Phase III Trial BI 695502 Plus Chemotherapy vs. Avastin® Plus Chemotherapy in Patients With Lung Cancer
Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT02272413
Collaborator
(none)
671
189
2
40.3
3.6
0.1
Study Details
Study Description
Brief Summary
The objective of this phase III trial is to establish statistical equivalence in terms of efficacy (best overall response rate [ORR], proportion of patients with complete response [CR] plus partial response [PR]) until 18 weeks of first-line treatment with BI 695502 plus chemotherapy versus Avastin® plus chemotherapy followed by maintenance monotherapy with either BI 695502 or Avastin®.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
671 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double-blind Phase III Trial to Evaluate Efficacy and Safety of BI 695502 Plus Chemotherapy Versus Avastin® Plus Chemotherapy in Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer
Actual Study Start Date
:
Jul 8, 2015
Actual Primary Completion Date
:
Jun 30, 2017
Actual Study Completion Date
:
Nov 16, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: BI 695502
|
Drug: BI 695502
|
| Active Comparator: Avastin
|
Drug: Avastin
|
Outcome Measures
Primary Outcome Measures
- Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment [Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier.]
ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks.
Secondary Outcome Measures
- Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® [From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days.]
The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®: Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), Thromboembolic events (arterial or venous), Febrile neutropenia, Gastrointestinal perforations, Hypertension, Proteinuria, Pulmonary hemorrhage, Other hemorrhages (not including pulmonary hemorrhages), Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs.
- Progression-Free Survival (PFS) Time as Determined by Investigator Assessment [Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks).]
PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique.
- Overall Survival (OS) Time [From baseline until death due to any cause, ie., up to 35 cycles (105 weeks).]
OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique.
- Duration of Response (DOR) as Determined by Investigator Assessment [Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks).]
DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
Adult patients aged >=18 years with histologically or cytologically confirmed advanced nonsquamous non-small cell lung cancer (nsNSCLC). Mixed tumors should be categorized according to the predominant histology.
Note: NSCLC should be predominantly nonsquamous. Recurrent or metastatic disease (Stage IV) with an indication for therapy with paclitaxel + carboplatin + Avastin®.
Patients harboring tumors with unknown or without activating epidermal growth factor receptor (EGFR) / anaplastic lymphoma receptor tyrosine kinase (ALK) mutation maybe included provided chemotherapy is standard of care. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on independent central review.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
Adequate hepatic, renal, and bone marrow function:
Life expectancy > 6 months based on clinical judgment. Further inclusion criteria apply.
Exclusion criteria:
Prior therapy with monoclonal antibodies or small molecule inhibitors against Vascular Endothelial Growth Factor (VEGF) or VEGF receptors, including Avastin®.
Prior systemic therapy for metastatic disease. Prior systemic anticancer therapy or radiotherapy for locally advanced nsNSCLC if completed <12 months prior to Screening.
Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer of the skin or pre-invasive cancer of the cervix.
Symptomatic brain metastasis. Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung, NSCLC not specified (NS) or NSCLC not otherwise specified(NOS).
Any unresolved toxicity > Common Toxicity Criteria Grade 1 (except alopecia) from previous anticancer therapy (including radiotherapy).
