Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma

Sponsor

Amgen (Industry)

Overall Status

Completed

CT.gov ID

NCT01080391

Collaborator

(none)

792

Enrollment

127

Locations

Arms

88.7

Actual Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective was to compare progression-free survival in adults with relapsed multiple myeloma who are receiving CRd vs participants receiving Rd in a randomized multicenter setting.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Multiple Myeloma	Drug: Dexamethasone Drug: Lenalidomide Drug: Carfilzomib	Phase 3

Detailed Description

This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for adults with relapsed multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive either the control Rd or CRd. Randomization will be stratified by β2 microglobulin levels (< vs ≥ 2.5 mg/L), prior bortezomib (no vs yes), and prior lenalidomide (no vs yes). Participants will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity (whichever occurs first).

Study Design

Study Type:

Interventional

Actual Enrollment :

792 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Multicenter, Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma

Actual Study Start Date :

Jul 14, 2010

Actual Primary Completion Date :

Jun 16, 2014

Actual Study Completion Date :

Dec 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lenalidomide and Dexamethasone (Rd) Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22.	Drug: Dexamethasone 40 mg orally or IV on days 1, 8, 15, 22 Drug: Lenalidomide 25 mg orally on days 1-21 Other Names: Revlimid
Experimental: Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher.	Drug: Dexamethasone 40 mg orally or IV on days 1, 8, 15, 22 Drug: Lenalidomide 25 mg orally on days 1-21 Other Names: Revlimid Drug: Carfilzomib 20 mg/m², 27 mg/m² intravenously Other Names: PR-171 Kyprolis®

Arm

Intervention/Treatment

Active Comparator: Lenalidomide and Dexamethasone (Rd)

Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22.

Drug: Dexamethasone

40 mg orally or IV on days 1, 8, 15, 22

Drug: Lenalidomide

25 mg orally on days 1-21

Other Names:

Revlimid

Experimental: Carfilzomib, Lenalidomide, and Dexamethasone (CRd)

Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher.

Drug: Dexamethasone

40 mg orally or IV on days 1, 8, 15, 22

Drug: Lenalidomide

25 mg orally on days 1-21

Other Names:

Revlimid

Drug: Carfilzomib

20 mg/m², 27 mg/m² intravenously

Other Names:

PR-171

Kyprolis®

Outcome Measures

Primary Outcome Measures

Progression-free Survival (PFS) [From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.]
Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). One or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).

Secondary Outcome Measures

Overall Survival [From randomization through the data cutoff date of 28 April 2017 for the final analysis of overall survival; median follow up time was 67.1 months in each treatment group.]
Overall survival (OS) was defined as the duration from randomization to death due to any cause. Participants who were still alive were censored at the date when the participant was last known to be alive or the data cutoff date, whichever occurred earlier.
Overall Response Rate [From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.]
Overall response rate is defined as the percentage of participants who achieved either a confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response based on the Independent Review Committee (IRC) assessed response outcome. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
Disease Control Rate [From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.]
Disease control rate was defined as the percentage of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks according to International Myeloma Working Group - Uniform Response Criteria (IMWG-URC) (MR was determined using European Group for Blood and Marrow Transplantation criteria).
Duration of Response [From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months.]
Duration of response (DOR) was calculated for participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Duration of Disease Control [From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months.]
Duration of disease control (DDC) was calculated for participants who achieved disease control. DDC was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores [Cycle 1 Day 1 (Baseline), Day 1 of Cycles 3, 6, 12, 18]
Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Symptomatic multiple myeloma
Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):

Serum M-protein ≥ 0.5 g/dL
Urine Bence-Jones protein ≥ 200 mg/24 hours
For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)

Prior treatment with at least one, but no more than three, regimens for multiple myeloma
Documented relapse or progressive disease on or after any regimen
Achieved a response to at least one prior regimen
Age ≥ 18 years
Life expectancy ≥ 3 months
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Adequate hepatic function, with serum alanine aminotransferase (ALT) ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to randomization
Absolute neutrophil count ≥ 1.0 × 10^9/L within 21 days prior to randomization
Hemoglobin ≥ 8 g/dL (80 g/L) within 21 days prior to randomization
Platelet count ≥ 50 × 10^{9/L (≥ 30 × 10}9/L if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization
Creatinine clearance (CrCl) ≥ 50 mL/minute within 21 days prior to randomization
Written informed consent in accordance with federal, local, and institutional guidelines
Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception
Male subjects must agree to practice contraception

Exclusion Criteria:

If previously treated with bortezomib (alone or in combination), progression during treatment
If previously treated with a lenalidomide and dexamethasone (len/dex) combination:

Progression during the first 3 months of initiating treatment
Any progression during treatment if the len/dex combination was the subject's most recent line of therapy

Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
Prior carfilzomib treatment
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
Waldenström's macroglobulinemia or IgM myeloma
Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization
Radiotherapy to multiple sites or immunotherapy/antibody therapy within 28 days prior to randomization; localized radiotherapy to a single site within 7 days prior to randomization
Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 21 days prior to randomization
Pregnant or lactating females
Major surgery within 21 days prior to randomization
Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
Known human immunodeficiency virus infection
Active hepatitis B or C infection
Myocardial infarction within 4 months prior to randomization, New York Hear Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
Other malignancy, including myelodysplastic syndromes (MDS), within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization
Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
Ongoing graft-vs-host disease
Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization
Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85259
2	Providence St. Joseph Medical Center	Burbank	California	United States	91505
3	St. Jude Hospital Yorba Linda dba; St. Joseph Heritage Healthcare	Santa Rosa	California	United States	94503
4	Stanford University	Stanford	California	United States	94305
5	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
6	Cancer and Blood Disease Center	Lecanto	Florida	United States	34461
7	Rush University Medical Center	Chicago	Illinois	United States	60612
8	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
9	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
10	The University of Michigan - Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
11	Mayo Clinic	Rochester	Minnesota	United States	55905
12	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
13	NYU Clinical Cancer Center	New York	New York	United States	10016
14	Weill Cornell Medical College	New York	New York	United States	10021
15	Associates in Oncology and Hematology	Chattanooga	Tennessee	United States	37404
16	The Don & Sybil Harrington Cancer Center	Amarillo	Texas	United States	79106
17	Baylor Sammons Cancer Center	Dallas	Texas	United States	75246
18	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390-8565
19	The University of Texas, MD Anderson Cancer Center	Houston	Texas	United States	77030
20	Scott and White Memorial Hospital	Temple	Texas	United States	76508
21	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
22	Froedtert & Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
23	Medizinische Universitat Wien	Wien		Austria	1090
24	Wilhelminspital der Stadt Wien, Zentrum fur Onkologie und Hamatologie	Wien		Austria	1171
25	Ziekenhuisnetwerk Antwerpen - AZ Stuivenberg	Antwerpen		Belgium	2060
26	AZ Sint-Jan AV	Brugge		Belgium	8000
27	UZ Brussel	Brussels		Belgium	1090
28	Institut Jules Bordet	Bruxelles		Belgium	1000
29	Cliniques Universitaires Saint-Luc	Bruxelles		Belgium	1200
30	UZ Leuven	Leuven		Belgium	3000
31	University Multiprofile Hospital for Active Treatment, "Dr. Georgi Stranski"	Pleven		Bulgaria	5800
32	University Multiprofile Hospital for Active Treatment "Sveti Georgi"	Plovdiv		Bulgaria	4002
33	Military Medical Academy Multiprofile Hospital for Active Treatment	Sofia		Bulgaria	1606
34	Specialized Hospital for Active Treatment of Hematological Diseases	Sofia		Bulgaria	1756
35	Multiprofile Hospital for Active Treatment "Sveta Marina"	Varna		Bulgaria	9010
36	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
37	University of Alberta, Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
38	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
39	Cancer Care Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
40	General Hospital, Health Sciences Centre	St John's	Newfoundland and Labrador	Canada	A1B 3V6
41	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
42	McGill University Health Center, Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
43	Sir Mortimer B. Davis - Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
44	University Hospital Brno, Department of Internal Medicine - Hematooncology	Brno		Czechia	625 00
45	University Hospital Hradec Kralove	Hradec Kralove		Czechia	500 05
46	University Hospital Olomouc	Olomouc		Czechia	775 20
47	University Hospital Kralovske Vinohrady - Prague	Praha 10		Czechia	100 34
48	General University Hospital Prague	Praha 2		Czechia	128 08
49	Hospital Antoine Beclere	Clamart		France	92140
50	Clinique Victor Hugo - Centre Jean Bernard	Le Mans		France	72000
51	Hopital Claude Huriez	Lille		France	59037
52	CH de Mulhouse, Hopital Emile Muller	Mulhouse		France	68070
53	CHU Nantes Hotel Dieu	Nantes		France	44093
54	Hopital Saint-Antoine	Paris		France	75012
55	Groupe Hospitalier Necker - Enfants Malades	Paris		France	75015
56	Cancer Institut Universitaire de Toulouse-Oncopole (iUCT)	Toulouse		France	31100
57	Hopitaux de Brabois	Vandoeuvre-Les-Nancy		France	54511
58	University of Dusseldorf	Dusseldorf		Germany	40225
59	Krankenhaus Nordwest	Frankfurt am Main		Germany	60488
60	University of Hamburg-Eppendorf	Hamburg		Germany	20246
61	Universitat Heidelberg	Heidelberg		Germany	69120
62	Stiftungsklinikum Mittelrhein	Koblenz		Germany	56068
63	LMU Klinikum der Universitat	Munchen		Germany	81377
64	Universitatsklinikum Munster	Munster		Germany	48129
65	Universitatsklinikum Wurzburg	Wurzburg		Germany	97080
66	Alexandra Hospital	Athens		Greece	11528
67	University General Hospital of Patras	Patras		Greece	26500
68	St. Istvan and St. Laszlo Hospital of Budapest	Budapest		Hungary	H-1097
69	University of Debrecen, Medical and Health Science Center	Debrecen		Hungary	H-4032
70	Petz Aladar County Teaching Hospital	Gyor		Hungary	H-9032
71	Bekes County Pandy Kalman Hospital	Gyula		Hungary	H-5700
72	Kaposi Mor County Teaching Hospital	Kaposvar		Hungary	H-7400
73	University of Pecs	Pecs		Hungary	H-7624
74	University of Szeged, Albert Szent-Gyorgi Clinical Center	Szeged		Hungary	H-6720
75	Rambam Medical Center	Haifa		Israel	31096
76	Hadassah Medical Center, Ein Kerem	Jerusalem		Israel	91120
77	Western Gailee Hospital - Nahariya	Nahariya		Israel	22100
78	Rabin Medical Center	Petach Tikva		Israel	49100
79	The Chaim Sheba Medical Center	Ramat Gan		Israel	52621
80	Kaplan Medical Center	Rehovot		Israel	76100
81	Azienda Ospedallera Niguarda Ca Granda	Milano		Italy	20162
82	Azienda Ospedllero Maggiore della Carita	Novara		Italy	28100
83	Azienda Ospedaliera Pisana Ospendale Santa Chiara - Main	Pisa		Italy	56216
84	Ospedale S. Eugenio	Roma		Italy	00144
85	Azienda Ospedaliera Citta della Salute e della Scienza di Torino	Torino		Italy	10126
86	Erasmus MC, Department of Haematology	Rotterdam		Netherlands	3015 CE
87	University Clinical Centre, Department of Hematologii Transplantologii	Gdansk		Poland	80-952
88	Samodzielny Publ. Szp. Wojewodzki w Gorzow Wlkp.	Gorzow Wielkopolski		Poland	66-400
89	Independent Public Teaching Hospital of Medical University of Silesia in Katowice	Katowice		Poland	40-027
90	Nicolaus Copernicus Memorial Provincial Specialist Hospital in Lodz	Lodz		Poland	93-510
91	Szpital Wojewwodzki im. dr Ludwika Rydygiera w Suwalkach	Suwalki		Poland	16-400
92	Nicolaus Copernicus Municipal Specialist Hospital	Torun		Poland	87-100
93	Maria Sklodowska-Curie Institute of Oncology	Warszawa		Poland	02-781
94	Zamojski Non-Public Hospital	Zamosc		Poland	22-400
95	Fundeni Clinical Institute, "Stefan Berceanu" Center for Hematology and Bone Marrow Transplantation	Bucharest		Romania	022328
96	Coltea Clinical Hospital	Bucharest		Romania	030-171
97	Bucharest University Emergency Hospital	Bucharest		Romania	050098
98	Regional Institute of Iasi	Iasi		Romania	700483
99	State Medical Institution Komi Republican Oncological Center	Syktyvkar	Komi Republic	Russian Federation	167904
100	First Republican Clinical Hospital under the Ministry of Healthcare of the Republic of Udmurtia	Izhevsk		Russian Federation	426039
101	Federal State Budgetary Scientific Institution: N.N. Blokhin Russian Cancer Research Center	Moscow		Russian Federation	115478
102	Moscow State Medical Institution Municipal City Clinical Hospital n.a. S.P. Botkin	Moscow		Russian Federation	125101
103	Federal State Budget Institution: Hematology Research Center under MoH	Moscow		Russian Federation	125167
104	FSBI: Russian Research Institute of Hematology and Blood Transfusion under the Ferderal Agency for M&B	St. Petersburg		Russian Federation	191024
105	State Higher Educational Institution: St Petersburg State Medical University n.a.I.P Pavlov	St. Petersburg		Russian Federation	197022
106	SHEI: First St. Petersburg State Medical University N.a.I.P Pavlov under MoH, Clinic of Bone Marrow Transplant	St. Petersburg		Russian Federation	197101
107	Federal State Budget Institute: Federal Almalov Medical Research Centre under Ministry of Healthcare	St. Petersburg		Russian Federation	197341
108	Clinical Center of Serbia, Clinic of Hematology	Belgrade		Serbia	11000
109	Clinical Hospital Center Bezanijska Kosa	Belgrade		Serbia	11000
110	Military Medical Academy, Clinic of Hematology	Belgrade		Serbia	11000
111	Clinical Center Nis, Clinic of Hematology	Nis		Serbia	18 000
112	Clinical Center of Vojvodina, Clinic of Hematology	Novi Sad		Serbia	21 000
113	Hospital Universitario Germans Trias i Pujol	Badalona		Spain	08916
114	Hospital Clinic I Provincial	Barcelona		Spain	08036
115	Hospital Universitario de Salamanca	Salamanca		Spain	37007
116	Hospital Donostia	San Sebastian		Spain	20014
117	Hospital Universitario y Politeecnico La Fe	Valencia		Spain	46026
118	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
119	Sahlgrenska Universitetssjukhuset	Goteborg		Sweden	SE-41345
120	Karolinska Universitetsjukhuset i Huddinge	Stockholm		Sweden	SE-14186
121	Karolinska Universitetssjukhuset Solna, Hematologiskt Centrum	Stockholm		Sweden	SE-17176
122	St. Bartholomew's Hospital	London		United Kingdom	EC1A 7BE
123	Royal Free Hampstead	London		United Kingdom	NW3 2QG
124	St. Georges Hospital	London		United Kingdom	SW17 0QT
125	Nottingham University Hospitals (City Campus)	Nottingham		United Kingdom	NG5 1PB
126	Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT
127	The Royal Wolverhampton Hospital NHS Trust	Wolverhampton		United Kingdom	WV10 OQP

