A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma
Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT01776840
Collaborator
Pharmacyclics LLC. (Industry)
523
203
2
151
2.6
0
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This is a randomized (individuals assigned to study treatment by chance), double blind (neither physician nor participant knows the treatment that the participant receives), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab (BR) with BR alone in participants newly diagnosed with mantle cell lymphoma (MCL) who are 65 years of age or older. Approximately 520 participants will be randomly assigned in a 1:1 ratio and stratified by simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score (low risk [0-3] versus intermediate risk [4-5] versus high risk [6-11]). The treatment phase will extend from randomization until discontinuation of all study treatment or the clinical cutoff for the end of study. A cycle is defined as 28 days. All participants will receive open-label (identity of assigned study drug will be known) BR background therapy for a maximum of 6 cycles; participants with a complete response or partial response will continue to receive open-label background therapy with rituximab maintenance every second cycle for a maximum of 12 additional doses. In addition to the background therapy, all participants will receive blinded study drug (ibrutinib or placebo). Participants randomized to treatment Arm A will receive placebo capsules and participants randomized to treatment Arm B will receive ibrutinib capsules. Study drug will be administered daily and continuously until disease progression, unacceptable toxicity, or study end. Participants with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, or study end. Participants with progressive disease must discontinue all study treatment. For participants who discontinue background therapy and do not have progressive disease, treatment with study drug will continue until disease progression or unacceptable toxicity or the clinical cutoff for the final analysis of progression-free survival (PFS). Participants receiving BR, rituximab, or ibrutinib at the clinical cutoff for the final analysis of PFS will continue open-label treatment until disease progression or unacceptable toxicity. Placebo will be stopped when the study is unblinded for the clinical cutoff for the final analysis of PFS. The posttreatment follow-up phase will begin once a participant discontinues bendamustine and rituximab and study drug. Participants who discontinue for reasons other than disease progression must continue to have disease evaluations as outlined in the protocol. Participants who discontinue due to disease progression will be followed for survival and subsequent anti-MCL therapy. The posttreatment follow-up phase will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first. Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 180, and 265 PFS events have been observed, respectively. The interim analyses and the final analysis of PFS will take place at these 3 clinical cutoffs, respectively; participant treatment assignment will be unblinded and placebo treatment will be stopped at the clinical cutoff for the final analysis of PFS. Treatment unblinding and stopping of placebo treatment could occur before the planned final analysis of PFS if recommended by the independent Data Monitoring Committee (DMC) after an interim analysis. The last cutoff will occur at the end of study, when 60% of the randomized participants have died or the Sponsor terminates the study, whichever comes first. Efficacy assessments will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Safety will be monitored throughout the study and summarized. Blood samples will be drawn for assessment of pharmacokinetic parameters. Blood and bone marrow will be collected for assessment of minimal residual disease and biomarker studies.
Study Design
Study Type:
Interventional
Actual Enrollment
:
523 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma
Actual Study Start Date
:
May 16, 2013
Actual Primary Completion Date
:
Jun 30, 2021
Anticipated Study Completion Date
:
Dec 15, 2025
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Treatment Arm A
|
Drug: Bendamustine
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
Drug: Rituximab
375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses
Drug: Placebo
4 capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or the final analysis of progression-free survival
|
| Experimental: Treatment Arm B
|
Drug: Bendamustine
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
Drug: Rituximab
375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses
Drug: Ibrutinib
560 mg (4 x 140 mg capsules) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end
|
Outcome Measures
Primary Outcome Measures
- Progression-free Survival (PFS) [Up to 97 months]
Progression-free survival (PFS) is defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever is first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD is defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters [cm] in any axis, 50% increase in sum of product of diameters [SPD] of greater than [>] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis).
Secondary Outcome Measures
- Overall Survival [Up to 97 months]
Overall survival is defined as the time from the date of randomization to the date of the participant's death.
- Complete Response Rate [Up to 97 months]
Complete response (CR) rate is defined as the percentage of participants who achieve CR (based on investigator assessment) on or prior to the initiation of subsequent anticancer therapy. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if positron emission tomography (PET) negative; regression to normal size on computed tomography (CT); spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
- Time-to-Next Treatment [Up to 97 months]
Time-to-next treatment was measured from the date of randomization to the start date of any anti-mantle cell lymphoma (anti-MCL) treatment subsequent to the study treatment.
- Percentage of Participants With Overall Response [Up to 97 months]
Percentage of participants with overall response that is participants who achieved CR or PR was reported. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. Criteria for PR: greater than or equal to (>=) 50% decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions.
- Minimal Residual Disease (MRD)-Negative Response Rate [Up to 97 months]
Minimal residual disease negative rate was defined as the percentage of participants with a best overall response of CR with MRD-negative disease status (that is, <5 mantle cell lymphoma [MCL] cell per 10,000 leukocytes for detection using the MRD assay), as assessed by flow cytometry of a bone marrow and/or peripheral blood sample.
- Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire [Up to 97 months]
Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline, death, or a missing assessment due to being "too ill", whichever occurred first. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
- Duration of Response (DoR) [Up to 97 months]
Duration of Response (DoR) was defined as the interval between the date of initial documentation of a response including PR and the date of first documented evidence of PD or death.
- Duration of Complete Response (DoCR) [Up to 97 months]
Duration of complete response (DoCR) was defined as the interval between the date of initial documentation of a CR and the date of first documented evidence of PD or death whichever occurs first, for participants who achieved CR.
- Time to Response [Up to 97 months]
Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response.
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Up to 97 months]
Number of participants with TEAEs were reported. Treatment-emergent adverse events are defined as adverse events with onset or worsening on or after date of first dose of study treatment up to and including 30 days after date of last dose of study medication, or the initiation of subsequent anticancer therapy, whichever is earlier.
- Oral Plasma Clearance (CL/F) of Ibrutinib [Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)]
CL/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling).
- Oral Volume of Distribution at Steady State of Ibrutinib [Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)]
Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling.
- Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State [Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)]
Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling.
- Minimum Observed Plasma Concentration of Ibrutinib [Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)]
Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling.
