: Ixazomib; IXAZOMIB capsules.; Other Names: MLN9708 ; Drug: Dexamethasone; Dexamethasone tablets.; Drug: Lenalidomide; Lenalidomide capsules.
Placebo Comparator: Placebo IXAZOMIB matching-placebo capsules orally once on Days 1,8,15 and lenalidomide 25 mg capsules orally on days 1-21 and dexamethasone 40mg tablets orally on Days 1,8, 15 and 22, during every 28-day cycle for the first 18 cycles. After Cycle 18 dexamethasone was discontinued and participants continued to receive ixazomib placebo-matching capsule and lenalidomide at reduced doses until progressive disease or unacceptable toxicity, whichever comes first, up to data cut-off date 2 December 2019.	Drug: Placebo; IXAZOMIB matching-placebo capsules.; Drug: Dexamethasone; Dexamethasone tablets.; Drug: Lenalidomide; Lenalidomide capsules.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Up to data cut off: 2 December 2019 (Up to approximately 79 months)]

   PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause according to International Myeloma Working Group (IMWG) criteria whichever occurs first. PD required one of the following: Increase of >=25% from nadir in: Serum M-component and/or (the absolute increase must be >=0.5 g/dL); Urine M-component and/or (the absolute increase must be >=200 mg/24 hours); in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Bone marrow plasma cell percentage: the absolute % must be >10%; development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.85 mmol/L).

Secondary Outcome Measures

1. Overall Survival (OS) [From the date of randomization to death due to any cause (Up to 87 months)]

   OS is defined as the time from the date of randomization to the date of death.

2. Complete Response (CR) Rate [Up to 27 months]

   CR rate is defined as the percentage of participants who achieve CR assessed by an IRC relative to the intent-to-treat (ITT) population during the treatment period. Percentage of participants with CR, as assessed by IMWG disease assessment criteria will be reported.

3. Pain Response Rate as Assessed by the Brief Pain Inventory- Short Form (BPI-SF) and Analgesic Use [Up to 27 months]

   Pain response rate is defined as percentage of participants with pain response. Pain response is defined as the occurrence of at least a 30% reduction from baseline in BPI-SF worst pain score over the last 24 hours without an increase in analgesic use for 2 consecutive measurements > 28 days apart, will be reported. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable).

4. Overall Response Rate (ORR) [Up to 27 months]

   ORR is defined as the percentage of participants who achieved partial response (PR) or better relative to the ITT population during treatment period.

5. Time to Response [Up to 27 months]

   Time to response is defined as the time from the date of randomization to the first documentation of PR or better, as measured by IMWG criteria.

6. Duration of Response [Up to 27 months]

   Duration of response is measured as the time from the date of first documentation of PR or better to the date of first documented progression (PD) for responders, as measured by IMWG criteria.

7. Time to Progression (TTP) [Up to 27 months]

   Time to progression is defined as the time from randomization to the date of first documented disease progression.

8. Progression Free Survival (PFS)-2 [Up to 87 months]

   PFS2 is defined as the time from the date of randomization to the date of documentation of disease progression on the subsequent line of anticancer therapy, as assessed by the investigator in accordance with IMWG criteria, or death due to any cause, whichever occurs first.

9. Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Score [Up to 27 months]

   Eastern Cooperative Oncology Group (ECOG) scale score ranged from 0 to 5, where 0 indicated normal activity and 5 indicated death.

10. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the first dose of study drug through 30 days after administration of the last dose of study drug (Up to 28 months)]

    An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.

11. Percentage of Participants With Abnormal Laboratory Values [From the first dose of study drug through 30 days after administration of the last dose of study drug (Up to 28 months)]

    The laboratory evaluations will include hematology, clinical chemistry and urinalysis.

12. Change From Baseline in Health-Related Quality of Life (HRQOL) Measured by European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale Total Score [Baseline to Month 27]

    EORTC-QLQ-C30 scale is used to assess HRQOL in cancer participants and contains 30 items. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better HRQOL; whereas for the symptom scales lower scores represent better HRQOL.

13. Change From Baseline in HRQOL Measured by EORTC-QLQ)-MY20 Scale [Baseline to Month 27]

    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. The scale has 20 questions. Raw scores are averaged, and transformed to 0-100 scale, where higher score is better quality of life.

14. OS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations [From the date of randomization to death due to any cause (Up to 87 months)]

    OS is defined as the time from the date of randomization to the date of death, as assessed in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16) mutations.

15. PFS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations [Up to 87 months]

    PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease based on central laboratory results and IMWG criteria as evaluated by an independent review committee (IRC) or death due to any cause, whichever occurs first, as assessed in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16) mutations.

16. Percentage of Participants With MRD-Negative Status as Assessed by Flow Cytometry [Up to 27 months]

    The absence of minimal residual disease (MRD negativity) will be tested in all participants who achieve a CR and maintained it until Cycle 18, using bone marrow aspirates. The frequency of MRD negativity, in each treatment arm will be determined, and its association with TTP, PFS, and OS will be evaluated.

17. Time to Pain Progression [Up to 27 months]

    Time to pain progression will be assessed as the time from randomization to the date of initial progression classification. Pain progression is defined as the occurrence of 1 of the following and confirmed by 2 consecutive evaluations (To qualify as progression, the participant must have a BPI-SF worst pain score > 4 during pain progression): 1) a ≥ 2 point and 30% increase from Baseline in BPI-SF worst pain score without an increase in analgesic use, or 2) a 25% or more increase in analgesic use from Baseline without a decrease in BPI-SF worst pain score from Baseline. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable).

18. Cmax: Maximum Plasma Concentration for IXAZOMIB and Its Metabolite MLN2238 [Cycle 1, Day 1 at multiple time points (up to 4 hours) post-dose and Day 14 at any time; Cycle 2-3, Day 1 pre-dose and Day 14 at any time; Cycles 4-12 pre-dose (Cycle length is 28 days)]

19. Percentage of Participants With New or Worsening of Existing Skeletal-related Events (SREs) [Baseline and up to Month 27]

    SRE is defined as new fractures [including vertebral compression fractures]), irradiation of or surgery on bone, or spinal cord compression).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female participants 18 years or older diagnosed with Multiple Myeloma according to standard criteria who have not received prior treatment for multiple myeloma.

2. Participants for whom lenalidomide and dexamethasone treatment is appropriate and who are not eligible for high-dose therapy followed by stem-cell transplantation (HDT-SCT) for 1 or more of the following reasons:

• The participant is 65 years of age or older.

• The participant is less than 65 years of age but has significant comorbid condition(s) that are, in the opinion of the investigator, likely to have a negative impact on tolerability of HDT-SCT.

1. Measurable disease as specified in study protocol.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

3. Meet the clinical laboratories criteria as specified in the protocol.

4. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence, and must also agree to ongoing pregnancy testing; must also adhere to the guidelines of the lenalidomide pregnancy prevention program.

5. Male participants who agree to practice effective barrier contraception or agree to practice true abstinence AND must adhere to the guidelines of the lenalidomide pregnancy prevention program.