Sponsors and Collaborators

Amgen

Investigators

Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

AmgenTrials clinical trials website

Publications

Responsible Party:

Amgen

ClinicalTrials.gov Identifier:

NCT01080391

Other Study ID Numbers:

PX-171-009

First Posted:

Mar 4, 2010

Last Update Posted:

Jan 14, 2019

Last Verified:

Dec 1, 2018

Keywords provided by Amgen

Multiple Myeloma

Additional relevant MeSH terms:

Multiple Myeloma

Neoplasms, Plasma Cell

Dexamethasone

Lenalidomide

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 14 July 2010 to 15 March 2012. The primary analysis was conducted using a data cut-off date of 16 June 2014 and the final safety analysis after last subject last visit date (05 December 2017).
Pre-assignment Detail	Eligible participants were randomized in a 1:1 ratio to one of two treatment groups. Randomization was stratified by β2 microglobulin level (< vs. ≥ 2.5 mg/L), prior bortezomib exposure (no vs. yes), and prior lenalidomide exposure (no vs. yes).

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Period Title: Overall Study
STARTED	396	396
Treated	389	392
COMPLETED	389	392
NOT COMPLETED	7	4

Baseline Characteristics

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)	Total
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.	Total of all reporting groups
Overall Participants	396	396	792
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.5 (9.04)	63.3 (9.21)	63.9 (9.14)
Sex: Female, Male (Count of Participants)
Female	164 41.4%	181 45.7%	345 43.6%
Male	232 58.6%	215 54.3%	447 56.4%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	1 0.3%	0 0%	1 0.1%
Asian/Native Hawaiian or Pacific Islander	3 0.8%	1 0.3%	4 0.5%
Black or African American	11 2.8%	12 3%	23 2.9%
White	377 95.2%	377 95.2%	754 95.2%
Other	4 1%	6 1.5%	10 1.3%
Serum β2 Microglobulin (Count of Participants)
< 2.5 mg/L	77 19.4%	77 19.4%	154 19.4%
≥ 2.5 mg/L	319 80.6%	319 80.6%	638 80.6%
Prior Bortezomib Exposure (Count of Participants)
Yes	261 65.9%	261 65.9%	522 65.9%
No	135 34.1%	135 34.1%	270 34.1%
Prior Lenalidomide Exposure (Count of Participants)
Yes	78 19.7%	80 20.2%	158 19.9%
No	318 80.3%	316 79.8%	634 80.1%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). One or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).
Time Frame	From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.

Outcome Measure Data

Analysis Population Description
ITT analysis set comprised of all randomized participants

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	396	396
Median (95% Confidence Interval) [months]	17.6	26.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone (Rd), Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Analysis was stratified by β2 microglobulin levels (< 2.5 mg/L vs. ≥ 2.5 mg/L), prior bortezomib (no vs. yes), and prior lenalidomide (no vs. yes)
	Method	Log Rank
	Comments	The stopping boundary for this analysis was 0.0127 based on 1-sided significance level (O'Brien-Fleming with Lan-DeMets spending function).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.690
	Confidence Interval	(2-Sided) 95% 0.570 to 0.834
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the duration from randomization to death due to any cause. Participants who were still alive were censored at the date when the participant was last known to be alive or the data cutoff date, whichever occurred earlier.
Time Frame	From randomization through the data cutoff date of 28 April 2017 for the final analysis of overall survival; median follow up time was 67.1 months in each treatment group.

Outcome Measure Data

Analysis Population Description
ITT analysis set comprised of all randomized participants

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	396	396
Median (95% Confidence Interval) [months]	40.4	48.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone (Rd), Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
	Comments	The final analysis of OS was to be performed after 510 deaths occur. A total of 510 deaths would provide 85% power to detect, with a 1-sided significance level of 0.025, a hazard ratio of 0.765 corresponding to a 23.5% reduction in risk for death for CRd versus Rd (39.2 vs. 30.0 months, respectively).
	Type of Statistical Test	Superiority
	Comments	The stopping boundary for this analysis was 0.0231 based on 1-sided significance level (O'Brien-Fleming with Lan-DeMets spending function).

Statistical Test of Hypothesis	p-Value	0.0045
	Comments
	Method	Log Rank
	Comments	Analysis was stratified by β2 microglobulin levels (< 2.5 mg/L vs. ≥ 2.5 mg/L), prior bortezomib (no vs. yes), and prior lenalidomide (no vs. yes).

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.794
	Confidence Interval	(2-Sided) 95% 0.667 to 0.945
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Response Rate
Description	Overall response rate is defined as the percentage of participants who achieved either a confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response based on the Independent Review Committee (IRC) assessed response outcome. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
Time Frame	From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.

Outcome Measure Data

Analysis Population Description
ITT analysis set comprised of all randomized participants

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	396	396
Number (95% Confidence Interval) [percentage of participants]	66.7 16.8%	87.1 22%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone (Rd), Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Cochran-Mantel Haenszel chi-square test
	Comments	Cochran-Mantel Haenszel chi-square test with β2 macroglobulin level, prior bortezomib, and prior lenalidomide as stratification factors.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.472
	Confidence Interval	(2-Sided) 95% 2.411 to 5.001
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% CI were estimated using the Mantel-Haenszel method.

4. Secondary Outcome

Title	Disease Control Rate
Description	Disease control rate was defined as the percentage of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks according to International Myeloma Working Group - Uniform Response Criteria (IMWG-URC) (MR was determined using European Group for Blood and Marrow Transplantation criteria).
Time Frame	From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.

Outcome Measure Data

Analysis Population Description
ITT analysis set comprised of all randomized participants

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	396	396
Number (95% Confidence Interval) [percentage of participants]	87.1 22%	92.7 23.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide and Dexamethasone (Rd), Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0044
	Comments
	Method	Cochran-Mantel Haenszel chi-square test
	Comments	Cochran-Mantel Haenszel chi-square test with β2 macroglobulin level, prior bortezomib, and prior lenalidomide as stratification factors.

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.897
	Confidence Interval	(2-Sided) 95% 1.17 to 3.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio and 95% CI were estimated using the Mantel-Haenszel method.

5. Secondary Outcome

Title	Duration of Response
Description	Duration of response (DOR) was calculated for participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Time Frame	From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months.

Outcome Measure Data

Analysis Population Description
The Intent to treat (ITT) population with participantant who achieved a best overall response of PR or better.