- Maximum Observed Plasma Concentration of Ibrutinib [Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)]
Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Eligibility Criteria
Criteria
Ages Eligible for Study:
65 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Diagnosis of mantle cell lymphoma (MCL) reviewed and approved by central laboratory: diagnosis must include morphology and expression of either cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5 and CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR)
-
Clinical Stage II, III, or IV by Ann Arbor Classification
-
At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
-
No prior therapies for MCL
-
Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1
-
Hematology and biochemical laboratory values within protocol-defined limits
-
Agrees to protocol-defined use of effective contraception
-
Negative blood or urine pregnancy test at screening
Exclusion Criteria:
-
Major surgery within 4 weeks of random assignment
-
Known central nervous system lymphoma
-
Diagnosed or treated for malignancy other than MCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before random assignment; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease
-
Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
-
History of stroke or intracranial hemorrhage within 6 months prior to random assignment
-
Requires anticoagulation with warfarin or equivalent vitamin K antagonists
-
Requires treatment with strong CYP3A inhibitors
-
Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
-
Vaccinated with live, attenuated vaccines within 4 weeks of random assignment
-
Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous antibiotics
-
Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Tucson | Arizona | United States | ||
| 2 | Burbank | California | United States | ||
| 3 | La Jolla | California | United States | ||
| 4 | Stanford | California | United States | ||
| 5 | Denver | Colorado | United States | ||
| 6 | New Haven | Connecticut | United States | ||
| 7 | Stamford | Connecticut | United States | ||
| 8 | Chicago | Illinois | United States | ||
| 9 | Maywood | Illinois | United States | ||
| 10 | Niles | Illinois | United States | ||
| 11 | Springfield | Illinois | United States | ||
| 12 | Goshen | Indiana | United States | ||
| 13 | Iowa City | Iowa | United States | ||
| 14 | Sioux City | Iowa | United States | ||
| 15 | Topeka | Kansas | United States | ||
| 16 | Westwood | Kansas | United States | ||
| 17 | Lexington | Kentucky | United States | ||
| 18 | Louisville | Kentucky | United States | ||
| 19 | Metairie | Louisiana | United States | ||
| 20 | Ann Arbor | Michigan | United States | ||
| 21 | Detroit | Michigan | United States | ||
| 22 | Jefferson City | Missouri | United States | ||
| 23 | Lincoln | Nebraska | United States | ||
| 24 | Hackensack | New Jersey | United States | ||
| 25 | New Brunswick | New Jersey | United States | ||
| 26 | Albuquerque | New Mexico | United States | ||
| 27 | Albany | New York | United States | ||
| 28 | Hawthorne | New York | United States | ||
| 29 | New York | New York | United States | ||
| 30 | Durham | North Carolina | United States | ||
| 31 | Greenville | North Carolina | United States | ||
| 32 | Bismarck | North Dakota | United States | ||
| 33 | Fargo | North Dakota | United States | ||
| 34 | Eugene | Oregon | United States | ||
| 35 | Portland | Oregon | United States | ||
| 36 | Philadelphia | Pennsylvania | United States | ||
| 37 | Greenville | South Carolina | United States | ||
| 38 | Watertown | South Dakota | United States | ||
| 39 | Nashville | Tennessee | United States | ||
| 40 | Houston | Texas | United States | ||
| 41 | San Antonio | Texas | United States | ||
| 42 | Burlington | Vermont | United States | ||
| 43 | Spokane | Washington | United States | ||
| 44 | Vancouver | Washington | United States | ||
| 45 | Buenos Aires | Argentina | |||
| 46 | Ciudad Autonoma de Buenos Aires | Argentina | |||
| 47 | Cordoba | Argentina | |||
| 48 | La Capital | Argentina | |||
| 49 | Parana | Argentina | |||
| 50 | Adelaide | Australia | |||
| 51 | Box Hill | Australia | |||
| 52 | Concord | Australia | |||
| 53 | Douglas | Australia | |||
| 54 | Gosford | Australia | |||
| 55 | Hobart | Australia | |||
| 56 | Prahran | Australia | |||
| 57 | South Brisbane | Australia | |||
| 58 | Antwerpen | Belgium | |||
| 59 | Brugge | Belgium | |||
| 60 | Brussels | Belgium | |||
| 61 | Gent | Belgium | |||
| 62 | Leuven | Belgium | |||
| 63 | Wilrijk | Belgium | |||
| 64 | Yvoir | Belgium | |||
| 65 | Barretos | Brazil | |||
| 66 | Goiânia | Brazil | |||
| 67 | Porto Alegre | Brazil | |||
| 68 | Ribeirao Preto | Brazil | |||
| 69 | Rio de Janeiro | Brazil | |||
| 70 | Sao Paulo | Brazil | |||
| 71 | São Paulol | Brazil | |||
| 72 | São Paulo | Brazil | |||
| 73 | Edmonton | Alberta | Canada | ||
| 74 | Vancouver | British Columbia | Canada | ||
| 75 | Hamilton | Ontario | Canada | ||
| 76 | Ottawa | Ontario | Canada | ||
| 77 | Montreal | Quebec | Canada | ||
| 78 | Beijing | China | |||
| 79 | Chengdu | China | |||
| 80 | Guangzhou | China | |||
| 81 | Hangzhou | China | |||
| 82 | Shanghai | China | |||
| 83 | Tianjin | China | |||
| 84 | Brno | Czechia | |||
| 85 | Hradec Kralove | Czechia | |||
| 86 | Praha 10 | Czechia | |||
| 87 | Creteil | France | |||
| 88 | F-75 730 Paris Cedex 15 | France | |||
| 89 | Grenoble | France | |||
| 90 | Nantes | France | |||
| 91 | Paris | France | |||
| 92 | Pessac | France | |||
| 93 | Tours Cedex 9 | France | |||
| 94 | Berlin | Germany | |||
| 95 | Heidelberg | Germany | |||
| 96 | Jena | Germany | |||
| 97 | Mainz | Germany | |||
| 98 | München | Germany | |||
| 99 | TÿBINGEN | Germany | |||
| 100 | Ulm | Germany | |||
| 101 | Villingen-Schwenningen | Germany | |||
| 102 | Athens Attica | Greece | |||
| 103 | Athens | Greece | |||
| 104 | Thessalonikis | Greece | |||
| 105 | Budapest N/a | Hungary | |||
| 106 | Debrecen | Hungary | |||
| 107 | Kaposvár | Hungary | |||
| 108 | Pécs N/a | Hungary | |||
| 109 | Szeged | Hungary | |||
| 110 | Dublin | Ireland | |||
| 111 | Galway | Ireland | |||
| 112 | Afula | Israel | |||
| 113 | Beer-Sheva | Israel | |||
| 114 | Haifa | Israel | |||
| 115 | Jerusalem | Israel | |||
| 116 | Nahariya | Israel | |||
| 117 | Petach Tikva | Israel | |||
| 118 | Ramat-Gan | Israel | |||
| 119 | Tel Aviv | Israel | |||
| 120 | Zerifin | Israel | |||
| 121 | Fukuoka | Japan | |||
| 122 | Hiroshima | Japan | |||
| 123 | Kyoto | Japan | |||
| 124 | Nagoya | Japan | |||
| 125 | Osaka | Japan | |||
| 126 | Sapporo | Japan | |||
| 127 | Sendai-shi | Japan | |||
| 128 | Suita | Japan | |||
| 129 | Tokyo | Japan | |||
| 130 | Gyeonggi-do | Korea, Republic of | |||
| 131 | Jeollanam-do | Korea, Republic of | |||
| 132 | Seoul | Korea, Republic of | |||
| 133 | Monterrey | Mexico | |||
| 134 | Oaxaca | Mexico | |||
| 135 | Amsterdam Zuidoost | Netherlands | |||
| 136 | Dordrecht | Netherlands | |||
| 137 | Groningen | Netherlands | |||
| 138 | Leiden | Netherlands | |||
| 139 | Rotterdam | Netherlands | |||
| 140 | Utrecht | Netherlands | |||
| 141 | Bydgoszcz | Poland | |||
| 142 | Krakow | Poland | |||
| 143 | Olsztyn | Poland | |||
| 144 | Warszawa | Poland | |||
| 145 | Wroclaw | Poland | |||
| 146 | San Juan | Puerto Rico | |||
| 147 | Chelyabinsk | Russian Federation | |||
| 148 | Ekaterinburg | Russian Federation | |||
| 149 | Krasnodar | Russian Federation | |||
| 150 | Moscow N/a | Russian Federation | |||
| 151 | Moscow | Russian Federation | |||
| 152 | Nizhny Novgorod | Russian Federation | |||
| 153 | Novosibirsk | Russian Federation | |||
| 154 | Petrozavodsk | Russian Federation | |||
| 155 | Ryazan | Russian Federation | |||
| 156 | St-Petersburg | Russian Federation | |||
| 157 | St.Petersurg | Russian Federation | |||
| 158 | Syktyvkar | Russian Federation | |||
| 159 | Volgograd | Russian Federation | |||
| 160 | Banska Bystrica | Slovakia | |||
| 161 | Bratislava | Slovakia | |||
| 162 | Kosice | Slovakia | |||
| 163 | Martin | Slovakia | |||
| 164 | Presov 1 | Slovakia | |||
| 165 | Barcelona | Spain | |||
| 166 | Madrid | Spain | |||
| 167 | Oviedo | Spain | |||
| 168 | Palma De Mallorca | Spain | |||
| 169 | Salamanca | Spain | |||
| 170 | Santiago De Compostela | Spain | |||
| 171 | Linköping | Sweden | |||
| 172 | Lund | Sweden | |||
| 173 | Stockholm | Sweden | |||
| 174 | Umeaa | Sweden | |||
| 175 | Uppsala | Sweden | |||
| 176 | Changhua | Taiwan | |||
| 177 | Kaohsiung County | Taiwan | |||
| 178 | Taichung | Taiwan | |||
| 179 | Tainan | Taiwan | |||
| 180 | Taipei | Taiwan | |||
| 181 | Taoyuan | Taiwan | |||
| 182 | Adana | Turkey | |||
| 183 | Ankara | Turkey | |||
| 184 | Diyarbakir | Turkey | |||
| 185 | Istanbul | Turkey | |||
| 186 | Izmir | Turkey | |||
| 187 | Kayseri | Turkey | |||
| 188 | Mersin | Turkey | |||
| 189 | Cherkassy | Ukraine | |||
| 190 | Donetsk | Ukraine | |||
| 191 | Khmelnitskiy | Ukraine | |||
| 192 | Kiev | Ukraine | |||
| 193 | Lviv | Ukraine | |||
| 194 | Canterbury | United Kingdom | |||
| 195 | Glasgow | United Kingdom | |||
| 196 | Leeds | United Kingdom | |||
| 197 | Leicester | United Kingdom | |||
| 198 | Liverpool | United Kingdom | |||
| 199 | London | United Kingdom | |||
| 200 | Manchester | United Kingdom | |||
| 201 | Plymouth | United Kingdom | |||
| 202 | Southampton | United Kingdom | |||
| 203 | Sutton | United Kingdom |
Sponsors and Collaborators
- Janssen Research & Development, LLC
- Pharmacyclics LLC.