6. Suitable venous access for the study-required blood sampling.

7. Must be able to take concurrent aspirin 70 mg to 325 mg daily (or enoxaparin if aspirin allergic).

8. Voluntary written consent.

9. Participant is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

1. Prior treatment for multiple myeloma with either standard of care treatment or investigational regimen.

2. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

3. Inability or unwillingness to receive antithrombotic therapy.

4. Female participants who are lactating or pregnant.

5. Major surgery or radiotherapy within 14 days before randomization.

6. Infection requiring intravenous antibiotics within 14 days before the first dose of study drug.

7. Central nervous system involvement.

8. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.

9. Evidence of current uncontrolled cardiovascular conditions within 6 months prior to randomization, including: Uncontrolled hypertension, cardiac arrhythmias, or congestive heart failure; Unstable angina, or Myocardial infarction.

10. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin,itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before randomization in the study.

11. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.

12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (e.g., peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause).

13. Psychiatric illness/social situation that would limit compliance with study requirements.

14. Known allergy to any of the study medications.

15. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.

16. Treatment with any investigational products within 60 days before randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Chandler	Arizona	United States
3		Tucson	Arizona	United States
4		Little Rock	Arkansas	United States
5		Anaheim	California	United States
6		Corona	California	United States
7		Fountain Valley	California	United States
8		Fullerton	California	United States
9		Irvine	California	United States
10		La Jolla	California	United States
11		Mission Hills	California	United States
12		Oakland	California	United States
13		Riverside	California	United States
14		San Diego	California	United States
15		San Jose	California	United States
16		San Leandro	California	United States
17		Santa Clara	California	United States
18		South San Francisco	California	United States
19		Vallejo	California	United States
20		Denver	Colorado	United States
21		Fort Collins	Colorado	United States
22		Hartford	Connecticut	United States
23		Plainville	Connecticut	United States
24		Fort Myers	Florida	United States
25		Jacksonville	Florida	United States
26		Miami Beach	Florida	United States
27		Miami	Florida	United States
28		West Palm Beach	Florida	United States
29		Atlanta	Georgia	United States
30		Marietta	Georgia	United States
31		Honolulu	Hawaii	United States
32		Iowa City	Iowa	United States
33		Sioux City	Iowa	United States
34		Louisville	Kentucky	United States
35		Shreveport	Louisiana	United States
36		Baltimore	Maryland	United States
37		Towson	Maryland	United States
38		Burlington	Massachusetts	United States
39		Worcester	Massachusetts	United States
40		Ann Arbor	Michigan	United States
41		Lansing	Michigan	United States
42		Southfield	Michigan	United States
43		Duluth	Minnesota	United States
44		Minneapolis	Minnesota	United States
45		Rochester	Minnesota	United States
46		Bridgeton	Missouri	United States
47		Kansas City	Missouri	United States
48		Little Silver	New Jersey	United States
49		Albuquerque	New Mexico	United States
50		Farmington	New Mexico	United States
51		Las Cruces	New Mexico	United States
52		Buffalo	New York	United States
53		Lake Success	New York	United States
54		New York	New York	United States
55		Poughkeepsie	New York	United States
56		Cincinnati	Ohio	United States
57		Cleveland	Ohio	United States
58		Tulsa	Oklahoma	United States
59		Eugene	Oregon	United States
60		Portland	Oregon	United States
61		Hershey	Pennsylvania	United States
62		Pittsburgh	Pennsylvania	United States
63		Scranton	Pennsylvania	United States
64		Charleston	South Carolina	United States
65		Cookeville	Tennessee	United States
66		Nashville	Tennessee	United States
67		Austin	Texas	United States
68		Galveston	Texas	United States
69		San Antonio	Texas	United States
70		Temple	Texas	United States
71		Tyler	Texas	United States
72		Christiansburg	Virginia	United States
73		Richmond	Virginia	United States
74		Everett	Washington	United States
75		Seattle	Washington	United States
76		Spokane	Washington	United States
77		Vancouver	Washington	United States
78		Yakima	Washington	United States
79		Brussel	Brussels	Belgium
80		Bruxelles	Brussels	Belgium
81		Yvoir	Namur	Belgium
82		Gent	Oost-Vlaanderen	Belgium
83		Leuven	Vlaams Brabant	Belgium
84		Roeselare	West-Vlaanderen	Belgium
85		Bruges		Belgium
86		Liege		Belgium
87		Calgary	Alberta	Canada
88		Edmonton	Alberta	Canada
89		Surrey	British Columbia	Canada
90		Victoria	British Columbia	Canada
91		St. John	New Brunswick	Canada
92		Halifax	Nova Scotia	Canada
93		Hamilton	Ontario	Canada
94		London	Ontario	Canada
95		Toronto	Ontario	Canada
96		Fleurimont	Quebec	Canada
97		Levis	Quebec	Canada
98		Montreal	Quebec	Canada
99		Nice	Alpes-Maritimes	France
100		Strasbourg	Bas-Rhin	France
101		Brest	Finistere	France
102		Saint-Brieuc	Finistere	France
103		Limoges	Haute-Vienne	France
104		Castelnau-le-Lez	Herault	France
105		La Tronche	Isere	France
106		Nantes	Loire-Atlantique	France
107		Angers	Maine-et-Loire	France
108		Reims	Marne	France
109		Vandoeuvre-les-nancy	Meurthe-et-Moselle	France
110		Vannes	Morbihan	France
111		Lille Cedex	Nord	France
112		Lens	Pas-de-Calais	France
113		Saint-priest-en-jarez	Rhone	France
114		Montivilliers	Seine-Maritime	France
115		Poitiers	Vienne	France
116		Amiens		France
117		Bayonne		France
118		Bordeaux		France
119		Caen		France
120		Chalon sur Saone		France
121		Creteil		France
122		Dunkerque		France
123		La Roche sur Yon		France
124		Le Chesnay		France
125		Le Mans cedex 2		France
126		Lille		France
127		Montpellier cedex 5		France
128		Mulhouse		France
129		Paris		France
130		Perigueux		France
131		Pierre Benite		France
132		Pontoise		France
133		Rouen		France
134		TOULOUSE Cedex 9		France
135		Tours		France
136		Goyang	Gyeonggido	Korea, Republic of
137		Seongnam-si	Gyeonggido	Korea, Republic of
138		Daegu		Korea, Republic of
139		Daejeon		Korea, Republic of
140		Incheon		Korea, Republic of
141		Jeonnam		Korea, Republic of
142		Seoul		Korea, Republic of
143		Auckland	North Island	New Zealand
144		Wellington	North Island	New Zealand
145		Christchurch	South Island	New Zealand
146		Dunedin	South Island	New Zealand
147		Hamilton		New Zealand
148		Ryazan		Russian Federation

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Jul 9, 2020
• Statistical Analysis Plan - Jan 14, 2020

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01850524
• Other Study ID Numbers: C16014; 2013-000326-54; U1111-1158-2646; 163325
• First Posted: May 9, 2013
• Last Update Posted: Aug 2, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Newly Diagnosed multiple myeloma; multiple myeloma; MLN9708; IXAZOMIB; Proteasome inhibitor; Tourmaline MM2
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Lenalidomide; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 168 investigative sites in multiple countries from 17 May 2013 up to data-cut-off: 2 December 2019. This study is ongoing.
Pre-assignment Detail	Participants with newly diagnosed multiple myeloma were enrolled in 1:1 ratio to receive ixazomib or placebo in addition to the background therapy of Lenalidomide and Dexamethasone (LenDex) in this study.