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	264	345
Median (95% Confidence Interval) [months]	21.2	28.6

6. Secondary Outcome

Title	Duration of Disease Control
Description	Duration of disease control (DDC) was calculated for participants who achieved disease control. DDC was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Time Frame	From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months.

Outcome Measure Data

Analysis Population Description
The Intent to treat (ITT) population with participantants who achieved disease control.

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	345	367
Median (95% Confidence Interval) [months]	18.9	28.7

7. Secondary Outcome

Title	Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores
Description	Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life.
Time Frame	Cycle 1 Day 1 (Baseline), Day 1 of Cycles 3, 6, 12, 18

Outcome Measure Data

Analysis Population Description
ITT analysis set participants with a baseline value.

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)	Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
Measure Participants	367	375
Cycle 1 Day 1 (Baseline)	58.1 (21.7)	58.3 (21.7)
Cycle 3, Day 1	56.8 (19.4)	59.9 (20.4)
Cycle 6, Day 1	58.9 (19.7)	62.5 (20.1)
Cycle 12, Day 1	57.3 (19.7)	62.7 (19.6)
Cycle 18, Day 1	59.9 (18.8)	64.3 (19.2)

Adverse Events

	Lenalidomide and Dexamethasone (Rd)		Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Time Frame	From the first dose of study drug to 30 days after the last dose or initiation of new anticancer therapy, whichever occurred first. Median treatment duration was 57 and 88 weeks in each treatment group respectively, with a maximum of 338 weeks.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Arm/Group Title	Lenalidomide and Dexamethasone (Rd)		Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Arm/Group Description	Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22.		Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lenalidomide and Dexamethasone (Rd)		Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	221/389 (56.8%)		256/392 (65.3%)
Blood and lymphatic system disorders
Anaemia	10/389 (2.6%)		8/392 (2%)
Bone marrow failure	1/389 (0.3%)		0/392 (0%)
Febrile neutropenia	4/389 (1%)		8/392 (2%)
Haemolytic anaemia	1/389 (0.3%)		1/392 (0.3%)
Leukopenia	1/389 (0.3%)		1/392 (0.3%)
Neutropenia	5/389 (1.3%)		4/392 (1%)
Pancytopenia	1/389 (0.3%)		0/392 (0%)
Platelet disorder	1/389 (0.3%)		0/392 (0%)
Thrombocytopenia	4/389 (1%)		5/392 (1.3%)
Cardiac disorders
Acute coronary syndrome	1/389 (0.3%)		0/392 (0%)
Acute myocardial infarction	1/389 (0.3%)		5/392 (1.3%)
Angina pectoris	4/389 (1%)		2/392 (0.5%)
Angina unstable	1/389 (0.3%)		0/392 (0%)
Arrhythmia	1/389 (0.3%)		1/392 (0.3%)
Atrial fibrillation	8/389 (2.1%)		9/392 (2.3%)
Atrial flutter	1/389 (0.3%)		1/392 (0.3%)
Atrial tachycardia	0/389 (0%)		1/392 (0.3%)
Atrioventricular block complete	0/389 (0%)		1/392 (0.3%)
Bradycardia	1/389 (0.3%)		1/392 (0.3%)
Cardiac arrest	1/389 (0.3%)		2/392 (0.5%)
Cardiac failure	3/389 (0.8%)		5/392 (1.3%)
Cardiac failure acute	0/389 (0%)		1/392 (0.3%)
Cardiac failure congestive	3/389 (0.8%)		5/392 (1.3%)
Cardiopulmonary failure	1/389 (0.3%)		1/392 (0.3%)
Coronary artery disease	0/389 (0%)		1/392 (0.3%)
Coronary artery occlusion	0/389 (0%)		2/392 (0.5%)
Coronary artery stenosis	1/389 (0.3%)		0/392 (0%)
Left ventricular dysfunction	0/389 (0%)		2/392 (0.5%)
Mitral valve incompetence	0/389 (0%)		1/392 (0.3%)
Myocardial infarction	3/389 (0.8%)		6/392 (1.5%)
Myocardial ischaemia	0/389 (0%)		2/392 (0.5%)
Pericardial effusion	0/389 (0%)		1/392 (0.3%)
Stress cardiomyopathy	0/389 (0%)		1/392 (0.3%)
Tachycardia	0/389 (0%)		1/392 (0.3%)
Ventricular arrhythmia	0/389 (0%)		1/392 (0.3%)
Ventricular tachycardia	0/389 (0%)		1/392 (0.3%)
Aortic valve stenosis	1/389 (0.3%)		0/392 (0%)
Bradyarrhythmia	0/389 (0%)		1/392 (0.3%)
Cardiac asthma	0/389 (0%)		1/392 (0.3%)
Supraventricular tachycardia	1/389 (0.3%)		0/392 (0%)
Left ventricular failure	1/389 (0.3%)		0/392 (0%)
Ear and labyrinth disorders
Vertigo	1/389 (0.3%)		0/392 (0%)
Endocrine disorders
Adrenal insufficiency	2/389 (0.5%)		0/392 (0%)
Hypothyroidism	1/389 (0.3%)		0/392 (0%)
Eye disorders
Cataract	1/389 (0.3%)		5/392 (1.3%)
Cataract nuclear	1/389 (0.3%)		0/392 (0%)
Cataract subcapsular	1/389 (0.3%)		0/392 (0%)
Retinal vein occlusion	1/389 (0.3%)		0/392 (0%)
Retinal detachment	0/389 (0%)		1/392 (0.3%)
Gastrointestinal disorders
Abdominal hernia obstructive	0/389 (0%)		1/392 (0.3%)
Abdominal pain	3/389 (0.8%)		4/392 (1%)
Abdominal pain upper	1/389 (0.3%)		0/392 (0%)
Colitis	0/389 (0%)		1/392 (0.3%)
Constipation	1/389 (0.3%)		0/392 (0%)
Dental caries	1/389 (0.3%)		0/392 (0%)
Diarrhoea	9/389 (2.3%)		7/392 (1.8%)
Diverticular perforation	0/389 (0%)		2/392 (0.5%)