Investigators
- Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01776840
Other Study ID Numbers:
- CR100967
- PCI-32765MCL3002
- U1111-1137-0389
- 2012-004056-11
First Posted:
Jan 28, 2013
Last Update Posted:
Aug 15, 2022
Last Verified:
Aug 1, 2022
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Janssen Research & Development, LLC
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Period Title: Overall Study | ||
| STARTED | 261 | 262 |
| COMPLETED | 103 | 107 |
| NOT COMPLETED | 158 | 155 |
Baseline Characteristics
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) | Total |
|---|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Total of all reporting groups |
| Overall Participants | 261 | 262 | 523 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
71.8
(5.04)
|
71.7
(5.2)
|
71.7
(5.12)
|
| Age, Customized (Count of Participants) | |||
| 70 years and over |
162
62.1%
|
154
58.8%
|
316
60.4%
|
| < 70 years |
99
37.9%
|
108
41.2%
|
207
39.6%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
83
31.8%
|
76
29%
|
159
30.4%
|
| Male |
178
68.2%
|
186
71%
|
364
69.6%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
18
6.9%
|
17
6.5%
|
35
6.7%
|
| Not Hispanic or Latino |
232
88.9%
|
234
89.3%
|
466
89.1%
|
| Unknown or Not Reported |
11
4.2%
|
11
4.2%
|
22
4.2%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
3
1.1%
|
3
0.6%
|
| Asian |
47
18%
|
42
16%
|
89
17%
|
| Black or African American |
2
0.8%
|
1
0.4%
|
3
0.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| White |
199
76.2%
|
206
78.6%
|
405
77.4%
|
| More than one race |
1
0.4%
|
1
0.4%
|
2
0.4%
|
| Unknown or Not Reported |
10
3.8%
|
9
3.4%
|
19
3.6%
|
| Other |
2
0.8%
|
0
0%
|
2
0.4%
|
| Region of Enrollment (Count of Participants) | |||
| ARGENTINA |
4
1.5%
|
0
0%
|
4
0.8%
|
| AUSTRALIA |
19
7.3%
|
12
4.6%
|
31
5.9%
|
| BELGIUM |
5
1.9%
|
10
3.8%
|
15
2.9%
|
| BRAZIL |
11
4.2%
|
10
3.8%
|
21
4%
|
| CANADA |
4
1.5%
|
7
2.7%
|
11
2.1%
|
| CHINA |
31
11.9%
|
26
9.9%
|
57
10.9%
|
| CZECH REPUBLIC |
7
2.7%
|
8
3.1%
|
15
2.9%
|
| FRANCE |
8
3.1%
|
13
5%
|
21
4%
|
| GERMANY |
3
1.1%
|
5
1.9%
|
8
1.5%
|
| GREECE |
4
1.5%
|
3
1.1%
|
7
1.3%
|
| HUNGARY |
5
1.9%
|
5
1.9%
|
10
1.9%
|
| IRELAND |
2
0.8%
|
0
0%
|
2
0.4%
|
| ISRAEL |
5
1.9%
|
9
3.4%
|
14
2.7%
|
| ITALY |
13
5%
|
13
5%
|
26
5%
|
| JAPAN |
7
2.7%
|
4
1.5%
|
11
2.1%
|
| MEXICO |
1
0.4%
|
2
0.8%
|
3
0.6%
|
| NETHERLANDS |
5
1.9%
|
3
1.1%
|
8
1.5%
|
| POLAND |
18
6.9%
|
17
6.5%
|
35
6.7%
|
| RUSSIAN FEDERATION |
15
5.7%
|
12
4.6%
|
27
5.2%
|
| SLOVAKIA |
1
0.4%
|
2
0.8%
|
3
0.6%
|
| SOUTH KOREA |
6
2.3%
|
6
2.3%
|
12
2.3%
|
| SPAIN |
13
5%
|
7
2.7%
|
20
3.8%
|
| SWEDEN |
9
3.4%
|
9
3.4%
|
18
3.4%
|
| TAIWAN |
2
0.8%
|
4
1.5%
|
6
1.1%
|
| TURKEY |
8
3.1%
|
6
2.3%
|
14
2.7%
|
| UKRAINE |
6
2.3%
|
5
1.9%
|
11
2.1%
|
| UNITED KINGDOM |
14
5.4%
|
16
6.1%
|
30
5.7%
|
| UNITED STATES |
35
13.4%
|
48
18.3%
|
83
15.9%
|
Outcome Measures
| Title | Progression-free Survival (PFS) |
|---|---|
| Description | Progression-free survival (PFS) is defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever is first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD is defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters [cm] in any axis, 50% increase in sum of product of diameters [SPD] of greater than [>] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis). |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent-to-treat (ITT) analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 116 | 152 |
| Median (95% Confidence Interval) [months] |
80.6
|
52.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ibrutinib + BR (Treatment B), Placebo + BR (Treatment A) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.011 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.75 | |
| Confidence Interval |
(2-Sided) 95% 0.59 to 0.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival |
|---|---|
| Description | Overall survival is defined as the time from the date of randomization to the date of the participant's death. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 104 | 107 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
| Title | Complete Response Rate |
|---|---|
| Description | Complete response (CR) rate is defined as the percentage of participants who achieve CR (based on investigator assessment) on or prior to the initiation of subsequent anticancer therapy. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if positron emission tomography (PET) negative; regression to normal size on computed tomography (CT); spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 261 | 262 |
| Number [percentage of participants] |
65.5
25.1%
|
57.6
22%
|
| Title | Time-to-Next Treatment |
|---|---|
| Description | Time-to-next treatment was measured from the date of randomization to the start date of any anti-mantle cell lymphoma (anti-MCL) treatment subsequent to the study treatment. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 52 | 106 |
| Median (95% Confidence Interval) [months] |
NA
|
92.0
|
| Title | Percentage of Participants With Overall Response |
|---|---|
| Description | Percentage of participants with overall response that is participants who achieved CR or PR was reported. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. Criteria for PR: greater than or equal to (>=) 50% decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 261 | 262 |
| Number [percentage of participants] |
89.7
34.4%
|
88.5
33.8%
|
| Title | Minimal Residual Disease (MRD)-Negative Response Rate |
|---|---|
| Description | Minimal residual disease negative rate was defined as the percentage of participants with a best overall response of CR with MRD-negative disease status (that is, <5 mantle cell lymphoma [MCL] cell per 10,000 leukocytes for detection using the MRD assay), as assessed by flow cytometry of a bone marrow and/or peripheral blood sample. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. CR participants with missing MRD data and participants who did not achieve a CR were considered nonresponders. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 261 | 262 |
| Number [percentage of participants] |
62.1
23.8%
|
56.5
21.6%
|
| Title | Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire |
|---|---|
| Description | Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline, death, or a missing assessment due to being "too ill", whichever occurred first. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 261 | 262 |
| Median (95% Confidence Interval) [months] |
17.4
|
22.2
|