Arm/Group Title	Placebo + LenDex	Ixazomib + LenDex
Arm/Group Description	Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.	Participants received Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
Period Title: Overall Study
STARTED	354	351
Intent-to-Treat (ITT) Population	354	351
Safety Population	349	354
Participants Completed Study Treatment Per Protocol	270	264
Per Protocol (PP) Population	295	298
Participants With Exposure of ≥ 19 Cycles	189	191
COMPLETED	0	0
NOT COMPLETED	354	351

Baseline Characteristics

Arm/Group Title	Placebo + LenDex	Ixazomib + LenDex	Total
Arm/Group Description	Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.	Participants received Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.	Total of all reporting groups
Overall Participants	354	351	705
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.7 (5.91)	73.5 (6.53)	73.6 (6.22)
Sex: Female, Male (Count of Participants)
Female	172 48.6%	179 51%	351 49.8%
Male	182 51.4%	172 49%	354 50.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 4%	12 3.4%	26 3.7%
Not Hispanic or Latino	340 96%	337 96%	677 96%
Unknown or Not Reported	0 0%	2 0.6%	2 0.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.3%	2 0.6%	3 0.4%
Asian	52 14.7%	44 12.5%	96 13.6%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.3%	1 0.1%
Black or African American	13 3.7%	11 3.1%	24 3.4%
White	285 80.5%	291 82.9%	576 81.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 0.8%	2 0.6%	5 0.7%
Region of Enrollment (Count of Participants)
France	136 38.4%	126 35.9%	262 37.2%
Belgium	37 10.5%	36 10.3%	73 10.4%
Russia	3 0.8%	2 0.6%	5 0.7%
Japan	28 7.9%	31 8.8%	59 8.4%
South Korea	20 5.6%	11 3.1%	31 4.4%
New Zealand	3 0.8%	3 0.9%	6 0.9%
United States	68 19.2%	79 22.5%	147 20.9%
Canada	59 16.7%	63 17.9%	122 17.3%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	164.7 (10.04)	164.3 (10.13)	164.5 (10.08)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	70.53 (15.353)	72.67 (16.995)	71.59 (16.215)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.789 (0.2306)	1.810 (0.2456)	1.800 (0.2383)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause according to International Myeloma Working Group (IMWG) criteria whichever occurs first. PD required one of the following: Increase of >=25% from nadir in: Serum M-component and/or (the absolute increase must be >=0.5 g/dL); Urine M-component and/or (the absolute increase must be >=200 mg/24 hours); in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Bone marrow plasma cell percentage: the absolute % must be >10%; development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.85 mmol/L).
Time Frame	Up to data cut off: 2 December 2019 (Up to approximately 79 months)

Outcome Measure Data

Analysis Population Description

ITT population included all participants who are randomized.

Arm/Group Title	Placebo + LenDex	Ixazomib + LenDex
Arm/Group Description	Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.	Participants received Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
Measure Participants	354	351
Median (95% Confidence Interval) [months]	21.8	35.3

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from the date of randomization to the date of death.
Time Frame	From the date of randomization to death due to any cause (Up to 87 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Complete Response (CR) Rate
Description	CR rate is defined as the percentage of participants who achieve CR assessed by an IRC relative to the intent-to-treat (ITT) population during the treatment period. Percentage of participants with CR, as assessed by IMWG disease assessment criteria will be reported.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Pain Response Rate as Assessed by the Brief Pain Inventory- Short Form (BPI-SF) and Analgesic Use
Description	Pain response rate is defined as percentage of participants with pain response. Pain response is defined as the occurrence of at least a 30% reduction from baseline in BPI-SF worst pain score over the last 24 hours without an increase in analgesic use for 2 consecutive measurements > 28 days apart, will be reported. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable).
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR is defined as the percentage of participants who achieved partial response (PR) or better relative to the ITT population during treatment period.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Time to Response
Description	Time to response is defined as the time from the date of randomization to the first documentation of PR or better, as measured by IMWG criteria.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Duration of Response
Description	Duration of response is measured as the time from the date of first documentation of PR or better to the date of first documented progression (PD) for responders, as measured by IMWG criteria.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression is defined as the time from randomization to the date of first documented disease progression.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Progression Free Survival (PFS)-2
Description	PFS2 is defined as the time from the date of randomization to the date of documentation of disease progression on the subsequent line of anticancer therapy, as assessed by the investigator in accordance with IMWG criteria, or death due to any cause, whichever occurs first.
Time Frame	Up to 87 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Score
Description	Eastern Cooperative Oncology Group (ECOG) scale score ranged from 0 to 5, where 0 indicated normal activity and 5 indicated death.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Time Frame	From the first dose of study drug through 30 days after administration of the last dose of study drug (Up to 28 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Percentage of Participants With Abnormal Laboratory Values
Description	The laboratory evaluations will include hematology, clinical chemistry and urinalysis.
Time Frame	From the first dose of study drug through 30 days after administration of the last dose of study drug (Up to 28 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Change From Baseline in Health-Related Quality of Life (HRQOL) Measured by European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale Total Score
Description	EORTC-QLQ-C30 scale is used to assess HRQOL in cancer participants and contains 30 items. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better HRQOL; whereas for the symptom scales lower scores represent better HRQOL.
Time Frame	Baseline to Month 27

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Change From Baseline in HRQOL Measured by EORTC-QLQ)-MY20 Scale
Description	EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. The scale has 20 questions. Raw scores are averaged, and transformed to 0-100 scale, where higher score is better quality of life.
Time Frame	Baseline to Month 27

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	OS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations
Description	OS is defined as the time from the date of randomization to the date of death, as assessed in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16) mutations.
Time Frame	From the date of randomization to death due to any cause (Up to 87 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	PFS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations
Description	PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease based on central laboratory results and IMWG criteria as evaluated by an independent review committee (IRC) or death due to any cause, whichever occurs first, as assessed in high-risk population carrying del(17p), amp(1q21), t(4;14), or t(14;16) mutations.
Time Frame	Up to 87 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	Percentage of Participants With MRD-Negative Status as Assessed by Flow Cytometry
Description	The absence of minimal residual disease (MRD negativity) will be tested in all participants who achieve a CR and maintained it until Cycle 18, using bone marrow aspirates. The frequency of MRD negativity, in each treatment arm will be determined, and its association with TTP, PFS, and OS will be evaluated.
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	Time to Pain Progression
Description	Time to pain progression will be assessed as the time from randomization to the date of initial progression classification. Pain progression is defined as the occurrence of 1 of the following and confirmed by 2 consecutive evaluations (To qualify as progression, the participant must have a BPI-SF worst pain score > 4 during pain progression): 1) a ≥ 2 point and 30% increase from Baseline in BPI-SF worst pain score without an increase in analgesic use, or 2) a 25% or more increase in analgesic use from Baseline without a decrease in BPI-SF worst pain score from Baseline. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable).
Time Frame	Up to 27 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Secondary Outcome