Diverticulum oesophageal	0/389 (0%)		1/392 (0.3%)
Duodenal stenosis	0/389 (0%)		1/392 (0.3%)
Enteritis	1/389 (0.3%)		0/392 (0%)
Gastrointestinal haemorrhage	2/389 (0.5%)		0/392 (0%)
Gastrooesophageal reflux disease	1/389 (0.3%)		0/392 (0%)
Ileus	0/389 (0%)		1/392 (0.3%)
Impaired gastric emptying	1/389 (0.3%)		0/392 (0%)
Intestinal obstruction	1/389 (0.3%)		1/392 (0.3%)
Large intestine perforation	0/389 (0%)		2/392 (0.5%)
Lower gastrointestinal haemorrhage	0/389 (0%)		1/392 (0.3%)
Nausea	1/389 (0.3%)		0/392 (0%)
Neutropenic colitis	0/389 (0%)		1/392 (0.3%)
Pancreatitis acute	0/389 (0%)		2/392 (0.5%)
Small intestinal obstruction	1/389 (0.3%)		0/392 (0%)
Small intestinal perforation	1/389 (0.3%)		0/392 (0%)
Vomiting	2/389 (0.5%)		0/392 (0%)
Duodenal ulcer	0/389 (0%)		1/392 (0.3%)
Umbilical hernia	0/389 (0%)		1/392 (0.3%)
General disorders
Asthenia	0/389 (0%)		2/392 (0.5%)
Chest pain	1/389 (0.3%)		1/392 (0.3%)
Death	2/389 (0.5%)		2/392 (0.5%)
Disease progression	8/389 (2.1%)		4/392 (1%)
Fatigue	0/389 (0%)		1/392 (0.3%)
General physical health deterioration	4/389 (1%)		0/392 (0%)
Influenza like illness	0/389 (0%)		1/392 (0.3%)
Malaise	1/389 (0.3%)		1/392 (0.3%)
Mucosal inflammation	1/389 (0.3%)		0/392 (0%)
Multi-organ failure	1/389 (0.3%)		2/392 (0.5%)
Non-cardiac chest pain	0/389 (0%)		2/392 (0.5%)
Pyrexia	9/389 (2.3%)		14/392 (3.6%)
Sudden death	1/389 (0.3%)		1/392 (0.3%)
Systemic inflammatory response syndrome	0/389 (0%)		1/392 (0.3%)
Disease progression	8/389 (2.1%)		5/392 (1.3%)
Drowning	0/389 (0%)		1/392 (0.3%)
Fatigue	1/389 (0.3%)		1/392 (0.3%)
General physical health deterioration	4/389 (1%)		2/392 (0.5%)
Multiple organ dysfunction syndrome	1/389 (0.3%)		2/392 (0.5%)
Non-cardiac chest pain	0/389 (0%)		3/392 (0.8%)
Pyrexia	12/389 (3.1%)		15/392 (3.8%)
Hepatobiliary disorders
Bile duct stone	0/389 (0%)		1/392 (0.3%)
Cholangitis	0/389 (0%)		2/392 (0.5%)
Cholecystitis	2/389 (0.5%)		0/392 (0%)
Cholecystitis acute	3/389 (0.8%)		4/392 (1%)
Cholelithiasis	1/389 (0.3%)		2/392 (0.5%)
Hepatitis toxic	0/389 (0%)		1/392 (0.3%)
Hepatotoxicity	1/389 (0.3%)		0/392 (0%)
Hepatic cirrhosis	0/389 (0%)		1/392 (0.3%)
Immune system disorders
Cytokine release syndrome	1/389 (0.3%)		0/392 (0%)
Drug hypersensitivity	0/389 (0%)		1/392 (0.3%)
Infections and infestations
Abdominal abscess	0/389 (0%)		1/392 (0.3%)
Bacteraemia	0/389 (0%)		2/392 (0.5%)
Bacterial infection	0/389 (0%)		1/392 (0.3%)
Bronchiolitis	1/389 (0.3%)		1/392 (0.3%)
Bronchitis	11/389 (2.8%)		9/392 (2.3%)
Bronchitis viral	1/389 (0.3%)		0/392 (0%)
Bronchopneumonia	7/389 (1.8%)		5/392 (1.3%)
Bronchopulmonary aspergillosis	1/389 (0.3%)		0/392 (0%)
Catheter site cellulitis	0/389 (0%)		1/392 (0.3%)
Cellulitis	4/389 (1%)		1/392 (0.3%)
Cholangitis suppurative	0/389 (0%)		1/392 (0.3%)
Chronic hepatitis C	0/389 (0%)		1/392 (0.3%)
Clostridial infection	0/389 (0%)		2/392 (0.5%)
Clostridium difficile colitis	0/389 (0%)		4/392 (1%)
Cystitis	1/389 (0.3%)		0/392 (0%)
Device related infection	1/389 (0.3%)		3/392 (0.8%)
Diverticulitis	1/389 (0.3%)		1/392 (0.3%)
Endocarditis	0/389 (0%)		2/392 (0.5%)
Enterocolitis bacterial	0/389 (0%)		1/392 (0.3%)
Erysipelas	1/389 (0.3%)		1/392 (0.3%)
Escherichia sepsis	0/389 (0%)		1/392 (0.3%)
Escherichia urinary tract infection	0/389 (0%)		1/392 (0.3%)
Gastroenteritis	5/389 (1.3%)		5/392 (1.3%)
Genitourinary tract infection	1/389 (0.3%)		0/392 (0%)
Gingivitis	0/389 (0%)		1/392 (0.3%)
Hepatic infection	1/389 (0.3%)		0/392 (0%)
Herpes zoster disseminated	1/389 (0.3%)		1/392 (0.3%)
Incision site infection	0/389 (0%)		1/392 (0.3%)
Infection	1/389 (0.3%)		1/392 (0.3%)
Influenza	2/389 (0.5%)		3/392 (0.8%)
Laryngitis bacterial	0/389 (0%)		1/392 (0.3%)
Listeria sepsis	1/389 (0.3%)		0/392 (0%)
Liver abscess	0/389 (0%)		1/392 (0.3%)
Lobar pneumonia	1/389 (0.3%)		2/392 (0.5%)
Lower respiratory tract infection	3/389 (0.8%)		2/392 (0.5%)
Lower respiratory tract infection viral	1/389 (0.3%)		0/392 (0%)
Lung infection	1/389 (0.3%)		3/392 (0.8%)
Neutropenic sepsis	0/389 (0%)		1/392 (0.3%)
Peritonitis	0/389 (0%)		1/392 (0.3%)
Pneumocystis jiroveci pneumonia	0/389 (0%)		1/392 (0.3%)
Pneumonia	52/389 (13.4%)		67/392 (17.1%)
Pneumonia bacterial	3/389 (0.8%)		0/392 (0%)
Pneumonia influenzal	0/389 (0%)		1/392 (0.3%)
Pneumonia respiratory syncytial viral	1/389 (0.3%)		1/392 (0.3%)
Pneumonia viral	1/389 (0.3%)		0/392 (0%)
Postoperative abscess	1/389 (0.3%)		0/392 (0%)
Pulmonary sepsis	1/389 (0.3%)		0/392 (0%)
Pyelonephritis acute	1/389 (0.3%)		0/392 (0%)
Respiratory syncytial virus bronchiolitis	0/389 (0%)		1/392 (0.3%)
Respiratory syncytial virus infection	1/389 (0.3%)		0/392 (0%)
Respiratory tract infection	8/389 (2.1%)		16/392 (4.1%)
Respiratory tract infection viral	2/389 (0.5%)		1/392 (0.3%)
Salmonella sepsis	0/389 (0%)		1/392 (0.3%)
Sepsis	5/389 (1.3%)		7/392 (1.8%)
Sepsis syndrome	0/389 (0%)		1/392 (0.3%)