History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding. Thrombotic or hemorrhagic event =< 6 months prior to Screening. Further exclusion criteria apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Pacific Cancer Medical Center, Inc. | Anaheim | California | United States | 92801 |
| 2 | Comprehensive Blood and Cancer Center | Bakersfield | California | United States | 93309 |
| 3 | Lalita Pandit, M.D., Inc. | Fountain Valley | California | United States | 92708 |
| 4 | Southern California Oncology Research Alliance | Los Angeles | California | United States | 90057 |
| 5 | Innovative Clinical Research, Inc. | Whittier | California | United States | 90603 |
| 6 | Ashland Bellefonte Cancer Center | Ashland | Kentucky | United States | 41101 |
| 7 | Reliant Medical Group | Worcester | Massachusetts | United States | 01608 |
| 8 | Detroit Clinical Research Center | Owosso | Michigan | United States | 48867 |
| 9 | Carolinas Cancer Care | Charlotte | North Carolina | United States | 28204-2839 |
| 10 | CENIT - Centro de Neurociencias, Investigacion y Tratamiento | Ciudad Autonoma Buenos Aires | Argentina | C1125ABD | |
| 11 | Sanatorio Delta | Rosario | Argentina | S2000BIF | |
| 12 | Sanatorio Parque | Rosario | Argentina | S2000DSV | |
| 13 | Centro Oncológico de Rosario | Rosario | Argentina | S2000KZE | |
| 14 | CPCO - Centro de Pesquisa Clinica em Oncologia | Cachoeiro de Itapemirim | Brazil | 29308-014 | |
| 15 | Hospital do Cancer do Ceara | Fortaleza | Brazil | 60430-230 | |
| 16 | Pronutrir | Fortaleza | Brazil | 60810-180 | |
| 17 | Hospital de Carida de de Ijui - CACON | Ijuí | Brazil | 98700-000 | |
| 18 | Hospital Bruno Born | Lajeado | Brazil | 95900-000 | |
| 19 | Hospital da Cidade de Passo Fundo | Passo Fundo | Brazil | 99010-260 | |
| 20 | Universidade de Caxias do Sul - IPCEM - Inst. de Pesq.clilni | Petrópolis | Brazil | 95070-560 | |
| 21 | Irmandade da Santa Casa de Misericórdia de Porto Alegre | Porto Alegre | Brazil | 90035-074 | |
| 22 | Hospital de Clínicas de Porto Alegre | Porto Alegre | Brazil | 90035-903 | |
| 23 | CEPHO - Centro de Estudos e Pesquisas em Hematologia e Oncologia | Santo André | Brazil | 09060-650 | |
| 24 | Clinica de Oncologia de Sorocaba | Sorocaba | Brazil | 18030-075 | |
| 25 | ICAVC - Instituto do Cancer Arnaldo Vieira de Carvalho | São Paulo | Brazil | 01209-000 | |
| 26 | ICESP - Instituto do Cancer do Estado de Sao Paulo | São Paulo | Brazil | 01246-000 | |
| 27 | MHAT - Dobrich, AD | Dobrich | Bulgaria | 9300 | |
| 28 | UMHAT Georgi Stranski, Clinic of Paediatrics, Pleven | Pleven | Bulgaria | 5800 | |
| 29 | Complex Oncological Center - Plovdiv, EOOD | Plovdiv | Bulgaria | 4004 | |
| 30 | DCC 1 - Ruse, EOOD | Ruse | Bulgaria | 7002 | |
| 31 | MHAT Serdika, EOOD, Sofia | Sofia | Bulgaria | 1303 | |
| 32 | MHAT 'Tokuda Hospital Sofia', EAD | Sofia | Bulgaria | 1407 | |
| 33 | SHATOD 'Dr. Marko Antonov Markov'-Varna, EOOD | Varna | Bulgaria | 9010 | |
| 34 | Clínica Santa María | Santiago | Chile | 7520349 | |
| 35 | Hospital Clínico San Borja Arriarán | Santiago | Chile | 8360160 | |
| 36 | Centro Internacional de Estudios Clinicos - CIEC | Santiago | Chile | 8420383 | |
| 37 | Instituto Clínico Oncológico del Sur - ICOS | Temuco | Chile | 4810469 | |
| 38 | Hospital Clinico Viña del Mar | Viña del Mar | Chile | 1741 | |
| 39 | General Hospital Pula | Pula | Croatia | 52100 | |
| 40 | Clinical Hospital Centar Sestre Milosrdnice | Zagreb | Croatia | 10000 | |
| 41 | University Clinic for Pulmonary Diseases | Zagreb | Croatia | 10000 | |
| 42 | Alexandria University Hospital | Alexandria | Egypt | 21131 | |
| 43 | Ain Shams University Hospital | Cairo | Egypt | 11566 | |