Title	Cmax: Maximum Plasma Concentration for IXAZOMIB and Its Metabolite MLN2238
Time Frame	Cycle 1, Day 1 at multiple time points (up to 4 hours) post-dose and Day 14 at any time; Cycle 2-3, Day 1 pre-dose and Day 14 at any time; Cycles 4-12 pre-dose (Cycle length is 28 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Secondary Outcome

Title	Percentage of Participants With New or Worsening of Existing Skeletal-related Events (SREs)
Description	SRE is defined as new fractures [including vertebral compression fractures]), irradiation of or surgery on bone, or spinal cord compression).
Time Frame	Baseline and up to Month 27

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From randomization to 30 days of last dose, or up to data cut-off date 2 December 2019 (up to approximately Month 79)
Adverse Event Reporting Description	Safety population included all participants who received at least 1 dose of any drug. 4 participants who were randomized to the placebo received ixazomib during the study and were included in the ixazomib arm for the safety population. 1 participant randomized to each arm withdrew from the study and were not included in the safety population. Data for safety is summarized as per the duration of exposure to study treatment (exposure up to 18 cycles; exposure ≥19 cycles).
Arm/Group Title	Placebo + LenDex (Exposure Up to 18 Cycles)		Ixazomib+ LenDex (Exposure Up to 18 Cycles)		Placebo + LenDex (Exposure ≥19 Cycles)		Ixazomib + LenDex (Exposure ≥19 Cycles)
Arm/Group Description	Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days).		Participants received ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days).		Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib placebo matching capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.		Participants received ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to data cut-off date 2 December 2019.
All Cause Mortality
	Placebo + LenDex (Exposure Up to 18 Cycles)		Ixazomib+ LenDex (Exposure Up to 18 Cycles)		Placebo + LenDex (Exposure ≥19 Cycles)		Ixazomib + LenDex (Exposure ≥19 Cycles)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/160 (10.6%)		21/163 (12.9%)		5/189 (2.6%)		6/191 (3.1%)
Serious Adverse Events
	Placebo + LenDex (Exposure Up to 18 Cycles)		Ixazomib+ LenDex (Exposure Up to 18 Cycles)		Placebo + LenDex (Exposure ≥19 Cycles)		Ixazomib + LenDex (Exposure ≥19 Cycles)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/160 (65.6%)		119/163 (73%)		113/189 (59.8%)		114/191 (59.7%)
Blood and lymphatic system disorders
Anaemia	2/160 (1.3%)		5/163 (3.1%)		2/189 (1.1%)		2/191 (1%)
Febrile neutropenia	2/160 (1.3%)		4/163 (2.5%)		2/189 (1.1%)		2/191 (1%)
Thrombocytopenia	1/160 (0.6%)		4/163 (2.5%)		1/189 (0.5%)		0/191 (0%)
Heparin-induced thrombocytopenia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Cardiac disorders
Cardiac failure	1/160 (0.6%)		3/163 (1.8%)		1/189 (0.5%)		2/191 (1%)
Cardiac failure congestive	5/160 (3.1%)		1/163 (0.6%)		2/189 (1.1%)		2/191 (1%)
Atrial fibrillation	3/160 (1.9%)		3/163 (1.8%)		3/189 (1.6%)		4/191 (2.1%)
Supraventricular tachycardia	2/160 (1.3%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Atrial flutter	2/160 (1.3%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Sinus bradycardia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Acute coronary syndrome	1/160 (0.6%)		0/163 (0%)		3/189 (1.6%)		1/191 (0.5%)
Acute myocardial infarction	1/160 (0.6%)		2/163 (1.2%)		0/189 (0%)		0/191 (0%)
Angina unstable	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Myocardial infarction	2/160 (1.3%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Angina pectoris	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Myocardial ischaemia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Atrioventricular block complete	0/160 (0%)		1/163 (0.6%)		2/189 (1.1%)		3/191 (1.6%)
Cardiac arrest	0/160 (0%)		4/163 (2.5%)		0/189 (0%)		0/191 (0%)
Cardio-respiratory arrest	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Ventricular tachycardia	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Ischaemic cardiomyopathy	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Cardiomyopathy	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Coronary artery disease	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Hypertensive heart disease	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Right ventricular failure	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Eye disorders
Eyelid ptosis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Angle closure glaucoma	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Optic nerve sheath haemorrhage	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Amaurosis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Cataract	0/160 (0%)		0/163 (0%)		3/189 (1.6%)		0/191 (0%)
Gastrointestinal disorders
Diarrhoea	1/160 (0.6%)		8/163 (4.9%)		1/189 (0.5%)		6/191 (3.1%)
Small intestinal obstruction	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		4/191 (2.1%)
Vomiting	0/160 (0%)		2/163 (1.2%)		1/189 (0.5%)		0/191 (0%)
Nausea	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Rectal haemorrhage	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Lower gastrointestinal haemorrhage	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Small intestinal haemorrhage	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Colitis	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Enterocolitis haemorrhagic	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Constipation	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		1/191 (0.5%)
Gastrooesophageal reflux disease	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Intestinal obstruction	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Volvulus	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Gastritis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Intestinal perforation	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Large intestine perforation	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		0/191 (0%)
Pancreatitis acute	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Pancreatitis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Faecaloma	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Abdominal wall haematoma	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Rectal prolapse	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Abdominal pain upper	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Intestinal ischaemia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Oesophagitis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Retroperitoneal haemorrhage	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Umbilical hernia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Inguinal hernia	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		0/191 (0%)
Proctalgia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Dental caries	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Periodontal disease	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Duodenal ulcer	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Gastric volvulus	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Enteritis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Diverticular perforation	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Haemorrhoids	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Abdominal adhesions	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Stomatitis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
General disorders
General physical health deterioration	5/160 (3.1%)		5/163 (3.1%)		2/189 (1.1%)		3/191 (1.6%)