Septic shock	4/389 (1%)		3/392 (0.8%)
Sinusitis	2/389 (0.5%)		4/392 (1%)
Staphylococcal bacteraemia	0/389 (0%)		1/392 (0.3%)
Streptococcal bacteraemia	1/389 (0.3%)		1/392 (0.3%)
Testicular abscess	0/389 (0%)		1/392 (0.3%)
Tonsillitis	1/389 (0.3%)		0/392 (0%)
Tooth abscess	1/389 (0.3%)		0/392 (0%)
Tracheobronchitis	0/389 (0%)		2/392 (0.5%)
Tuberculosis	1/389 (0.3%)		0/392 (0%)
Upper respiratory tract infection	0/389 (0%)		4/392 (1%)
Urinary tract infection	2/389 (0.5%)		4/392 (1%)
Urosepsis	2/389 (0.5%)		1/392 (0.3%)
Arthritis infective	1/389 (0.3%)		0/392 (0%)
Atypical pneumonia	0/389 (0%)		1/392 (0.3%)
Cholangitis infective	0/389 (0%)		1/392 (0.3%)
Clostridium difficile infection	0/389 (0%)		2/392 (0.5%)
Epididymitis	0/389 (0%)		1/392 (0.3%)
Gastroenteritis salmonella	0/389 (0%)		1/392 (0.3%)
Hepatitis B	0/389 (0%)		1/392 (0.3%)
Osteomyelitis	0/389 (0%)		1/392 (0.3%)
Osteomyelitis bacterial	1/389 (0.3%)		0/392 (0%)
Pneumocystis jirovecii pneumonia	0/389 (0%)		1/392 (0.3%)
Progressive multifocal leukoencephalopathy	1/389 (0.3%)		0/392 (0%)
Staphylococcal infection	0/389 (0%)		1/392 (0.3%)
Staphylococcal sepsis	1/389 (0.3%)		0/392 (0%)
Stoma site abscess	0/389 (0%)		1/392 (0.3%)
Postoperative wound infection	0/389 (0%)		1/392 (0.3%)
Injury, poisoning and procedural complications
Concussion	0/389 (0%)		1/392 (0.3%)
Contusion	1/389 (0.3%)		0/392 (0%)
Fall	2/389 (0.5%)		1/392 (0.3%)
Femoral neck fracture	1/389 (0.3%)		0/392 (0%)
Femur fracture	3/389 (0.8%)		5/392 (1.3%)
Fibula fracture	0/389 (0%)		2/392 (0.5%)
Gallbladder injury	0/389 (0%)		1/392 (0.3%)
Hip fracture	3/389 (0.8%)		1/392 (0.3%)
Jaw fracture	1/389 (0.3%)		0/392 (0%)
Joint dislocation	1/389 (0.3%)		0/392 (0%)
Lumbar vertebral fracture	2/389 (0.5%)		1/392 (0.3%)
Multiple fractures	1/389 (0.3%)		0/392 (0%)
Road traffic accident	0/389 (0%)		2/392 (0.5%)
Spinal compression fracture	1/389 (0.3%)		1/392 (0.3%)
Splenic injury	1/389 (0.3%)		0/392 (0%)
Stress fracture	1/389 (0.3%)		0/392 (0%)
Subdural haematoma	1/389 (0.3%)		1/392 (0.3%)
Traumatic fracture	0/389 (0%)		2/392 (0.5%)
Facial bones fracture	0/389 (0%)		1/392 (0.3%)
Humerus fracture	0/389 (0%)		1/392 (0.3%)
Ligament sprain	0/389 (0%)		1/392 (0.3%)
Pubis fracture	0/389 (0%)		1/392 (0.3%)
Investigations
Alanine aminotransferase increased	0/389 (0%)		1/392 (0.3%)
Blood creatinine increased	1/389 (0.3%)		1/392 (0.3%)
Cardiac stress test abnormal	0/389 (0%)		1/392 (0.3%)
General physical condition abnormal	1/389 (0.3%)		0/392 (0%)
Haemoglobin decreased	0/389 (0%)		1/392 (0.3%)
Influenza A virus test positive	0/389 (0%)		2/392 (0.5%)
Intraocular pressure increased	0/389 (0%)		1/392 (0.3%)
Monoclonal immunoglobulin present	0/389 (0%)		1/392 (0.3%)
Respiratory syncytial virus test positive	0/389 (0%)		1/392 (0.3%)
Streptococcus test positive	0/389 (0%)		1/392 (0.3%)
Viral test positive	1/389 (0.3%)		0/392 (0%)
Weight decreased	0/389 (0%)		1/392 (0.3%)
Metabolism and nutrition disorders
Dehydration	1/389 (0.3%)		0/392 (0%)
Diabetes mellitus	1/389 (0.3%)		0/392 (0%)
Diabetic ketoacidosis	0/389 (0%)		1/392 (0.3%)
Electrolyte imbalance	1/389 (0.3%)		1/392 (0.3%)
Fluid overload	0/389 (0%)		1/392 (0.3%)
Gout	1/389 (0.3%)		0/392 (0%)
Hypercalcaemia	3/389 (0.8%)		0/392 (0%)
Hyperglycaemia	0/389 (0%)		3/392 (0.8%)
Hypoalbuminaemia	0/389 (0%)		1/392 (0.3%)
Hypocalcaemia	0/389 (0%)		2/392 (0.5%)
Hypokalaemia	1/389 (0.3%)		2/392 (0.5%)
Hyponatraemia	2/389 (0.5%)		1/392 (0.3%)
Mineral deficiency	1/389 (0.3%)		0/392 (0%)
Tumour lysis syndrome	0/389 (0%)		3/392 (0.8%)
Type 2 diabetes mellitus	1/389 (0.3%)		0/392 (0%)
Hypoglycaemia	0/389 (0%)		1/392 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/389 (0.3%)		1/392 (0.3%)
Arthritis	0/389 (0%)		1/392 (0.3%)
Back pain	4/389 (1%)		2/392 (0.5%)
Bone pain	1/389 (0.3%)		1/392 (0.3%)
Chondrocalcinosis pyrophosphate	1/389 (0.3%)		0/392 (0%)
Flank pain	0/389 (0%)		1/392 (0.3%)
Fracture pain	1/389 (0.3%)		0/392 (0%)
Gouty arthritis	1/389 (0.3%)		0/392 (0%)
Intervertebral disc compression	0/389 (0%)		1/392 (0.3%)
Joint swelling	1/389 (0.3%)		0/392 (0%)
Lumbar spinal stenosis	1/389 (0.3%)		0/392 (0%)
Muscular weakness	1/389 (0.3%)		1/392 (0.3%)
Musculoskeletal pain	1/389 (0.3%)		1/392 (0.3%)
Neck pain	2/389 (0.5%)		0/392 (0%)
Osteoarthritis	1/389 (0.3%)		0/392 (0%)
Osteonecrosis	1/389 (0.3%)		1/392 (0.3%)
Osteonecrosis of jaw	3/389 (0.8%)		2/392 (0.5%)
Pain in extremity	1/389 (0.3%)		1/392 (0.3%)
Pathological fracture	1/389 (0.3%)		2/392 (0.5%)
Rotator cuff syndrome	0/389 (0%)		1/392 (0.3%)
Spinal column stenosis	1/389 (0.3%)		0/392 (0%)
Tenosynovitis	0/389 (0%)		1/392 (0.3%)
Crystal arthropathy	0/389 (0%)		1/392 (0.3%)
Spinal pain	1/389 (0.3%)		1/392 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	2/389 (0.5%)		2/392 (0.5%)
Adenocarcinoma pancreas	0/389 (0%)		1/392 (0.3%)
Basal cell carcinoma	4/389 (1%)		5/392 (1.3%)