| 44 | National Cancer Institute, Cairo University | Cairo | Egypt | 11796 | |
| 45 | Nasser Institute | Cairo | Egypt | 12655 | |
| 46 | Oncology Centre- Mansoura University | Mansoura | Egypt | 1234 | |
| 47 | Menofiya University Hospital | Monofia | Egypt | 31111 | |
| 48 | Gesundheitszentrum Wetterau gGmbH | Bad Nauheim | Germany | 61231 | |
| 49 | Athens Hospital of Chest Diseases "Sotiria" | Athens | Greece | 11527 | |
| 50 | University General Hospital of Heraklion | Crete | Greece | 71201 | |
| 51 | University of Patras Medical School | Patras | Greece | 26504 | |
| 52 | Euromedica Kyanous Stavros General Hospital | Thessaloniki | Greece | 54645 | |
| 53 | Health Center of Thermi, Thessaloniki | Thessaloniki | Greece | 57001 | |
| 54 | Interbalkan Medical Center of Thessaloniki | Thessaloniki | Greece | 57001 | |
| 55 | National Koranyi TBC and Pulm. Internal Med. Clinic | Budapest | Hungary | 1121 | |
| 56 | Semmelweis University | Budapest | Hungary | 1125 | |
| 57 | Pulmonology Institute of Veszprem County, Farkasgyepu | Farkasgyepu | Hungary | 8582 | |
| 58 | Jasz-Nagykun-Szolnok Megyei Hetenyi G. Korhaz-Rendelointezet | Szolnok | Hungary | 5000 | |
| 59 | Markusovszky University Teaching Hospital | Szombathely | Hungary | 9700 | |
| 60 | Tudogyogyintezet Torokbalint | Torokbalint | Hungary | 2045 | |
| 61 | ASST di Cremona | Cremona | Italy | 26100 | |
| 62 | Osp. Umberto I | Lugo (RA) | Italy | 48022 | |
| 63 | Istituto Scientifico Romagnolo | Meldola (FC) | Italy | 47014 | |
| 64 | Azienda Ospedaliera Universitaria Pisana | Pisa | Italy | 56124 | |
| 65 | Aichi Medical University Hospital | Aichi, Nagakute | Japan | 480-1195 | |
| 66 | Aichi Cancer Center Aichi Hospital | Aichi, Okazaki | Japan | 444-0011 | |
| 67 | Tosei General Hospital | Aichi, Seto | Japan | 489-8642 | |
| 68 | Fujita Health University Hospital | Aichi, Toyoake | Japan | 470-1192 | |
| 69 | Aso Co.,Ltd Iizuka Hospital | Fukuoka, Iizuka | Japan | 820-8505 | |
| 70 | Gunma Prefectural Cancer Center | Gunma, Ota | Japan | 373-8550 | |
| 71 | Hyogo Prefectural Amagasaki General Medical Center | Hyogo, Amagasaki | Japan | 660-8550 | |
| 72 | Itami City Hospital | Hyogo, Itami | Japan | 664-8540 | |
| 73 | Kobe City Medical Center General Hospital | Hyogo, Kobe | Japan | 650-0047 | |
| 74 | Ibaraki Prefectural Central Hospital | Ibaraki, Kasama | Japan | 309-1793 | |
| 75 | Kagawa Rosai Hospital | Kagawa, Marugame | Japan | 763-8502 | |
| 76 | Kitasato University Hospital | Kanagawa, Sagamihara | Japan | 252-0375 | |
| 77 | Yokohama City University Hospital | Kanagawa, Yokohama | Japan | 236-0004 | |
| 78 | Uji-Tokushukai Medical Center | Kyoto, Uji | Japan | 611-0041 | |
| 79 | Matsusaka City Hospital | Mie, Matsusaka | Japan | 515-8544 | |
| 80 | Miyazaki Prefectural Miyazaki Hospital | Miyazaki, Miyazaki | Japan | 880-8510 | |
| 81 | Nara Hospital Kinki University Faculty of Medicine | Nara, Ikoma | Japan | 630-0293 | |
| 82 | Niigata Cancer Center Hospital | Niigata, Niigata | Japan | 951-8566 | |
| 83 | Kansai Medical University Hospital | Osaka, Hirakata | Japan | 573-1191 | |
| 84 | Osaka Medical Center for Cancer and Cardiovascular Diseases | Osaka, Osaka | Japan | 537-8511 | |
| 85 | Takatsuki Red Cross Hospital | Osaka, Takatsuki | Japan | 569-1096 | |
| 86 | Saitama Medical University International Medical Center | Saitama, Hidaka | Japan | 350-1298 | |
| 87 | National Hospital Organization Kinki-Chuo Chest Medical Center | Sakai-shi | Japan | 591-8555 | |
| 88 | Nippon Medical School Hospital | Tokyo, Bunkyo-ku | Japan | 113-8603 | |
| 89 | Nihon University Itabashi Hospital | Tokyo, Itabashi-ku | Japan | 173-8610 | |