Influenza like illness	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Multiple organ dysfunction syndrome	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Pyrexia	3/160 (1.9%)		3/163 (1.8%)		3/189 (1.6%)		4/191 (2.1%)
Sudden death	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		2/191 (1%)
Death	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Asthenia	2/160 (1.3%)		1/163 (0.6%)		1/189 (0.5%)		1/191 (0.5%)
Malaise	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		1/191 (0.5%)
Fatigue	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Non-cardiac chest pain	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		1/191 (0.5%)
Pain	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Chest pain	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Oedema peripheral	2/160 (1.3%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Generalised oedema	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Systemic inflammatory response syndrome	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Stent-graft endoleak	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Hyperthermia	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Complication associated with device	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Incarcerated hernia	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		2/191 (1%)
Cholecystitis	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Cholelithiasis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Cholecystitis chronic	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Hepatic function abnormal	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Cholangitis acute	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hepatic cirrhosis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Immune system disorders
Anaphylactic reaction	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Infections and infestations
Pneumonia	15/160 (9.4%)		20/163 (12.3%)		12/189 (6.3%)		19/191 (9.9%)
Bronchitis	0/160 (0%)		3/163 (1.8%)		5/189 (2.6%)		4/191 (2.1%)
Lung infection	1/160 (0.6%)		2/163 (1.2%)		1/189 (0.5%)		3/191 (1.6%)
Lower respiratory tract infection	2/160 (1.3%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Atypical pneumonia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Pleural infection	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Sepsis	4/160 (2.5%)		4/163 (2.5%)		4/189 (2.1%)		1/191 (0.5%)
Septic shock	4/160 (2.5%)		4/163 (2.5%)		0/189 (0%)		0/191 (0%)
Pulmonary sepsis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Sepsis syndrome	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Urosepsis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Urinary tract infection	1/160 (0.6%)		3/163 (1.8%)		3/189 (1.6%)		5/191 (2.6%)
Pyelonephritis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Cellulitis	2/160 (1.3%)		1/163 (0.6%)		2/189 (1.1%)		2/191 (1%)
Pneumonia bacterial	0/160 (0%)		0/163 (0%)		0/189 (0%)		2/191 (1%)
Cystitis bacterial	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Superinfection bacterial	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Arthritis bacterial	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Gastroenteritis	1/160 (0.6%)		4/163 (2.5%)		2/189 (1.1%)		1/191 (0.5%)
Diverticulitis	1/160 (0.6%)		0/163 (0%)		2/189 (1.1%)		0/191 (0%)
Appendicitis	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		0/191 (0%)
Appendicitis perforated	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Peritonitis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Staphylococcal sepsis	0/160 (0%)		3/163 (1.8%)		1/189 (0.5%)		0/191 (0%)
Toxic shock syndrome staphylococcal	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Staphylococcal bacteraemia	1/160 (0.6%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Cellulitis staphylococcal	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Influenza	3/160 (1.9%)		1/163 (0.6%)		3/189 (1.6%)		2/191 (1%)
Pneumonia influenzal	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Herpes zoster	0/160 (0%)		0/163 (0%)		0/189 (0%)		3/191 (1.6%)
Lower respiratory tract infection viral	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Viral upper respiratory tract infection	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Viral pharyngitis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Viral uveitis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Erysipelas	1/160 (0.6%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Pneumonia pneumococcal	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Tonsillitis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Upper respiratory tract infection	2/160 (1.3%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Bursitis infective	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Abscess jaw	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Osteomyelitis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Parainfluenzae virus infection	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Pneumonia parainfluenzae viral	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Bronchopulmonary aspergillosis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Sinusitis aspergillus	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Escherichia sepsis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Prostatitis Escherichia coli	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Pneumonia haemophilus	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Device related infection	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Respiratory tract infection	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Endocarditis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Pneumonia legionella	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Soft tissue infection	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Respiratory syncytial virus infection	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Clostridium difficile colitis	1/160 (0.6%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Campylobacter gastroenteritis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Meningitis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Tooth infection	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Bartholinitis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Fungal oesophagitis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hepatitis E	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Pseudomonal sepsis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Injury, poisoning and procedural complications
Hip fracture	3/160 (1.9%)		0/163 (0%)		1/189 (0.5%)		4/191 (2.1%)
Humerus fracture	0/160 (0%)		1/163 (0.6%)		2/189 (1.1%)		2/191 (1%)
Femur fracture	1/160 (0.6%)		0/163 (0%)		4/189 (2.1%)		2/191 (1%)
Femoral neck fracture	0/160 (0%)		1/163 (0.6%)		3/189 (1.6%)		1/191 (0.5%)
Radius fracture	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		1/191 (0.5%)
Ankle fracture	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Upper limb fracture	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Lower limb fracture	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Ulna fracture	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Spinal compression fracture	3/160 (1.9%)		0/163 (0%)		1/189 (0.5%)		1/191 (0.5%)
Cervical vertebral fracture	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Thoracic vertebral fracture	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Lumbar vertebral fracture	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Spinal fracture	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Accidental overdose	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		2/191 (1%)
Fall	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		2/191 (1%)