Colon cancer	0/389 (0%)		2/392 (0.5%)
Colorectal cancer	0/389 (0%)		1/392 (0.3%)
Gastrointestinal neoplasm	1/389 (0.3%)		0/392 (0%)
Gastrointestinal stromal tumour	1/389 (0.3%)		0/392 (0%)
Hepatic neoplasm malignant	1/389 (0.3%)		0/392 (0%)
Leukaemia plasmacytic	0/389 (0%)		1/392 (0.3%)
Malignant melanoma	1/389 (0.3%)		0/392 (0%)
Malignant neoplasm of pleura	0/389 (0%)		1/392 (0.3%)
Multiple myeloma	2/389 (0.5%)		0/392 (0%)
Myelodysplastic syndrome	4/389 (1%)		1/392 (0.3%)
Non-small cell lung cancer	1/389 (0.3%)		0/392 (0%)
Pancreatic carcinoma metastatic	0/389 (0%)		1/392 (0.3%)
Pancreatic neoplasm	0/389 (0%)		1/392 (0.3%)
Plasmacytoma	1/389 (0.3%)		2/392 (0.5%)
Rectal cancer	1/389 (0.3%)		0/392 (0%)
Squamous cell carcinoma	3/389 (0.8%)		2/392 (0.5%)
Squamous cell carcinoma of skin	1/389 (0.3%)		2/392 (0.5%)
Adenocarcinoma of colon	0/389 (0%)		1/392 (0.3%)
B precursor type acute leukaemia	0/389 (0%)		1/392 (0.3%)
Bowen's disease	1/389 (0.3%)		0/392 (0%)
Glioblastoma	1/389 (0.3%)		0/392 (0%)
Hepatic cancer	1/389 (0.3%)		0/392 (0%)
Laryngeal cancer	0/389 (0%)		1/392 (0.3%)
Lung adenocarcinoma	1/389 (0.3%)		0/392 (0%)
Non-Hodgkin's lymphoma	1/389 (0.3%)		0/392 (0%)
Plasma cell leukaemia	0/389 (0%)		1/392 (0.3%)
Plasma cell myeloma	2/389 (0.5%)		0/392 (0%)
Rectal adenocarcinoma	2/389 (0.5%)		0/392 (0%)
Nervous system disorders
Altered state of consciousness	0/389 (0%)		1/392 (0.3%)
Amyotrophic lateral sclerosis	1/389 (0.3%)		0/392 (0%)
Cauda equina syndrome	0/389 (0%)		1/392 (0.3%)
Cerebral cyst	0/389 (0%)		1/392 (0.3%)
Cerebral haemorrhage	1/389 (0.3%)		0/392 (0%)
Cerebrovascular accident	10/389 (2.6%)		4/392 (1%)
Cognitive disorder	0/389 (0%)		1/392 (0.3%)
Coma	1/389 (0.3%)		0/392 (0%)
Convulsion	2/389 (0.5%)		0/392 (0%)
Haemorrhage intracranial	0/389 (0%)		1/392 (0.3%)
Headache	0/389 (0%)		2/392 (0.5%)
Hydrocephalus	0/389 (0%)		1/392 (0.3%)
Loss of consciousness	0/389 (0%)		1/392 (0.3%)
Myxoedema coma	1/389 (0.3%)		0/392 (0%)
Neuralgia	1/389 (0.3%)		0/392 (0%)
Paraparesis	0/389 (0%)		1/392 (0.3%)
Polyneuropathy	1/389 (0.3%)		0/392 (0%)
Spinal cord compression	3/389 (0.8%)		2/392 (0.5%)
Syncope	2/389 (0.5%)		3/392 (0.8%)
Transient ischaemic attack	3/389 (0.8%)		0/392 (0%)
VIth nerve paralysis	1/389 (0.3%)		0/392 (0%)
Cerebral ischaemia	0/389 (0%)		1/392 (0.3%)
Guillain-Barre syndrome	0/389 (0%)		1/392 (0.3%)
Ischaemic cerebral infarction	0/389 (0%)		1/392 (0.3%)
Ischaemic stroke	0/389 (0%)		1/392 (0.3%)
Seizure	2/389 (0.5%)		0/392 (0%)
Psychiatric disorders
Completed suicide	0/389 (0%)		1/392 (0.3%)
Confusional state	1/389 (0.3%)		1/392 (0.3%)
Disorientation	0/389 (0%)		2/392 (0.5%)
Mental status changes	1/389 (0.3%)		0/392 (0%)
Personality change	0/389 (0%)		1/392 (0.3%)
Psychiatric decompensation	0/389 (0%)		1/392 (0.3%)
Renal and urinary disorders
Haematuria	0/389 (0%)		1/392 (0.3%)
Nephropathy	1/389 (0.3%)		0/392 (0%)
Nephrotic syndrome	0/389 (0%)		1/392 (0.3%)
Prerenal failure	1/389 (0.3%)		0/392 (0%)
Renal failure	1/389 (0.3%)		1/392 (0.3%)
Renal failure acute	4/389 (1%)		6/392 (1.5%)
Renal failure chronic	1/389 (0.3%)		0/392 (0%)
Renal impairment	1/389 (0.3%)		1/392 (0.3%)
Urinary retention	1/389 (0.3%)		1/392 (0.3%)
Acute kidney injury	4/389 (1%)		8/392 (2%)
Chronic kidney disease	1/389 (0.3%)		0/392 (0%)
Urethral prolapse	0/389 (0%)		1/392 (0.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/389 (0%)		1/392 (0.3%)
Epididymitis	0/389 (0%)		1/392 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/389 (0%)		4/392 (1%)
Alveolitis	0/389 (0%)		1/392 (0.3%)
Bronchitis chronic	0/389 (0%)		1/392 (0.3%)
Bronchopneumopathy	0/389 (0%)		1/392 (0.3%)
Bronchospasm	2/389 (0.5%)		0/392 (0%)
Chronic obstructive pulmonary disease	1/389 (0.3%)		3/392 (0.8%)
Dyspnoea	3/389 (0.8%)		4/392 (1%)
Eosinophilic pneumonia	0/389 (0%)		1/392 (0.3%)
Interstitial lung disease	1/389 (0.3%)		1/392 (0.3%)
Lung disorder	4/389 (1%)		2/392 (0.5%)
Pleural effusion	1/389 (0.3%)		1/392 (0.3%)
Pleural fibrosis	0/389 (0%)		1/392 (0.3%)
Pneumonia aspiration	0/389 (0%)		2/392 (0.5%)
Pneumonitis	1/389 (0.3%)		1/392 (0.3%)
Pulmonary embolism	8/389 (2.1%)		12/392 (3.1%)
Pulmonary oedema	0/389 (0%)		4/392 (1%)
Respiratory disorder	1/389 (0.3%)		0/392 (0%)
Respiratory failure	4/389 (1%)		1/392 (0.3%)
Laryngospasm	0/389 (0%)		1/392 (0.3%)
Obstructive airways disorder	1/389 (0.3%)		0/392 (0%)
Skin and subcutaneous tissue disorders
Acute generalised exanthematous pustulosis	1/389 (0.3%)		0/392 (0%)
Rash	1/389 (0.3%)		4/392 (1%)
Vascular disorders
Aortic aneurysm	0/389 (0%)		1/392 (0.3%)
Circulatory collapse	0/389 (0%)		1/392 (0.3%)
Deep vein thrombosis	6/389 (1.5%)		9/392 (2.3%)
Embolism	0/389 (0%)		2/392 (0.5%)
Haematoma	1/389 (0.3%)		0/392 (0%)
Hypertension	1/389 (0.3%)		0/392 (0%)
Hypotension	3/389 (0.8%)		2/392 (0.5%)
Orthostatic hypotension	1/389 (0.3%)		0/392 (0%)