| Title | Duration of Response (DoR) |
|---|---|
| Description | Duration of Response (DoR) was defined as the interval between the date of initial documentation of a response including PR and the date of first documented evidence of PD or death. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a PR or better were included in the analysis of duration of response. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 234 | 232 |
| Median (95% Confidence Interval) [months] |
81
|
63.5
|
| Title | Duration of Complete Response (DoCR) |
|---|---|
| Description | Duration of complete response (DoCR) was defined as the interval between the date of initial documentation of a CR and the date of first documented evidence of PD or death whichever occurs first, for participants who achieved CR. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a CR or better were included in the analysis of duration of complete response. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 171 | 151 |
| Median (95% Confidence Interval) [months] |
NA
|
78.1
|
| Title | Time to Response |
|---|---|
| Description | Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a PR or better were included in the analysis of time to response. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 234 | 232 |
| Median (Full Range) [months] |
2.79
|
2.79
|
| Title | Number of Participants With Treatment-emergent Adverse Events (TEAEs) |
|---|---|
| Description | Number of participants with TEAEs were reported. Treatment-emergent adverse events are defined as adverse events with onset or worsening on or after date of first dose of study treatment up to and including 30 days after date of last dose of study medication, or the initiation of subsequent anticancer therapy, whichever is earlier. |
| Time Frame | Up to 97 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Analysis Set included all randomized participants who received at least 1 dose of study drug (ibrutinib or placebo). |
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) |
|---|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 259 | 260 |
| Count of Participants [Participants] |
259
99.2%
|
257
98.1%
|
| Title | Oral Plasma Clearance (CL/F) of Ibrutinib |
|---|---|
| Description | CL/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling). |
| Time Frame | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) |
|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 259 |
| Mean (Standard Error) [liter per hour (L/h)] |
1123
(4.83)
|
| Title | Oral Volume of Distribution at Steady State of Ibrutinib |
|---|---|
| Description | Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling. |
| Time Frame | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) |
|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 259 |
| Mean (Standard Error) [liter] |
7286
(7.87)
|
| Title | Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State |
|---|---|
| Description | Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling. |
| Time Frame | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) |
|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 259 |
| Mean (Standard Deviation) [nanogram*hour per milliliter (ng*h/mL)] |
425
(267)
|
| Title | Minimum Observed Plasma Concentration of Ibrutinib |
|---|---|
| Description | Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling. |
| Time Frame | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) |
|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 259 |
| Mean (Standard Deviation) [nanograms per milliliter (ng/mL)] |
3.90
(2.64)
|
| Title | Maximum Observed Plasma Concentration of Ibrutinib |
|---|---|
| Description | Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling. |
| Time Frame | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment. |
| Arm/Group Title | Ibrutinib + BR (Treatment B) |
|---|---|
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. |
| Measure Participants | 259 |
| Mean (Standard Deviation) [ng/mL] |
74.5
(48.3)
|
Adverse Events
| Time Frame | Up to 97 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Safety analysis set included all randomized participants who received at least 1 dose of study drug (ibrutinib or placebo). | |||
| Arm/Group Title | Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) | ||
| Arm/Group Description | Participants received 560 milligrams (mg) (4*140 mg capsule) ibrutinib capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenously [IV] on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. | ||
All Cause Mortality |
||||
| Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 103/259 (39.8%) | 107/260 (41.2%) | ||
Serious Adverse Events |
||||
| Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 197/259 (76.1%) | 156/260 (60%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 4/259 (1.5%) | 3/260 (1.2%) | ||
| Febrile Neutropenia | 16/259 (6.2%) | 9/260 (3.5%) | ||
| Leukocytosis | 1/259 (0.4%) | 0/260 (0%) | ||
| Lymphadenitis | 3/259 (1.2%) | 1/260 (0.4%) | ||
| Methaemoglobinaemia | 1/259 (0.4%) | 0/260 (0%) | ||
| Neutropenia | 3/259 (1.2%) | 3/260 (1.2%) | ||
| Pancytopenia | 0/259 (0%) | 1/260 (0.4%) | ||
| Splenic Infarction | 0/259 (0%) | 1/260 (0.4%) | ||
| Thrombocytopenia | 2/259 (0.8%) | 3/260 (1.2%) | ||
| Cardiac disorders | ||||
| Acute Coronary Syndrome | 0/259 (0%) | 1/260 (0.4%) | ||
| Acute Myocardial Infarction | 1/259 (0.4%) | 4/260 (1.5%) | ||
| Angina Pectoris | 1/259 (0.4%) | 0/260 (0%) | ||
| Arrhythmia | 1/259 (0.4%) | 0/260 (0%) | ||
| Atrial Fibrillation | 13/259 (5%) | 4/260 (1.5%) | ||
| Atrial Flutter | 3/259 (1.2%) | 1/260 (0.4%) | ||
| Atrioventricular Block | 0/259 (0%) | 1/260 (0.4%) | ||
| Bradycardia | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Cardiac Arrest | 3/259 (1.2%) | 1/260 (0.4%) | ||
| Cardiac Failure | 3/259 (1.2%) | 0/260 (0%) | ||
| Cardio-Respiratory Arrest | 1/259 (0.4%) | 0/260 (0%) | ||
| Cardiomyopathy | 1/259 (0.4%) | 0/260 (0%) | ||
| Cardiopulmonary Failure | 0/259 (0%) | 2/260 (0.8%) | ||
| Coronary Artery Disease | 0/259 (0%) | 1/260 (0.4%) | ||
| Coronary Artery Stenosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Ischaemic Cardiomyopathy | 1/259 (0.4%) | 0/260 (0%) | ||
| Left Ventricular Failure | 0/259 (0%) | 1/260 (0.4%) | ||
| Mitral Valve Stenosis | 1/259 (0.4%) | 0/260 (0%) | ||
| Myocardial Infarction | 1/259 (0.4%) | 6/260 (2.3%) | ||
| Myocardial Ischaemia | 2/259 (0.8%) | 0/260 (0%) | ||
| Nodal Rhythm | 0/259 (0%) | 1/260 (0.4%) | ||
| Pericardial Effusion | 1/259 (0.4%) | 0/260 (0%) | ||