Pelvic fracture	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		1/191 (0.5%)
Aortic injury	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Joint dislocation	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Overdose	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Cystitis radiation	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Skin laceration	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Post procedural haemorrhage	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Urinary retention postoperative	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Investigations
Platelet count decreased	0/160 (0%)		0/163 (0%)		0/189 (0%)		2/191 (1%)
International normalised ratio increased	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Weight decreased	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Blood alkaline phosphatase increased	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Staphylococcus test positive	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Blast cells present	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Blood creatinine increased	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Metabolism and nutrition disorders
Dehydration	1/160 (0.6%)		6/163 (3.7%)		1/189 (0.5%)		3/191 (1.6%)
Decreased appetite	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		5/191 (2.6%)
Hypercalcaemia	4/160 (2.5%)		1/163 (0.6%)		1/189 (0.5%)		1/191 (0.5%)
Hypocalcaemia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Hyponatraemia	1/160 (0.6%)		0/163 (0%)		2/189 (1.1%)		3/191 (1.6%)
Fluid overload	1/160 (0.6%)		2/163 (1.2%)		0/189 (0%)		0/191 (0%)
Hypervolaemia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Hypokalaemia	0/160 (0%)		2/163 (1.2%)		2/189 (1.1%)		0/191 (0%)
Malnutrition	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Failure to thrive	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hypomagnesaemia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Diabetic ketoacidosis	2/160 (1.3%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Tumour lysis syndrome	1/160 (0.6%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Hyperglycaemia	2/160 (1.3%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/160 (1.9%)		2/163 (1.2%)		2/189 (1.1%)		2/191 (1%)
Musculoskeletal chest pain	1/160 (0.6%)		2/163 (1.2%)		2/189 (1.1%)		0/191 (0%)
Musculoskeletal pain	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Pain in extremity	2/160 (1.3%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Neck pain	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Pathological fracture	4/160 (2.5%)		3/163 (1.8%)		4/189 (2.1%)		2/191 (1%)
Osteoporotic fracture	0/160 (0%)		0/163 (0%)		0/189 (0%)		2/191 (1%)
Bone pain	1/160 (0.6%)		2/163 (1.2%)		0/189 (0%)		0/191 (0%)
Spinal pain	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Kyphosis	2/160 (1.3%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Spinal stenosis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Arthralgia	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Chondrocalcinosis pyrophosphate	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Chondrocalcinosis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Crystal arthropathy	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Haemarthrosis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Arthritis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Sarcopenia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Muscular weakness	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Bone lesion	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Intervertebral disc protrusion	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Spinal osteoarthritis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Synovitis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Osteolysis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Mobility decreased	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/160 (0.6%)		2/163 (1.2%)		5/189 (2.6%)		11/191 (5.8%)
Squamous cell carcinoma of skin	1/160 (0.6%)		0/163 (0%)		4/189 (2.1%)		5/191 (2.6%)
Bowen's disease	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		1/191 (0.5%)
Plasma cell myeloma	1/160 (0.6%)		3/163 (1.8%)		1/189 (0.5%)		0/191 (0%)
Plasma cell leukaemia	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Prostate cancer	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		3/191 (1.6%)
Prostate cancer recurrent	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Adenocarcinoma of colon	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Colorectal adenocarcinoma	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Adenocarcinoma pancreas	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Pancreatic carcinoma	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Malignant melanoma	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		1/191 (0.5%)
Metastatic malignant melanoma	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Superficial spreading melanoma stage unspecified	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Bladder transitional cell carcinoma	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Gastric cancer	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Lung carcinoma cell type unspecified stage I	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Lung neoplasm malignant	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Breast cancer	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Gallbladder adenocarcinoma	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Erythroleukaemia	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Colon adenoma	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Squamous cell carcinoma of lung	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Cancer pain	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Transitional cell cancer of the renal pelvis and ureter	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Papillary thyroid cancer	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Sarcomatoid carcinoma	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Squamous cell carcinoma	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Large granular lymphocytosis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Chronic myeloid leukaemia	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Metastases to liver	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Nervous system disorders
Cerebrovascular accident	2/160 (1.3%)		2/163 (1.2%)		1/189 (0.5%)		3/191 (1.6%)
Ischaemic stroke	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		1/191 (0.5%)
Cerebral haematoma	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Haemorrhage intracranial	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Intraventricular haemorrhage	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Thalamic infarction	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Thalamus haemorrhage	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Cerebral haemorrhage	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Cerebral infarction	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Embolic stroke	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Lacunar infarction	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Syncope	1/160 (0.6%)		5/163 (3.1%)		5/189 (2.6%)		3/191 (1.6%)
Lethargy	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Loss of consciousness	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Epilepsy	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		2/191 (1%)
Seizure	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Transient ischaemic attack	0/160 (0%)		2/163 (1.2%)		2/189 (1.1%)		0/191 (0%)