| 90 | Japan Anti-Tuberculosis Association Fukujuji Hospital | Tokyo, Kiyose | Japan | 204-8522 | |
| 91 | Toranomon Hospital | Tokyo, Minato-ku | Japan | 105-8470 | |
| 92 | Chungbuk National University Hospital | Cheongju-si | Korea, Republic of | 361-711 | |
| 93 | Chonnam National University Hwasun Hospital | Hwasun-gun | Korea, Republic of | 519-763 | |
| 94 | Gachon University Gil Medical Center | Incheon | Korea, Republic of | 21565 | |
| 95 | Asan Medical Center | Seoul | Korea, Republic of | 05505 | |
| 96 | Korea University Guro Hospital | Seoul | Korea, Republic of | 08308 | |
| 97 | The Catholic University of Korea, St.Vincent's Hospital | Suwon-si | Korea, Republic of | 16247 | |
| 98 | Hospital Pulau Pinang | Georgetown Pulau Pinang | Malaysia | 10990 | |
| 99 | University Malaya Medical Centre | Kuala Lumpur | Malaysia | 59100 | |
| 100 | Hospital Tengku Ampuan Afzan | Kuantan | Malaysia | 25100 | |
| 101 | Investigacion Biomedica para el Desarrollo de Farmacos | El Salto | Mexico | 45680 | |
| 102 | Unidad de Atencion Medica e Investigacion en Salud S.C. | Merida | Mexico | 97000 | |
| 103 | Axis Heilsa S. de R.L. de C.V., Monterrey | Monterrey | Mexico | 64060 | |
| 104 | Clinical Medical Research S.C | Orizaba | Mexico | 94300 | |
| 105 | Hospital San Jose Querétaro | Queretaro | Mexico | 76090 | |
| 106 | Centro Hemato Oncológico Privado | Toluca | Mexico | 50080 | |
| 107 | Dr. Pablo O. Torre Memorial Hospital | Bacolod City | Philippines | 6100 | |
| 108 | Cebu Doctors Hospital | Cebu City | Philippines | 6000 | |
| 109 | Perpetual Succour Hospital (Cebu) | Cebu City | Philippines | 6000 | |
| 110 | Manila Doctors Hospital | Manila | Philippines | 1000 | |
| 111 | Lung Center of the Philippines | Quezon City | Philippines | 1100 | |
| 112 | Wojewodzkie Centrum Szpitalne Kotliny Jeleniogorskiej | Jelenia Gora | Poland | 58-506 | |
| 113 | KO-MED Centra Kliniczne Lublin II | Lublin | Poland | 20-362 | |
| 114 | Zofia Tarnowska domo Zamoyska,RegHosp.Cardiol.Dep,Tarnobrzeg | Tarnobrzeg | Poland | 39-400 | |
| 115 | The Provincial Polyclinical Hospital in Torun | Torun | Poland | 87-100 | |
| 116 | Onco.Cent. - Instit. of Maria Sklodowskiej-Curie | Warszawa | Poland | 02-781 | |
| 117 | Magodent Sp. Z o.o. | Warszawa | Poland | 04-125 | |
| 118 | CHUC - Centro Hospitalar e Universitário de Coimbra, EPE | Coimbra | Portugal | 3041-801 | |
| 119 | Centro Hospitalar Lisboa Norte Hospital Pulido Valente | Lisboa | Portugal | 1769-001 | |
| 120 | IPO Porto Francisco Gentil, EPE | Porto | Portugal | 4200-072 | |
| 121 | Centro Hospitalar de Entre o Douro e Vouga, E.P.E. - Hospital de São Sebastião | Santa Maria da Feira | Portugal | 4520-211 | |
| 122 | Centro Hospitalar de Vila Nova de Gaia | Vila Nova de Gaia | Portugal | 4434-502 | |
| 123 | Baia Mare Emergency County Hospital | Baia Mare | Romania | 430031 | |
| 124 | Institute of Oncology 'Prof. Dr. Alexandru Trestioreanu' | Bucuresti | Romania | 022328 | |
| 125 | Spitalul Clinic Judetean de Urgenta Cluj Napoca | Cluj Napoca | Romania | 400349 | |
| 126 | Spitalul Militar de Urgenta Dr.Papilian, Cluj-Napoca | Cluj-Napoca | Romania | 400132 | |
| 127 | S.C Oncocenter Oncologie Clinica S.R.L | Timisoara | Romania | 300210 | |
| 128 | SBIH of Arkhangelsk reg. "Arkhangelsk Clin. Onc. Dispensary" | Arkhangelsk | Russian Federation | 163045 | |
| 129 | St.Auton.Heal.Inst."Rep.Clin.Onc.Disp.of MoH of Rep. Tatarstan" | Kazan | Russian Federation | 420029 | |
| 130 | RBIH "Kursk regional clinical oncology dispensary" | Kursk | Russian Federation | 305035 | |
| 131 | FSBI "N.N Blokhin Med.Res.Cent.Onc."MoH of RF | Moscow | Russian Federation | 115478 | |
| 132 | BHI of Omsk region - Clinical Oncology Dispensary | Omsk | Russian Federation | 644013 | |