| Silent Myocardial Infarction | 1/259 (0.4%) | 0/260 (0%) | ||
| Sinus Node Dysfunction | 1/259 (0.4%) | 0/260 (0%) | ||
| Supraventricular Tachycardia | 1/259 (0.4%) | 0/260 (0%) | ||
| Ventricular Extrasystoles | 0/259 (0%) | 1/260 (0.4%) | ||
| Congenital, familial and genetic disorders | ||||
| Odontogenic Cyst | 0/259 (0%) | 1/260 (0.4%) | ||
| Endocrine disorders | ||||
| Hyperaldosteronism | 1/259 (0.4%) | 0/260 (0%) | ||
| Eye disorders | ||||
| Cataract | 0/259 (0%) | 1/260 (0.4%) | ||
| Exophthalmos | 0/259 (0%) | 1/260 (0.4%) | ||
| Retinal Detachment | 1/259 (0.4%) | 0/260 (0%) | ||
| Ulcerative Keratitis | 0/259 (0%) | 1/260 (0.4%) | ||
| Gastrointestinal disorders | ||||
| Abdominal Pain | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Abdominal Pain Upper | 3/259 (1.2%) | 0/260 (0%) | ||
| Acute Abdomen | 1/259 (0.4%) | 0/260 (0%) | ||
| Anal Haemorrhage | 2/259 (0.8%) | 0/260 (0%) | ||
| Colitis | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Constipation | 0/259 (0%) | 2/260 (0.8%) | ||
| Dental Caries | 1/259 (0.4%) | 0/260 (0%) | ||
| Diarrhoea | 7/259 (2.7%) | 2/260 (0.8%) | ||
| Gastric Perforation | 1/259 (0.4%) | 0/260 (0%) | ||
| Gastric Ulcer | 1/259 (0.4%) | 0/260 (0%) | ||
| Gastric Ulcer Haemorrhage | 1/259 (0.4%) | 0/260 (0%) | ||
| Gastritis | 3/259 (1.2%) | 0/260 (0%) | ||
| Gastritis Haemorrhagic | 1/259 (0.4%) | 0/260 (0%) | ||
| Haematochezia | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Ileus | 1/259 (0.4%) | 0/260 (0%) | ||
| Inguinal Hernia | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Intestinal Obstruction | 0/259 (0%) | 1/260 (0.4%) | ||
| Intestinal Perforation | 0/259 (0%) | 1/260 (0.4%) | ||
| Mouth Haemorrhage | 1/259 (0.4%) | 0/260 (0%) | ||
| Mouth Ulceration | 1/259 (0.4%) | 0/260 (0%) | ||
| Nausea | 4/259 (1.5%) | 1/260 (0.4%) | ||
| Proctitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Small Intestinal Obstruction | 1/259 (0.4%) | 0/260 (0%) | ||
| Umbilical Hernia | 1/259 (0.4%) | 0/260 (0%) | ||
| Upper Gastrointestinal Haemorrhage | 1/259 (0.4%) | 0/260 (0%) | ||
| Vomiting | 5/259 (1.9%) | 0/260 (0%) | ||
| General disorders | ||||
| Asthenia | 0/259 (0%) | 2/260 (0.8%) | ||
| Chest Discomfort | 0/259 (0%) | 1/260 (0.4%) | ||
| Chest Pain | 2/259 (0.8%) | 2/260 (0.8%) | ||
| Chills | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Death | 3/259 (1.2%) | 0/260 (0%) | ||
| Fatigue | 1/259 (0.4%) | 0/260 (0%) | ||
| General Physical Health Deterioration | 4/259 (1.5%) | 0/260 (0%) | ||
| Localised Oedema | 1/259 (0.4%) | 0/260 (0%) | ||
| Malaise | 3/259 (1.2%) | 0/260 (0%) | ||
| Mucosal Inflammation | 0/259 (0%) | 1/260 (0.4%) | ||
| Multiple Organ Dysfunction Syndrome | 3/259 (1.2%) | 0/260 (0%) | ||
| Non-Cardiac Chest Pain | 1/259 (0.4%) | 0/260 (0%) | ||
| Oedema Peripheral | 2/259 (0.8%) | 0/260 (0%) | ||
| Pyrexia | 19/259 (7.3%) | 14/260 (5.4%) | ||
| Sudden Death | 2/259 (0.8%) | 0/260 (0%) | ||
| Hepatobiliary disorders | ||||
| Cholecystitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Cholecystitis Acute | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Cholelithiasis | 0/259 (0%) | 1/260 (0.4%) | ||
| Hepatic Function Abnormal | 0/259 (0%) | 1/260 (0.4%) | ||
| Immune system disorders | ||||
| Anaphylactic Reaction | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Drug Hypersensitivity | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Hypersensitivity | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Serum Sickness | 1/259 (0.4%) | 0/260 (0%) | ||
| Infections and infestations | ||||
| Abscess Intestinal | 1/259 (0.4%) | 0/260 (0%) | ||
| Abscess Limb | 2/259 (0.8%) | 0/260 (0%) | ||
| Appendicitis | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Arthritis Bacterial | 0/259 (0%) | 1/260 (0.4%) | ||
| Bacterial Sepsis | 0/259 (0%) | 1/260 (0.4%) | ||
| Bronchitis | 6/259 (2.3%) | 4/260 (1.5%) | ||
| Bronchopulmonary Aspergillosis | 4/259 (1.5%) | 0/260 (0%) | ||
| Campylobacter Gastroenteritis | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Campylobacter Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Candida Sepsis | 1/259 (0.4%) | 0/260 (0%) | ||
| Cellulitis | 8/259 (3.1%) | 3/260 (1.2%) | ||
| Clostridium Colitis | 0/259 (0%) | 1/260 (0.4%) | ||
| Clostridium Difficile Colitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Clostridium Difficile Infection | 3/259 (1.2%) | 0/260 (0%) | ||
| Covid-19 | 1/259 (0.4%) | 0/260 (0%) | ||
| Covid-19 Pneumonia | 4/259 (1.5%) | 2/260 (0.8%) | ||
| Cystitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Cytomegalovirus Colitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Cytomegalovirus Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Device Related Infection | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Disseminated Varicella Zoster Virus Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Diverticulitis | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Epididymitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Epiglottitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Erysipelas | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Escherichia Bacteraemia | 2/259 (0.8%) | 0/260 (0%) | ||
| Escherichia Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Fungal Oesophagitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Gastroenteritis | 3/259 (1.2%) | 1/260 (0.4%) | ||
| Gastroenteritis Salmonella | 0/259 (0%) | 1/260 (0.4%) | ||
| Gastroenteritis Viral | 1/259 (0.4%) | 0/260 (0%) | ||
| Hepatitis B | 1/259 (0.4%) | 0/260 (0%) | ||
| Hepatitis B Reactivation | 0/259 (0%) | 1/260 (0.4%) | ||
| Herpes Zoster | 2/259 (0.8%) | 3/260 (1.2%) | ||
| Herpes Zoster Oticus | 0/259 (0%) | 1/260 (0.4%) | ||
| Histoplasmosis Disseminated | 1/259 (0.4%) | 0/260 (0%) | ||
| Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Infective Exacerbation of Chronic Obstructive Airways Disease | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Influenza | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Listeriosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Localised Infection | 2/259 (0.8%) | 0/260 (0%) | ||
| Lower Respiratory Tract Infection | 5/259 (1.9%) | 0/260 (0%) | ||
| Lung Abscess | 1/259 (0.4%) | 0/260 (0%) | ||
| Meningococcal Bacteraemia | 1/259 (0.4%) | 0/260 (0%) | ||
| Moraxella Infection | 0/259 (0%) | 1/260 (0.4%) | ||
| Nosocomial Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Oesophageal Candidiasis | 0/259 (0%) | 1/260 (0.4%) | ||
| Oral Candidiasis | 1/259 (0.4%) | 0/260 (0%) | ||
| Oropharyngeal Candidiasis | 1/259 (0.4%) | 0/260 (0%) | ||
| Osteomyelitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Osteomyelitis Chronic | 0/259 (0%) | 1/260 (0.4%) | ||
| Otitis Media | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Parasitic Gastroenteritis | 1/259 (0.4%) | 0/260 (0%) | ||
| Paronychia | 1/259 (0.4%) | 0/260 (0%) | ||
| Periorbital Cellulitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Pharyngitis | 0/259 (0%) | 1/260 (0.4%) | ||
| Pneumococcal Bacteraemia | 0/259 (0%) | 1/260 (0.4%) | ||
| Pneumocystis Jirovecii Pneumonia | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Pneumonia | 55/259 (21.2%) | 34/260 (13.1%) | ||
| Pneumonia Bacterial | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Pneumonia Cytomegaloviral | 0/259 (0%) | 1/260 (0.4%) | ||
| Pneumonia Fungal | 2/259 (0.8%) | 0/260 (0%) | ||
| Pneumonia Pneumococcal | 0/259 (0%) | 1/260 (0.4%) | ||
| Pneumonia Pseudomonal | 0/259 (0%) | 2/260 (0.8%) | ||
| Pneumonia Viral | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Postoperative Wound Infection | 0/259 (0%) | 1/260 (0.4%) | ||
| Progressive Multifocal Leukoencephalopathy | 0/259 (0%) | 1/260 (0.4%) | ||
| Pseudomembranous Colitis | 0/259 (0%) | 2/260 (0.8%) | ||
| Pseudomonas Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Pulmonary Sepsis | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Pulmonary Tuberculosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Pyelonephritis | 1/259 (0.4%) | 0/260 (0%) | ||
| Pyelonephritis Chronic | 1/259 (0.4%) | 0/260 (0%) | ||
| Respiratory Syncytial Virus Infection | 0/259 (0%) | 1/260 (0.4%) | ||
| Respiratory Tract Infection | 5/259 (1.9%) | 2/260 (0.8%) | ||
| Sepsis | 9/259 (3.5%) | 6/260 (2.3%) | ||
| Septic Shock | 3/259 (1.2%) | 2/260 (0.8%) | ||
| Sialoadenitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Sinusitis | 4/259 (1.5%) | 2/260 (0.8%) | ||
| Sinusitis Bacterial | 1/259 (0.4%) | 0/260 (0%) | ||
| Sinusitis Fungal | 1/259 (0.4%) | 0/260 (0%) | ||
| Skin Infection | 2/259 (0.8%) | 0/260 (0%) | ||
| Soft Tissue Infection | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Staphylococcal Bacteraemia | 2/259 (0.8%) | 0/260 (0%) | ||
| Staphylococcal Infection | 1/259 (0.4%) | 0/260 (0%) | ||
| Staphylococcal Sepsis | 1/259 (0.4%) | 0/260 (0%) | ||
| Streptococcal Bacteraemia | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Suspected Covid-19 | 1/259 (0.4%) | 0/260 (0%) | ||
| Toxoplasmosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Upper Respiratory Tract Infection | 4/259 (1.5%) | 3/260 (1.2%) | ||
| Urinary Tract Infection | 7/259 (2.7%) | 2/260 (0.8%) | ||
| Urosepsis | 1/259 (0.4%) | 3/260 (1.2%) | ||
| Vascular Device Infection | 0/259 (0%) | 1/260 (0.4%) | ||
| Injury, poisoning and procedural complications | ||||
| Facial Bones Fracture | 0/259 (0%) | 1/260 (0.4%) | ||
| Fall | 0/259 (0%) | 1/260 (0.4%) | ||
| Femur Fracture | 2/259 (0.8%) | 0/260 (0%) | ||
| Head Injury | 0/259 (0%) | 1/260 (0.4%) | ||
| Hip Fracture | 1/259 (0.4%) | 0/260 (0%) | ||
| Humerus Fracture | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Infusion Related Reaction | 2/259 (0.8%) | 4/260 (1.5%) | ||
| Joint Dislocation | 1/259 (0.4%) | 0/260 (0%) | ||
| Limb Injury | 1/259 (0.4%) | 0/260 (0%) | ||
| Pelvic Fracture | 1/259 (0.4%) | 0/260 (0%) | ||
| Skin Laceration | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Spinal Fracture | 0/259 (0%) | 1/260 (0.4%) | ||
| Stoma Complication | 0/259 (0%) | 1/260 (0.4%) | ||
| Subdural Haematoma | 4/259 (1.5%) | 4/260 (1.5%) | ||
| Toxicity to Various Agents | 1/259 (0.4%) | 0/260 (0%) | ||
| Traumatic Intracranial Haemorrhage | 1/259 (0.4%) | 0/260 (0%) | ||
| Wound | 1/259 (0.4%) | 0/260 (0%) | ||
| Investigations | ||||
| Alanine Aminotransferase Increased | 2/259 (0.8%) | 0/260 (0%) | ||
| Aspartate Aminotransferase Increased | 2/259 (0.8%) | 0/260 (0%) | ||
| Blood Creatinine Increased | 0/259 (0%) | 2/260 (0.8%) | ||
| Bronchoscopy | 1/259 (0.4%) | 0/260 (0%) | ||
| Cytomegalovirus Test Positive | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Gastrointestinal Stoma Output Increased | 1/259 (0.4%) | 0/260 (0%) | ||
| Neutrophil Count Decreased | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Platelet Count Decreased | 1/259 (0.4%) | 3/260 (1.2%) | ||
| Scan Abnormal | 1/259 (0.4%) | 0/260 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased Appetite | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Dehydration | 4/259 (1.5%) | 5/260 (1.9%) | ||
| Diabetes Mellitus | 0/259 (0%) | 1/260 (0.4%) | ||
| Gout | 1/259 (0.4%) | 0/260 (0%) | ||
| Hyperglycaemia | 0/259 (0%) | 2/260 (0.8%) | ||
| Hyperkalaemia | 0/259 (0%) | 1/260 (0.4%) | ||
| Hypoglycaemia | 0/259 (0%) | 1/260 (0.4%) | ||
| Hypokalaemia | 0/259 (0%) | 1/260 (0.4%) | ||
| Hyponatraemia | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Metabolic Acidosis | 1/259 (0.4%) | 0/260 (0%) | ||
| Tumour Lysis Syndrome | 3/259 (1.2%) | 3/260 (1.2%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 1/259 (0.4%) | 0/260 (0%) | ||
| Arthritis | 1/259 (0.4%) | 0/260 (0%) | ||
| Back Pain | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Finger Deformity | 0/259 (0%) | 1/260 (0.4%) | ||
| Flank Pain | 0/259 (0%) | 2/260 (0.8%) | ||
| Jaw Cyst | 1/259 (0.4%) | 0/260 (0%) | ||
| Muscular Weakness | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Musculoskeletal Chest Pain | 1/259 (0.4%) | 0/260 (0%) | ||
| Myalgia | 0/259 (0%) | 1/260 (0.4%) | ||
| Osteoarthritis | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Osteoporosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Osteoporotic Fracture | 1/259 (0.4%) | 0/260 (0%) | ||
| Pain in Extremity | 0/259 (0%) | 1/260 (0.4%) | ||
| Rhabdomyolysis | 1/259 (0.4%) | 0/260 (0%) | ||
| Spinal Disorder | 0/259 (0%) | 1/260 (0.4%) | ||
| Spinal Osteoarthritis | 1/259 (0.4%) | 0/260 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Acute Myeloid Leukaemia | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Adenocarcinoma Gastric | 0/259 (0%) | 1/260 (0.4%) | ||
| Adenocarcinoma of Colon | 2/259 (0.8%) | 2/260 (0.8%) | ||
| Appendix Cancer | 0/259 (0%) | 1/260 (0.4%) | ||
| Basal Cell Carcinoma | 2/259 (0.8%) | 4/260 (1.5%) | ||
| Benign Anorectal Neoplasm | 0/259 (0%) | 1/260 (0.4%) | ||
| Bladder Transitional Cell Carcinoma | 2/259 (0.8%) | 0/260 (0%) | ||
| Bowen's Disease | 0/259 (0%) | 1/260 (0.4%) | ||
| Brain Neoplasm Malignant | 1/259 (0.4%) | 0/260 (0%) | ||
| Cholesteatoma | 0/259 (0%) | 1/260 (0.4%) | ||
| Chronic Myelomonocytic Leukaemia | 0/259 (0%) | 1/260 (0.4%) | ||