Presyncope	0/160 (0%)		0/163 (0%)		0/189 (0%)		2/191 (1%)
Peripheral sensory neuropathy	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Spinal claudication	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Spinal cord compression	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Cervicobrachial syndrome	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Demyelinating polyneuropathy	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Hepatic encephalopathy	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Nervous system disorder	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Encephalopathy	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hypoxic-ischaemic encephalopathy	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Posterior reversible encephalopathy syndrome	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Peroneal nerve palsy	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hyperaesthesia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Hemiplegia	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Product Issues
Device breakage	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Device loosening	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Device malfunction	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Psychiatric disorders
Confusional state	1/160 (0.6%)		1/163 (0.6%)		5/189 (2.6%)		2/191 (1%)
Delirium	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Depression	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		1/191 (0.5%)
Anxiety	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Hallucination	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Obsessive thoughts	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Renal and urinary disorders
Acute kidney injury	8/160 (5%)		5/163 (3.1%)		2/189 (1.1%)		3/191 (1.6%)
Renal failure	3/160 (1.9%)		1/163 (0.6%)		0/189 (0%)		2/191 (1%)
Renal impairment	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Chronic kidney disease	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Haematuria	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Urinary retention	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Urinary tract obstruction	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Focal segmental glomerulosclerosis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Nephritis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Renal tubular disorder	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Reproductive system and breast disorders
Cystocele	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Testicular oedema	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Benign prostatic hyperplasia	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		0/191 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	2/160 (1.3%)		1/163 (0.6%)		0/189 (0%)		3/191 (1.6%)
Chronic obstructive pulmonary disease	0/160 (0%)		2/163 (1.2%)		0/189 (0%)		1/191 (0.5%)
Pulmonary embolism	7/160 (4.4%)		4/163 (2.5%)		5/189 (2.6%)		1/191 (0.5%)
Respiratory failure	1/160 (0.6%)		3/163 (1.8%)		1/189 (0.5%)		1/191 (0.5%)
Acute respiratory failure	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Dyspnoea	0/160 (0%)		5/163 (3.1%)		0/189 (0%)		0/191 (0%)
Pneumonia aspiration	2/160 (1.3%)		3/163 (1.8%)		1/189 (0.5%)		0/191 (0%)
Pneumonitis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Interstitial lung disease	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Lung infiltration	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Acute pulmonary oedema	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Acute respiratory distress syndrome	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Pulmonary oedema	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Epistaxis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Hypoxia	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Haemoptysis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Paranasal cyst	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Pleural effusion	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/160 (0%)		4/163 (2.5%)		0/189 (0%)		1/191 (0.5%)
Rash macular	0/160 (0%)		2/163 (1.2%)		0/189 (0%)		0/191 (0%)
Rash papular	0/160 (0%)		2/163 (1.2%)		0/189 (0%)		0/191 (0%)
Rash erythematous	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Rash generalised	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Toxic skin eruption	0/160 (0%)		2/163 (1.2%)		0/189 (0%)		0/191 (0%)
Drug eruption	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Drug reaction with eosinophilia and systemic symptoms	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Stevens-Johnson syndrome	1/160 (0.6%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Toxic epidermal necrolysis	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Dermatitis allergic	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Dermal cyst	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Decubitus ulcer	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Vascular disorders
Deep vein thrombosis	3/160 (1.9%)		2/163 (1.2%)		5/189 (2.6%)		3/191 (1.6%)
Venous thrombosis limb	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Hypotension	1/160 (0.6%)		1/163 (0.6%)		2/189 (1.1%)		1/191 (0.5%)
Orthostatic hypotension	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Peripheral ischaemia	0/160 (0%)		1/163 (0.6%)		1/189 (0.5%)		0/191 (0%)
Peripheral artery stenosis	0/160 (0%)		0/163 (0%)		0/189 (0%)		1/191 (0.5%)
Phlebitis	0/160 (0%)		1/163 (0.6%)		2/189 (1.1%)		0/191 (0%)
Aortic stenosis	0/160 (0%)		0/163 (0%)		1/189 (0.5%)		0/191 (0%)
Embolism	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Thrombosis	1/160 (0.6%)		0/163 (0%)		0/189 (0%)		0/191 (0%)
Hypovolaemic shock	0/160 (0%)		1/163 (0.6%)		0/189 (0%)		0/191 (0%)
Other (Not Including Serious) Adverse Events
	Placebo + LenDex (Exposure Up to 18 Cycles)		Ixazomib+ LenDex (Exposure Up to 18 Cycles)		Placebo + LenDex (Exposure ≥19 Cycles)		Ixazomib + LenDex (Exposure ≥19 Cycles)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/160 (100%)		163/163 (100%)		189/189 (100%)		191/191 (100%)
Blood and lymphatic system disorders
Anaemia	56/160 (35%)		51/163 (31.3%)		50/189 (26.5%)		55/191 (28.8%)
Thrombocytopenia	15/160 (9.4%)		32/163 (19.6%)		11/189 (5.8%)		24/191 (12.6%)
Neutropenia	36/160 (22.5%)		15/163 (9.2%)		48/189 (25.4%)		38/191 (19.9%)
Cardiac disorders
Cardiac failure	3/160 (1.9%)		9/163 (5.5%)		0/189 (0%)		0/191 (0%)
Atrial fibrillation	8/160 (5%)		6/163 (3.7%)		11/189 (5.8%)		6/191 (3.1%)
Palpitations	0/160 (0%)		0/163 (0%)		8/189 (4.2%)		11/191 (5.8%)
Ear and labyrinth disorders
Vertigo	0/160 (0%)		0/163 (0%)		17/189 (9%)		21/191 (11%)
Hypoacusis	0/160 (0%)		0/163 (0%)		6/189 (3.2%)		10/191 (5.2%)
Eye disorders
Cataract	0/160 (0%)		0/163 (0%)		41/189 (21.7%)		54/191 (28.3%)
Vision blurred	0/160 (0%)		0/163 (0%)		22/189 (11.6%)		25/191 (13.1%)
Dry eye	0/160 (0%)		0/163 (0%)		6/189 (3.2%)		17/191 (8.9%)
Gastrointestinal disorders
Diarrhoea	48/160 (30%)		68/163 (41.7%)		113/189 (59.8%)		144/191 (75.4%)
Constipation	61/160 (38.1%)		59/163 (36.2%)		82/189 (43.4%)		91/191 (47.6%)
Nausea	35/160 (21.9%)		55/163 (33.7%)		62/189 (32.8%)		76/191 (39.8%)
Vomiting	13/160 (8.1%)		41/163 (25.2%)		32/189 (16.9%)		64/191 (33.5%)
Dry mouth	14/160 (8.8%)		11/163 (6.7%)		12/189 (6.3%)		13/191 (6.8%)
Stomatitis	9/160 (5.6%)		10/163 (6.1%)		7/189 (3.7%)		15/191 (7.9%)
Abdominal pain upper	13/160 (8.1%)		8/163 (4.9%)		29/189 (15.3%)		23/191 (12%)
Abdominal pain	10/160 (6.3%)		7/163 (4.3%)		38/189 (20.1%)		28/191 (14.7%)
Dyspepsia	16/160 (10%)		5/163 (3.1%)		22/189 (11.6%)		21/191 (11%)
Haemorrhoids	0/160 (0%)		0/163 (0%)		15/189 (7.9%)		12/191 (6.3%)