| 133 | SBIH of Stavropol territory "Pyatigorsk Oncol. Dispensary" | Pyatigorsk | Russian Federation | 357502 | |
| 134 | GUZ Leningradskaya Regional Clin. Hospital, St. Petersburg | St. Petersburg | Russian Federation | 194291 | |
| 135 | 1stPavlov St.Med.Univ.St.-Petersburg Res.Inst. | St. Petersburg | Russian Federation | 197022 | |
| 136 | SPb SBIH "City Clinical Oncological Dispensary" | St. Petersburg | Russian Federation | 197022 | |
| 137 | FSBI "N.N. Petrov National Medical Research Center of Oncology" of MoH of RF | St. Petersburg | Russian Federation | 197758 | |
| 138 | Institute for Oncol & Radiol of Serbia, Clinic f. Med. Onco. | Belgrade | Serbia | 11000 | |
| 139 | Clinical Center Bezanijska kosa, Belgrade | Belgrade | Serbia | 11080 | |
| 140 | Clinic of Pulmonary Diseases and Tuberculosis 'Knez Selo' | Gornji Matejevac | Serbia | 18204 | |
| 141 | Clinical Center Kragujevac | Kragujevac | Serbia | 34000 | |
| 142 | Inst. for Pulm. Diseases of Vojvodine, Clinic f. Pulm. Oncol | Sremska Kamenica | Serbia | 21204 | |
| 143 | GVI Cape Gate Oncology Centre | Cape Town | South Africa | 7570 | |
| 144 | Rondebosch Oncology Centre | Cape town | South Africa | 7700 | |
| 145 | GVI Oncology Outeniqua Unit | George | South Africa | 6530 | |
| 146 | West Rand Oncology Centre, Johannesburg | Johannesburg | South Africa | 1709 | |
| 147 | Langenhoven Drive Oncology Centre | Port Elizabeth | South Africa | 6045 | |
| 148 | Hospital Infanta Cristina | Badajoz | Spain | 06007 | |
| 149 | Hospital General Universitario Gregorio Marañón | Madrid | Spain | 28007 | |
| 150 | Hospital La Paz | Madrid | Spain | 28046 | |
| 151 | Hospital Clínico de Santiago | Santiago de Compostela | Spain | 15706 | |
| 152 | Hospital Virgen del Rocío | Sevilla | Spain | 41013 | |
| 153 | Hospital Nuestra Señora de Valme | Sevilla | Spain | 41014 | |
| 154 | Instituto Valenciano de Oncología | Valencia | Spain | 46009 | |
| 155 | Hospital Miguel Servet | Zaragoza | Spain | 50009 | |
| 156 | Songklanagarind Hospital | Hat Yai | Thailand | 90110 | |
| 157 | Ubonratchathani Cancer Hospital, Muang | Muang | Thailand | 34000 | |
| 158 | Udonthani Cancer Hospital, Muang | Muang | Thailand | 41330 | |
| 159 | Maharaj Nakorn Chiang Mai Hospital | Muang | Thailand | 50200 | |
| 160 | Lampang Hospital | Muang | Thailand | 52000 | |
| 161 | Naresuan University Hospital | Muang | Thailand | 65000 | |
| 162 | Akdeniz University Medical Faculty | Antalya | Turkey | 7058 | |
| 163 | Inonu Uni. Med. Fac., Battalgazi | Battalgazi | Turkey | 44280 | |
| 164 | Dicle University Medical Faculty | Diyarbakir | Turkey | 21080 | |
| 165 | Trakya Universitesi Tip Fakultesi | Edirne | Turkey | 22030 | |
| 166 | Gaziantep University | Gaziantep | Turkey | 27310 | |
| 167 | Bezmi Alem Foundation University Medical Faculty Hospital | Istanbul | Turkey | 34093 | |
| 168 | Yeditepe University Medical School Hospital | Istanbul | Turkey | 34752 | |
| 169 | Fatih University Faculty of Medicince, Istanbul | Istanbul | Turkey | 34844 | |
| 170 | CTPI Chernihiv Regional Oncological Dispensary, Chernihiv | Chernihiv | Ukraine | 14029 | |
| 171 | Munic.Instit."City Clin.Hosp.#4" of Dnipro City Council | Dnipropetrovsk | Ukraine | 49102 | |
| 172 | CHI Kharkiv Regional Clinical Oncological Center | Kharkiv | Ukraine | 61070 | |
| 173 | Kherson Regional Oncologic Dispensary, Kherson | Kherson | Ukraine | 73000 | |
| 174 | Treatment-Diagnostic CTR of Private Enterprise, Kirovohrad | Kirovohrad | Ukraine | 25006 | |
| 175 | CI Kryvyi Rih Oncological Dispensary of DRC | Kryvyi Rih, Dnipropetrovsk | Ukraine | 50048 | |
| 176 | National Institute of Cancer | Kyiv | Ukraine | 03022 | |