| Gastric Cancer | 1/259 (0.4%) | 0/260 (0%) | ||
| Intestinal Adenocarcinoma | 1/259 (0.4%) | 0/260 (0%) | ||
| Invasive Ductal Breast Carcinoma | 1/259 (0.4%) | 0/260 (0%) | ||
| Langerhans' Cell Histiocytosis | 1/259 (0.4%) | 0/260 (0%) | ||
| Laryngeal Squamous Cell Carcinoma | 0/259 (0%) | 1/260 (0.4%) | ||
| Lung Adenocarcinoma | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Malignant Melanoma | 0/259 (0%) | 2/260 (0.8%) | ||
| Metastatic Malignant Melanoma | 1/259 (0.4%) | 0/260 (0%) | ||
| Myelodysplastic Syndrome | 0/259 (0%) | 1/260 (0.4%) | ||
| Non-Small Cell Lung Cancer | 0/259 (0%) | 1/260 (0.4%) | ||
| Ocular Neoplasm | 0/259 (0%) | 1/260 (0.4%) | ||
| Prostate Cancer | 2/259 (0.8%) | 2/260 (0.8%) | ||
| Renal Cell Carcinoma | 1/259 (0.4%) | 0/260 (0%) | ||
| Skin Squamous Cell Carcinoma Metastatic | 1/259 (0.4%) | 0/260 (0%) | ||
| Small Cell Lung Cancer Metastatic | 0/259 (0%) | 1/260 (0.4%) | ||
| Squamous Cell Carcinoma of Lung | 2/259 (0.8%) | 2/260 (0.8%) | ||
| Squamous Cell Carcinoma of Skin | 2/259 (0.8%) | 4/260 (1.5%) | ||
| Thyroid Cancer | 1/259 (0.4%) | 0/260 (0%) | ||
| Transitional Cell Carcinoma | 0/259 (0%) | 1/260 (0.4%) | ||
| Nervous system disorders | ||||
| Amnesia | 1/259 (0.4%) | 0/260 (0%) | ||
| Amyotrophic Lateral Sclerosis | 1/259 (0.4%) | 0/260 (0%) | ||
| Brain Oedema | 0/259 (0%) | 1/260 (0.4%) | ||
| Carotid Artery Stenosis | 1/259 (0.4%) | 0/260 (0%) | ||
| Central Nervous System Lesion | 0/259 (0%) | 1/260 (0.4%) | ||
| Cerebral Ischaemia | 0/259 (0%) | 1/260 (0.4%) | ||
| Cerebrovascular Accident | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Dizziness | 0/259 (0%) | 1/260 (0.4%) | ||
| Facial Paralysis | 0/259 (0%) | 1/260 (0.4%) | ||
| Haemorrhagic Stroke | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Headache | 0/259 (0%) | 1/260 (0.4%) | ||
| Ischaemic Stroke | 3/259 (1.2%) | 0/260 (0%) | ||
| Lacunar Stroke | 1/259 (0.4%) | 0/260 (0%) | ||
| Loss of Consciousness | 1/259 (0.4%) | 0/260 (0%) | ||
| Peripheral Motor Neuropathy | 0/259 (0%) | 1/260 (0.4%) | ||
| Post Herpetic Neuralgia | 0/259 (0%) | 1/260 (0.4%) | ||
| Presyncope | 0/259 (0%) | 1/260 (0.4%) | ||
| Quadriplegia | 1/259 (0.4%) | 0/260 (0%) | ||
| Seizure | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Spinal Cord Compression | 1/259 (0.4%) | 0/260 (0%) | ||
| Subarachnoid Haemorrhage | 0/259 (0%) | 1/260 (0.4%) | ||
| Syncope | 5/259 (1.9%) | 5/260 (1.9%) | ||
| Thalamic Infarction | 0/259 (0%) | 1/260 (0.4%) | ||
| Transient Global Amnesia | 0/259 (0%) | 1/260 (0.4%) | ||
| Transient Ischaemic Attack | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Vascular Encephalopathy | 1/259 (0.4%) | 0/260 (0%) | ||
| Product Issues | ||||
| Device End of Service | 1/259 (0.4%) | 0/260 (0%) | ||
| Psychiatric disorders | ||||
| Anxiety | 1/259 (0.4%) | 0/260 (0%) | ||
| Confusional State | 0/259 (0%) | 1/260 (0.4%) | ||
| Delirium | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Depression | 1/259 (0.4%) | 0/260 (0%) | ||
| Renal and urinary disorders | ||||
| Acute Kidney Injury | 7/259 (2.7%) | 2/260 (0.8%) | ||
| Calculus Urinary | 0/259 (0%) | 1/260 (0.4%) | ||
| Haematuria | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Renal Colic | 0/259 (0%) | 1/260 (0.4%) | ||
| Renal Cyst Haemorrhage | 1/259 (0.4%) | 0/260 (0%) | ||
| Renal Impairment | 3/259 (1.2%) | 0/260 (0%) | ||
| Urinary Retention | 0/259 (0%) | 1/260 (0.4%) | ||
| Urinary Tract Obstruction | 2/259 (0.8%) | 0/260 (0%) | ||
| Reproductive system and breast disorders | ||||
| Balanoposthitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Benign Prostatic Hyperplasia | 2/259 (0.8%) | 1/260 (0.4%) | ||
| Prostatitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute Pulmonary Oedema | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Acute Respiratory Distress Syndrome | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Acute Respiratory Failure | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Asthma | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Atelectasis | 0/259 (0%) | 1/260 (0.4%) | ||
| Bronchiectasis | 2/259 (0.8%) | 0/260 (0%) | ||
| Bronchopneumopathy | 0/259 (0%) | 1/260 (0.4%) | ||
| Bronchospasm | 1/259 (0.4%) | 0/260 (0%) | ||
| Chronic Obstructive Pulmonary Disease | 1/259 (0.4%) | 5/260 (1.9%) | ||
| Cough | 1/259 (0.4%) | 0/260 (0%) | ||
| Dyspnoea | 0/259 (0%) | 1/260 (0.4%) | ||
| Haemoptysis | 0/259 (0%) | 2/260 (0.8%) | ||
| Haemothorax | 1/259 (0.4%) | 0/260 (0%) | ||
| Hydrothorax | 1/259 (0.4%) | 0/260 (0%) | ||
| Hypersensitivity Pneumonitis | 1/259 (0.4%) | 0/260 (0%) | ||
| Hypoxia | 0/259 (0%) | 2/260 (0.8%) | ||
| Interstitial Lung Disease | 1/259 (0.4%) | 1/260 (0.4%) | ||
| Lung Infiltration | 0/259 (0%) | 1/260 (0.4%) | ||
| Organising Pneumonia | 1/259 (0.4%) | 0/260 (0%) | ||
| Pleural Effusion | 7/259 (2.7%) | 2/260 (0.8%) | ||
| Pleurisy | 1/259 (0.4%) | 0/260 (0%) | ||
| Pneumonia Aspiration | 1/259 (0.4%) | 0/260 (0%) | ||
| Pneumonitis | 2/259 (0.8%) | 2/260 (0.8%) | ||
| Pneumothorax | 0/259 (0%) | 1/260 (0.4%) | ||
| Productive Cough | 1/259 (0.4%) | 0/260 (0%) | ||
| Pulmonary Embolism | 1/259 (0.4%) | 2/260 (0.8%) | ||
| Pulmonary Haemorrhage | 0/259 (0%) | 1/260 (0.4%) | ||
| Respiratory Distress | 1/259 (0.4%) | 0/260 (0%) | ||
| Respiratory Failure | 5/259 (1.9%) | 1/260 (0.4%) | ||
| Tonsillar Disorder | 0/259 (0%) | 1/260 (0.4%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Actinic Keratosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Dermatitis Allergic | 1/259 (0.4%) | 0/260 (0%) | ||
| Dermatitis Bullous | 1/259 (0.4%) | 0/260 (0%) | ||
| Diabetic Foot | 1/259 (0.4%) | 0/260 (0%) | ||
| Drug Eruption | 1/259 (0.4%) | 0/260 (0%) | ||
| Drug Reaction with Eosinophilia and Systemic Symptoms | 1/259 (0.4%) | 0/260 (0%) | ||
| Rash | 5/259 (1.9%) | 1/260 (0.4%) | ||
| Rash Maculo-Papular | 5/259 (1.9%) | 0/260 (0%) | ||
| Urticaria | 0/259 (0%) | 1/260 (0.4%) | ||
| Surgical and medical procedures | ||||
| Coronary Artery Bypass | 0/259 (0%) | 1/260 (0.4%) | ||
| Tracheostomy Closure | 0/259 (0%) | 1/260 (0.4%) | ||
| Vascular disorders | ||||
| Aortic Stenosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Arterial Thrombosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Deep Vein Thrombosis | 0/259 (0%) | 1/260 (0.4%) | ||
| Embolism | 1/259 (0.4%) | 0/260 (0%) | ||
| Giant Cell Arteritis | 1/259 (0.4%) | 0/260 (0%) | ||
| Haematoma | 0/259 (0%) | 1/260 (0.4%) | ||
| Hypertension | 1/259 (0.4%) | 0/260 (0%) | ||
| Hypertensive Crisis | 1/259 (0.4%) | 0/260 (0%) | ||