Gastrooesophageal reflux disease	0/160 (0%)		0/163 (0%)		9/189 (4.8%)		11/191 (5.8%)
Abdominal distension	0/160 (0%)		0/163 (0%)		11/189 (5.8%)		10/191 (5.2%)
Toothache	0/160 (0%)		0/163 (0%)		14/189 (7.4%)		8/191 (4.2%)
Inguinal hernia	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		5/191 (2.6%)
General disorders
Oedema peripheral	52/160 (32.5%)		66/163 (40.5%)		64/189 (33.9%)		105/191 (55%)
Fatigue	53/160 (33.1%)		41/163 (25.2%)		52/189 (27.5%)		68/191 (35.6%)
Asthenia	44/160 (27.5%)		36/163 (22.1%)		52/189 (27.5%)		59/191 (30.9%)
Pyrexia	20/160 (12.5%)		30/163 (18.4%)		29/189 (15.3%)		33/191 (17.3%)
Peripheral swelling	8/160 (5%)		8/163 (4.9%)		11/189 (5.8%)		17/191 (8.9%)
Malaise	0/160 (0%)		0/163 (0%)		15/189 (7.9%)		16/191 (8.4%)
Influenza like illness	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		16/191 (8.4%)
Non-cardiac chest pain	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		14/191 (7.3%)
Chills	10/160 (6.3%)		11/163 (6.7%)		7/189 (3.7%)		11/191 (5.8%)
Infections and infestations
Urinary tract infection	14/160 (8.8%)		19/163 (11.7%)		27/189 (14.3%)		29/191 (15.2%)
Bronchitis	13/160 (8.1%)		13/163 (8%)		49/189 (25.9%)		73/191 (38.2%)
Nasopharyngitis	13/160 (8.1%)		13/163 (8%)		71/189 (37.6%)		62/191 (32.5%)
Upper respiratory tract infection	17/160 (10.6%)		10/163 (6.1%)		47/189 (24.9%)		48/191 (25.1%)
Herpes zoster	0/160 (0%)		0/163 (0%)		4/189 (2.1%)		23/191 (12%)
Rhinitis	0/160 (0%)		0/163 (0%)		21/189 (11.1%)		22/191 (11.5%)
Pneumonia	0/160 (0%)		0/163 (0%)		16/189 (8.5%)		22/191 (11.5%)
Sinusitis	0/160 (0%)		0/163 (0%)		6/189 (3.2%)		17/191 (8.9%)
Conjunctivitis	0/160 (0%)		0/163 (0%)		5/189 (2.6%)		17/191 (8.9%)
Gastroenteritis	0/160 (0%)		0/163 (0%)		15/189 (7.9%)		14/191 (7.3%)
Influenza	0/160 (0%)		0/163 (0%)		19/189 (10.1%)		13/191 (6.8%)
Cystitis	0/160 (0%)		0/163 (0%)		12/189 (6.3%)		13/191 (6.8%)
Cellulitis	0/160 (0%)		0/163 (0%)		2/189 (1.1%)		11/191 (5.8%)
Pharyngitis	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		10/191 (5.2%)
Tooth infection	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		9/191 (4.7%)
Injury, poisoning and procedural complications
Fall	9/160 (5.6%)		8/163 (4.9%)		33/189 (17.5%)		40/191 (20.9%)
Contusion	0/160 (0%)		0/163 (0%)		20/189 (10.6%)		16/191 (8.4%)
Procedural pain	0/160 (0%)		0/163 (0%)		11/189 (5.8%)		6/191 (3.1%)
Investigations
Weight decreased	20/160 (12.5%)		24/163 (14.7%)		30/189 (15.9%)		35/191 (18.3%)
Neutrophil count decreased	11/160 (6.9%)		5/163 (3.1%)		13/189 (6.9%)		18/191 (9.4%)
Blood creatinine increased	8/160 (5%)		6/163 (3.7%)		11/189 (5.8%)		15/191 (7.9%)
Platelet count decreased	0/160 (0%)		0/163 (0%)		12/189 (6.3%)		14/191 (7.3%)
Metabolism and nutrition disorders
Decreased appetite	45/160 (28.1%)		34/163 (20.9%)		34/189 (18%)		45/191 (23.6%)
Hypokalaemia	16/160 (10%)		33/163 (20.2%)		30/189 (15.9%)		38/191 (19.9%)
Dehydration	11/160 (6.9%)		10/163 (6.1%)		5/189 (2.6%)		11/191 (5.8%)
Hyponatraemia	6/160 (3.8%)		10/163 (6.1%)		0/189 (0%)		0/191 (0%)
Hypophosphataemia	2/160 (1.3%)		9/163 (5.5%)		0/189 (0%)		0/191 (0%)
Hypocalcaemia	13/160 (8.1%)		6/163 (3.7%)		11/189 (5.8%)		4/191 (2.1%)
Hypomagnesaemia	8/160 (5%)		6/163 (3.7%)		11/189 (5.8%)		11/191 (5.8%)
Gout	0/160 (0%)		0/163 (0%)		14/189 (7.4%)		10/191 (5.2%)
Hyperglycaemia	0/160 (0%)		0/163 (0%)		15/189 (7.9%)		6/191 (3.1%)
Musculoskeletal and connective tissue disorders
Back pain	34/160 (21.3%)		26/163 (16%)		68/189 (36%)		64/191 (33.5%)
Pain in extremity	29/160 (18.1%)		18/163 (11%)		47/189 (24.9%)		50/191 (26.2%)
Arthralgia	19/160 (11.9%)		17/163 (10.4%)		65/189 (34.4%)		57/191 (29.8%)
Muscle spasms	27/160 (16.9%)		15/163 (9.2%)		50/189 (26.5%)		52/191 (27.2%)
Musculoskeletal chest pain	12/160 (7.5%)		12/163 (7.4%)		27/189 (14.3%)		25/191 (13.1%)
Muscular weakness	12/160 (7.5%)		9/163 (5.5%)		18/189 (9.5%)		16/191 (8.4%)
Musculoskeletal pain	6/160 (3.8%)		9/163 (5.5%)		50/189 (26.5%)		42/191 (22%)
Neck pain	9/160 (5.6%)		7/163 (4.3%)		24/189 (12.7%)		21/191 (11%)
Myalgia	9/160 (5.6%)		5/163 (3.1%)		23/189 (12.2%)		31/191 (16.2%)
Bone pain	10/160 (6.3%)		4/163 (2.5%)		22/189 (11.6%)		19/191 (9.9%)
Osteoarthritis	0/160 (0%)		0/163 (0%)		13/189 (6.9%)		20/191 (10.5%)
Arthritis	0/160 (0%)		0/163 (0%)		4/189 (2.1%)		16/191 (8.4%)
Joint swelling	0/160 (0%)		0/163 (0%)		11/189 (5.8%)		11/191 (5.8%)
Pathological fracture	0/160 (0%)		0/163 (0%)		20/189 (10.6%)		9/191 (4.7%)
Nervous system disorders
Dizziness	31/160 (19.4%)		27/163 (16.6%)		36/189 (19%)		31/191 (16.2%)
Peripheral sensory neuropathy	27/160 (16.9%)		23/163 (14.1%)		57/189 (30.2%)		83/191 (43.5%)
Headache	22/160 (13.8%)		15/163 (9.2%)		35/189 (18.5%)		32/191 (16.8%)
Tremor	23/160 (14.4%)		14/163 (8.6%)		27/189 (14.3%)		19/191 (9.9%)
Dysgeusia	14/160 (8.8%)		9/163 (5.5%)		12/189 (6.3%)		32/191 (16.8%)
Paraesthesia	13/160 (8.1%)		9/163 (5.5%)		21/189 (11.1%)		24/191 (12.6%)
Somnolence	8/160 (5%)		3/163 (1.8%)		0/189 (0%)		0/191 (0%)
Hypoaesthesia	0/160 (0%)		0/163 (0%)		11/189 (5.8%)		16/191 (8.4%)
Sciatica	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		16/191 (8.4%)
Neuropathy peripheral	0/160 (0%)		0/163 (0%)		9/189 (4.8%)		14/191 (7.3%)
Syncope	0/160 (0%)		0/163 (0%)		6/189 (3.2%)		13/191 (6.8%)
Psychiatric disorders
Insomnia	27/160 (16.9%)		30/163 (18.4%)		68/189 (36%)		70/191 (36.6%)
Anxiety	15/160 (9.4%)		22/163 (13.5%)		21/189 (11.1%)		25/191 (13.1%)
Depression	10/160 (6.3%)		18/163 (11%)		15/189 (7.9%)		23/191 (12%)
Confusional state	15/160 (9.4%)		16/163 (9.8%)		11/189 (5.8%)		10/191 (5.2%)
Agitation	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		11/191 (5.8%)
Irritability	0/160 (0%)		0/163 (0%)		11/189 (5.8%)		4/191 (2.1%)
Respiratory, thoracic and mediastinal disorders
Cough	24/160 (15%)		28/163 (17.2%)		37/189 (19.6%)		52/191 (27.2%)
Dyspnoea	32/160 (20%)		21/163 (12.9%)		26/189 (13.8%)		38/191 (19.9%)
Rhinorrhoea	0/160 (0%)		0/163 (0%)		7/189 (3.7%)		14/191 (7.3%)
Epistaxis	11/160 (6.9%)		7/163 (4.3%)		16/189 (8.5%)		12/191 (6.3%)
Dyspnoea exertional	0/160 (0%)		0/163 (0%)		14/189 (7.4%)		12/191 (6.3%)
Oropharyngeal pain	0/160 (0%)		0/163 (0%)		12/189 (6.3%)		12/191 (6.3%)
Productive cough	8/160 (5%)		2/163 (1.2%)		5/189 (2.6%)		12/191 (6.3%)
Hiccups	0/160 (0%)		0/163 (0%)		10/189 (5.3%)		5/191 (2.6%)
Dysphonia	0/160 (0%)		0/163 (0%)		12/189 (6.3%)		3/191 (1.6%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	18/160 (11.3%)		37/163 (22.7%)		20/189 (10.6%)		43/191 (22.5%)
Pruritus	9/160 (5.6%)		13/163 (8%)		23/189 (12.2%)		26/191 (13.6%)
Dry skin	8/160 (5%)		11/163 (6.7%)		22/189 (11.6%)		31/191 (16.2%)
Rash macular	3/160 (1.9%)		11/163 (6.7%)		11/189 (5.8%)		27/191 (14.1%)
Erythema	2/160 (1.3%)		11/163 (6.7%)		19/189 (10.1%)		15/191 (7.9%)
Rash	7/160 (4.4%)		10/163 (6.1%)		6/189 (3.2%)		16/191 (8.4%)
Night sweats	9/160 (5.6%)		9/163 (5.5%)		0/189 (0%)		0/191 (0%)
Rash papular	8/160 (5%)		8/163 (4.9%)		4/189 (2.1%)		12/191 (6.3%)
Rash erythematous	10/160 (6.3%)		6/163 (3.7%)		3/189 (1.6%)		18/191 (9.4%)
Hyperhidrosis	8/160 (5%)		5/163 (3.1%)		0/189 (0%)		0/191 (0%)
Pruritus generalised	0/160 (0%)		0/163 (0%)		7/189 (3.7%)		14/191 (7.3%)
Alopecia	0/160 (0%)		0/163 (0%)		8/189 (4.2%)		13/191 (6.8%)
Urticaria	0/160 (0%)		0/163 (0%)		5/189 (2.6%)		10/191 (5.2%)
Vascular disorders
Hypertension	9/160 (5.6%)		6/163 (3.7%)		18/189 (9.5%)		24/191 (12.6%)
Hypotension	12/160 (7.5%)		17/163 (10.4%)		11/189 (5.8%)		15/191 (7.9%)
Haematoma	0/160 (0%)		0/163 (0%)		7/189 (3.7%)		10/191 (5.2%)
Flushing	0/160 (0%)		0/163 (0%)		12/189 (6.3%)		6/191 (3.1%)
Hot flush	0/160 (0%)		0/163 (0%)		14/189 (7.4%)		4/191 (2.1%)
Deep vein thrombosis	15/160 (9.4%)		5/163 (3.1%)		13/189 (6.9%)		4/191 (2.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.