Thrombophlebitis	0/389 (0%)		1/392 (0.3%)
Thrombosis	0/389 (0%)		3/392 (0.8%)
Vasculitis	1/389 (0.3%)		0/392 (0%)
Venous thrombosis	1/389 (0.3%)		0/392 (0%)
Peripheral ischaemia	1/389 (0.3%)		0/392 (0%)
Venous thrombosis limb	1/389 (0.3%)		0/392 (0%)
Other (Not Including Serious) Adverse Events
	Lenalidomide and Dexamethasone (Rd)		Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	358/389 (92%)		370/392 (94.4%)
Blood and lymphatic system disorders
Anaemia	154/389 (39.6%)		166/392 (42.3%)
Leukopenia	22/389 (5.7%)		33/392 (8.4%)
Neutropenia	133/389 (34.2%)		157/392 (40.1%)
Thrombocytopenia	94/389 (24.2%)		115/392 (29.3%)
Eye disorders
Cataract	36/389 (9.3%)		39/392 (9.9%)
Vision blurred	15/389 (3.9%)		24/392 (6.1%)
Gastrointestinal disorders
Abdominal pain	27/389 (6.9%)		32/392 (8.2%)
Abdominal pain upper	12/389 (3.1%)		28/392 (7.1%)
Constipation	69/389 (17.7%)		81/392 (20.7%)
Diarrhoea	143/389 (36.8%)		170/392 (43.4%)
Dyspepsia	22/389 (5.7%)		24/392 (6.1%)
Nausea	57/389 (14.7%)		82/392 (20.9%)
Vomiting	34/389 (8.7%)		49/392 (12.5%)
Toothache	12/389 (3.1%)		20/392 (5.1%)
General disorders
Asthenia	56/389 (14.4%)		69/392 (17.6%)
Chills	9/389 (2.3%)		25/392 (6.4%)
Fatigue	119/389 (30.6%)		128/392 (32.7%)
Oedema peripheral	75/389 (19.3%)		85/392 (21.7%)
Pyrexia	78/389 (20.1%)		105/392 (26.8%)
Asthenia	57/389 (14.7%)		72/392 (18.4%)
Chills	9/389 (2.3%)		26/392 (6.6%)
Fatigue	124/389 (31.9%)		132/392 (33.7%)
Oedema peripheral	66/389 (17%)		78/392 (19.9%)
Peripheral swelling	21/389 (5.4%)		21/392 (5.4%)
Pyrexia	80/389 (20.6%)		110/392 (28.1%)
Infections and infestations
Bronchitis	56/389 (14.4%)		75/392 (19.1%)
Influenza	14/389 (3.6%)		26/392 (6.6%)
Nasopharyngitis	65/389 (16.7%)		87/392 (22.2%)
Pneumonia	29/389 (7.5%)		45/392 (11.5%)
Respiratory tract infection	39/389 (10%)		41/392 (10.5%)
Sinusitis	18/389 (4.6%)		24/392 (6.1%)
Upper respiratory tract infection	81/389 (20.8%)		115/392 (29.3%)
Urinary tract infection	21/389 (5.4%)		36/392 (9.2%)
Viral infection	11/389 (2.8%)		28/392 (7.1%)
Viral upper respiratory tract infection	68/389 (17.5%)		80/392 (20.4%)
Investigations
Alanine aminotransferase increased	15/389 (3.9%)		21/392 (5.4%)
Blood creatinine increased	21/389 (5.4%)		27/392 (6.9%)
Neutrophil count decreased	22/389 (5.7%)		21/392 (5.4%)
Weight decreased	20/389 (5.1%)		14/392 (3.6%)
Metabolism and nutrition disorders
Decreased appetite	35/389 (9%)		47/392 (12%)
Hyperglycaemia	39/389 (10%)		48/392 (12.2%)
Hypocalcaemia	49/389 (12.6%)		65/392 (16.6%)
Hypokalaemia	58/389 (14.9%)		114/392 (29.1%)
Hypomagnesaemia	29/389 (7.5%)		40/392 (10.2%)
Hypophosphataemia	33/389 (8.5%)		57/392 (14.5%)
Hyperuricaemia	11/389 (2.8%)		22/392 (5.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	57/389 (14.7%)		57/392 (14.5%)
Back pain	81/389 (20.8%)		73/392 (18.6%)
Bone pain	36/389 (9.3%)		39/392 (9.9%)
Muscle spasms	82/389 (21.1%)		106/392 (27%)
Muscular weakness	24/389 (6.2%)		28/392 (7.1%)
Musculoskeletal chest pain	29/389 (7.5%)		26/392 (6.6%)
Musculoskeletal pain	36/389 (9.3%)		25/392 (6.4%)
Myalgia	22/389 (5.7%)		25/392 (6.4%)
Pain in extremity	42/389 (10.8%)		48/392 (12.2%)
Nervous system disorders
Dizziness	45/389 (11.6%)		54/392 (13.8%)
Dysgeusia	21/389 (5.4%)		14/392 (3.6%)
Headache	32/389 (8.2%)		56/392 (14.3%)
Neuropathy peripheral	28/389 (7.2%)		34/392 (8.7%)
Paraesthesia	23/389 (5.9%)		27/392 (6.9%)
Peripheral sensory neuropathy	27/389 (6.9%)		25/392 (6.4%)
Tremor	32/389 (8.2%)		28/392 (7.1%)
Psychiatric disorders
Anxiety	17/389 (4.4%)		33/392 (8.4%)
Insomnia	65/389 (16.7%)		81/392 (20.7%)
Respiratory, thoracic and mediastinal disorders
Cough	70/389 (18%)		116/392 (29.6%)
Dyspnoea	59/389 (15.2%)		76/392 (19.4%)
Dyspnoea exertional	19/389 (4.9%)		23/392 (5.9%)
Oropharyngeal pain	22/389 (5.7%)		28/392 (7.1%)
Epistaxis	17/389 (4.4%)		20/392 (5.1%)
Productive cough	12/389 (3.1%)		21/392 (5.4%)
Skin and subcutaneous tissue disorders
Erythema	13/389 (3.3%)		30/392 (7.7%)
Hyperhidrosis	18/389 (4.6%)		28/392 (7.1%)
Pruritus	16/389 (4.1%)		31/392 (7.9%)
Rash	59/389 (15.2%)		50/392 (12.8%)
Vascular disorders
Deep vein thrombosis	11/389 (2.8%)		21/392 (5.4%)
Hypertension	30/389 (7.7%)		62/392 (15.8%)
Hypotension	22/389 (5.7%)		26/392 (6.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

Results Point of Contact

Name/Title	Study Director
Organization	Amgen Inc.
Phone	866-572-6436
Email	medinfo@amgen.com

Responsible Party:

Amgen

ClinicalTrials.gov Identifier:

NCT01080391

Other Study ID Numbers:

PX-171-009

First Posted:

Mar 4, 2010

Last Update Posted:

Jan 14, 2019

Last Verified:

Dec 1, 2018

Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma

Study Details

Study Description

Brief Summary

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

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Certain Agreements

Results Point of Contact