| Hypertensive Urgency | 1/259 (0.4%) | 0/260 (0%) | ||
| Hypotension | 2/259 (0.8%) | 2/260 (0.8%) | ||
| Peripheral Artery Aneurysm | 1/259 (0.4%) | 0/260 (0%) | ||
| Raynaud's Phenomenon | 1/259 (0.4%) | 0/260 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Ibrutinib + BR (Treatment B) | Placebo + BR (Treatment A) | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 256/259 (98.8%) | 255/260 (98.1%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 83/259 (32%) | 60/260 (23.1%) | ||
| Leukopenia | 26/259 (10%) | 14/260 (5.4%) | ||
| Lymphopenia | 18/259 (6.9%) | 14/260 (5.4%) | ||
| Neutropenia | 109/259 (42.1%) | 104/260 (40%) | ||
| Thrombocytopenia | 61/259 (23.6%) | 43/260 (16.5%) | ||
| Cardiac disorders | ||||
| Atrial Fibrillation | 30/259 (11.6%) | 14/260 (5.4%) | ||
| Palpitations | 9/259 (3.5%) | 13/260 (5%) | ||
| Ear and labyrinth disorders | ||||
| Vertigo | 11/259 (4.2%) | 13/260 (5%) | ||
| Eye disorders | ||||
| Cataract | 21/259 (8.1%) | 16/260 (6.2%) | ||
| Dry Eye | 16/259 (6.2%) | 5/260 (1.9%) | ||
| Vision Blurred | 14/259 (5.4%) | 10/260 (3.8%) | ||
| Gastrointestinal disorders | ||||
| Abdominal Pain | 25/259 (9.7%) | 29/260 (11.2%) | ||
| Abdominal Pain Upper | 19/259 (7.3%) | 10/260 (3.8%) | ||
| Constipation | 51/259 (19.7%) | 66/260 (25.4%) | ||
| Diarrhoea | 117/259 (45.2%) | 96/260 (36.9%) | ||
| Dry Mouth | 18/259 (6.9%) | 6/260 (2.3%) | ||
| Dyspepsia | 21/259 (8.1%) | 21/260 (8.1%) | ||
| Gastrooesophageal Reflux Disease | 18/259 (6.9%) | 16/260 (6.2%) | ||
| Nausea | 107/259 (41.3%) | 107/260 (41.2%) | ||
| Stomatitis | 21/259 (8.1%) | 6/260 (2.3%) | ||
| Vomiting | 56/259 (21.6%) | 48/260 (18.5%) | ||
| General disorders | ||||
| Asthenia | 30/259 (11.6%) | 25/260 (9.6%) | ||
| Chest Pain | 14/259 (5.4%) | 12/260 (4.6%) | ||
| Chills | 17/259 (6.6%) | 39/260 (15%) | ||
| Fatigue | 78/259 (30.1%) | 77/260 (29.6%) | ||
| Influenza Like Illness | 14/259 (5.4%) | 13/260 (5%) | ||
| Malaise | 12/259 (4.6%) | 14/260 (5.4%) | ||
| Mucosal Inflammation | 14/259 (5.4%) | 15/260 (5.8%) | ||
| Oedema Peripheral | 50/259 (19.3%) | 42/260 (16.2%) | ||
| Pyrexia | 86/259 (33.2%) | 76/260 (29.2%) | ||
| Immune system disorders | ||||
| Hypogammaglobulinaemia | 8/259 (3.1%) | 14/260 (5.4%) | ||
| Infections and infestations | ||||
| Bronchitis | 33/259 (12.7%) | 36/260 (13.8%) | ||
| Cellulitis | 15/259 (5.8%) | 4/260 (1.5%) | ||
| Conjunctivitis | 26/259 (10%) | 6/260 (2.3%) | ||
| Herpes Zoster | 13/259 (5%) | 27/260 (10.4%) | ||
| Influenza | 9/259 (3.5%) | 16/260 (6.2%) | ||
| Lower Respiratory Tract Infection | 13/259 (5%) | 9/260 (3.5%) | ||
| Nasopharyngitis | 24/259 (9.3%) | 28/260 (10.8%) | ||
| Oral Candidiasis | 18/259 (6.9%) | 7/260 (2.7%) | ||
| Pneumonia | 53/259 (20.5%) | 38/260 (14.6%) | ||
| Rhinitis | 10/259 (3.9%) | 13/260 (5%) | ||
| Sinusitis | 25/259 (9.7%) | 34/260 (13.1%) | ||
| Skin Infection | 18/259 (6.9%) | 5/260 (1.9%) | ||
| Upper Respiratory Tract Infection | 69/259 (26.6%) | 68/260 (26.2%) | ||
| Urinary Tract Infection | 35/259 (13.5%) | 32/260 (12.3%) | ||
| Injury, poisoning and procedural complications | ||||
| Contusion | 22/259 (8.5%) | 12/260 (4.6%) | ||
| Fall | 15/259 (5.8%) | 13/260 (5%) | ||
| Infusion Related Reaction | 19/259 (7.3%) | 26/260 (10%) | ||
| Investigations | ||||
| Alanine Aminotransferase Increased | 23/259 (8.9%) | 12/260 (4.6%) | ||
| Aspartate Aminotransferase Increased | 24/259 (9.3%) | 14/260 (5.4%) | ||
| Blood Creatinine Increased | 23/259 (8.9%) | 22/260 (8.5%) | ||
| Lymphocyte Count Decreased | 32/259 (12.4%) | 26/260 (10%) | ||
| Neutrophil Count Decreased | 38/259 (14.7%) | 43/260 (16.5%) | ||
| Platelet Count Decreased | 41/259 (15.8%) | 28/260 (10.8%) | ||
| Weight Decreased | 26/259 (10%) | 20/260 (7.7%) | ||
| White Blood Cell Count Decreased | 30/259 (11.6%) | 34/260 (13.1%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased Appetite | 54/259 (20.8%) | 36/260 (13.8%) | ||
| Hyperglycaemia | 15/259 (5.8%) | 10/260 (3.8%) | ||
| Hyperuricaemia | 22/259 (8.5%) | 20/260 (7.7%) | ||
| Hypocalcaemia | 17/259 (6.6%) | 7/260 (2.7%) | ||
| Hypokalaemia | 39/259 (15.1%) | 30/260 (11.5%) | ||
| Hypomagnesaemia | 24/259 (9.3%) | 18/260 (6.9%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 45/259 (17.4%) | 44/260 (16.9%) | ||
| Back Pain | 35/259 (13.5%) | 37/260 (14.2%) | ||
| Muscle Spasms | 21/259 (8.1%) | 13/260 (5%) | ||
| Muscular Weakness | 15/259 (5.8%) | 5/260 (1.9%) | ||
| Myalgia | 31/259 (12%) | 30/260 (11.5%) | ||
| Pain in Extremity | 18/259 (6.9%) | 24/260 (9.2%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Squamous Cell Carcinoma of Skin | 12/259 (4.6%) | 13/260 (5%) | ||
| Nervous system disorders | ||||
| Dizziness | 22/259 (8.5%) | 19/260 (7.3%) | ||
| Headache | 33/259 (12.7%) | 40/260 (15.4%) | ||
| Paraesthesia | 13/259 (5%) | 13/260 (5%) | ||
| Psychiatric disorders | ||||
| Anxiety | 14/259 (5.4%) | 17/260 (6.5%) | ||
| Depression | 16/259 (6.2%) | 12/260 (4.6%) | ||
| Insomnia | 29/259 (11.2%) | 28/260 (10.8%) | ||
| Renal and urinary disorders | ||||
| Haematuria | 15/259 (5.8%) | 7/260 (2.7%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 77/259 (29.7%) | 85/260 (32.7%) | ||
| Dyspnoea | 26/259 (10%) | 45/260 (17.3%) | ||
| Epistaxis | 31/259 (12%) | 12/260 (4.6%) | ||
| Nasal Congestion | 7/259 (2.7%) | 14/260 (5.4%) | ||
| Oropharyngeal Pain | 22/259 (8.5%) | 23/260 (8.8%) | ||
| Productive Cough | 15/259 (5.8%) | 18/260 (6.9%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Dry Skin | 21/259 (8.1%) | 10/260 (3.8%) | ||
| Erythema | 13/259 (5%) | 12/260 (4.6%) | ||
| Pruritus | 46/259 (17.8%) | 56/260 (21.5%) | ||
| Rash | 95/259 (36.7%) | 57/260 (21.9%) | ||
| Rash Maculo-Papular | 22/259 (8.5%) | 10/260 (3.8%) | ||
| Skin Lesion | 16/259 (6.2%) | 10/260 (3.8%) | ||
| Urticaria | 16/259 (6.2%) | 7/260 (2.7%) | ||
| Vascular disorders | ||||
| Haematoma | 20/259 (7.7%) | 3/260 (1.2%) | ||
| Hypertension | 35/259 (13.5%) | 29/260 (11.2%) | ||
| Hypotension | 21/259 (8.1%) | 16/260 (6.2%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.
Results Point of Contact
| Name/Title | EXECUTIVE MEDICAL DIRECTOR |
|---|---|
| Organization | Janssen Research & Development, LLC |
| Phone | 844-434-4210 |
| ClinicalTrialDisclosure@its.jnj.com |
Responsible Party:
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01776840
Other Study ID Numbers:
- CR100967
- PCI-32765MCL3002
- U1111-1137-0389
- 2012-004056-11
First Posted:
Jan 28, 2013
Last Update Posted:
Aug 15, 2022
Last Verified:
Aug 1, 2022