| 177 | Medical and Preventive Treatment Inst. Volyn Regional, Lutsk | Lutsk | Ukraine | 43018 | |
| 178 | CI of LRC Lviv Onco.Reg.Treat.&Diag.Cent. | Lviv | Ukraine | 79031 | |
| 179 | Poltava Regional Clinical Oncological Dispensary, Poltava | Poltava | Ukraine | 38011 | |
| 180 | Sumy Regional Oncology Center | Sumy | Ukraine | 40005 | |
| 181 | CI of TRC Ternopil RC Oncological Dispensary Thoracic Dept | Ternopil | Ukraine | 46023 | |
| 182 | Uzhgorod National University, Oncology Centre | Uzhgorod | Ukraine | 88000 | |
| 183 | Transcarpathian Reg Clin Oncological Dispensary, Uzhgorod | Uzhgorod | Ukraine | 88014 | |
| 184 | Vinnytsia Regional Clinical Oncological Dispensary | Vinnytsia | Ukraine | 21029 | |
| 185 | CI Zapor Reg Cl Oncological Dispensary of ZRC, Zhaporizhzhia | Zhaporizhzhia | Ukraine | 69040 | |
| 186 | Cheltenham General Hospital | Cheltenham | United Kingdom | GL53 7AN | |
| 187 | Wythenshawe Hospital | Manchester | United Kingdom | M23 9LT | |
| 188 | Can Tho Oncology Hospital | Can Tho | Vietnam | 000000 | |
| 189 | Bach Mai hospital | Hanoi | Vietnam | 100000 |
Sponsors and Collaborators
- Boehringer Ingelheim
Investigators
- Study Chair: Boehringer Ingelheim, Boehringer Ingelheim
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT02272413
Other Study ID Numbers:
- 1302.5
- 2014-002161-30
First Posted:
Oct 23, 2014
Last Update Posted:
Jan 13, 2020
Last Verified:
Dec 1, 2019
Study Results
Participant Flow
| Recruitment Details | Phase III, randomized, double-blind, multicenter, active comparator, parallel 2-arm trial in patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). From 21December2017, Sponsor recommended, patients to be switched from BI 695502 to reference product Avastin® (commercially available) as soon as it was available at clinical site. |
|---|---|
| Pre-assignment Detail | All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated. |
| Arm/Group Title | BI 695502 | Avastin® US |
|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. |
| Period Title: Randomized Through Treatment Start | ||
| STARTED | 338 | 333 |
| Treated | 335 | 328 |
| COMPLETED | 335 | 328 |
| NOT COMPLETED | 3 | 5 |
| Period Title: Randomized Through Treatment Start | ||
| STARTED | 335 | 328 |
| COMPLETED | 42 | 46 |
| NOT COMPLETED | 293 | 282 |
| Period Title: Randomized Through Treatment Start | ||
| STARTED | 42 | 46 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 42 | 46 |
Baseline Characteristics
| Arm/Group Title | BI 695502 | Avastin® US | Total |
|---|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Total of all reporting groups |
| Overall Participants | 335 | 328 | 663 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
61.2
(9.89)
|
61.3
(9.22)
|
61.2
(9.55)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
121
36.1%
|
125
38.1%
|
246
37.1%
|
| Male |
214
63.9%
|
203
61.9%
|
417
62.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
43
12.8%
|
34
10.4%
|
77
11.6%
|
| Not Hispanic or Latino |
284
84.8%
|
285
86.9%
|
569
85.8%
|
| Unknown or Not Reported |
8
2.4%
|
9
2.7%
|
17
2.6%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
64
19.1%
|
71
21.6%
|
135
20.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
0.3%
|
1
0.3%
|
2
0.3%
|
| White |
258
77%
|
248
75.6%
|
506
76.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
12
3.6%
|
8
2.4%
|
20
3%
|
Outcome Measures
| Title | Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment |
|---|---|
| Description | ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks. |
| Time Frame | Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Best ORR (CR+PR) is reported for observed values. |
| Arm/Group Title | BI 695502 | Avastin® US |
|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. |
| Measure Participants | 335 | 328 |
| Number [Percentage of patients (%)] |
54.0
|
63.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian). | |
| Type of Statistical Test | Equivalence | |
| Comments | The null hypothesis was to be rejected in favor of equivalence if the 2-sided 90% confidence interval (CI) for the ratio in best ORR between the treatments was entirely contained within the equivalence margins of 0.736 to 1.359. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of best ORR |
| Estimated Value | 0.8550 | |
| Confidence Interval |
(2-Sided) 90% 0.7697 to 0.9506 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian). | |
| Type of Statistical Test | Equivalence | |
| Comments | Additional analysis of the primary endpoint was performed for Japan according to a local protocol amendment Japan. For the submission in Japan, to conclude on equivalence, the 2-sided 95% CI for the ratio of best ORR between the treatments had to be entirely contained within the equivalence margins of 0.736 to 1.359. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of best ORR |
| Estimated Value | 0.8550 | |
| Confidence Interval |
(2-Sided) 95% 0.7543 to 0.9700 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin® |
|---|---|
| Description | The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®: Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), Thromboembolic events (arterial or venous), Febrile neutropenia, Gastrointestinal perforations, Hypertension, Proteinuria, Pulmonary hemorrhage, Other hemorrhages (not including pulmonary hemorrhages), Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs. |
| Time Frame | From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Treated Set contained all patients who signed informed consent and who received at least one dose of trial drug. |
| Arm/Group Title | BI 695502 | Avastin® US |
|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. |
| Measure Participants | 335 | 328 |
| AtLeast 1 AE selected for Comparability Assessment |
52.50
|
45.10
|
| Infusion reactions |
16.70
|
13.10
|
| Thromboembolic events |
6.60
|
5.50
|
| Febrile neutropenia |
3.90
|
3.40
|
| Gastrointestinal perforations |
2.10
|
0.60
|
| Hypertension |
15.50
|
16.20
|
| Proteinuria |
15.80
|
14.60
|
| Pulmonary haemorrhage |
1.20
|
0.90
|
| Other hemorrhages |
20.00
|
16.20
|
| Wound-healing complications/abscess/fistulas |
2.70
|
2.10
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | At least 1 AE selected for comparability assessment, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.16 | |
| Confidence Interval |
(2-Sided) 95% 0.99 to 1.37 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Infusion reactions, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.28 | |
| Confidence Interval |
(2-Sided) 95% 0.88 to 1.88 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Thromboembolic events, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio |
| Estimated Value | 1.20 | |
| Confidence Interval |
(2-Sided) 95% 0.64 to 2.32 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Febrile neutropenia, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.16 | |
| Confidence Interval |
(2-Sided) 95% 0.51 to 2.76 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Gastrointestinal perforations, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 3.43 | |
| Confidence Interval |
(2-Sided) 95% 0.79 to 32.82 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Hypertension, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.96 | |
| Confidence Interval |
(2-Sided) 95% 0.66 to 1.39 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Proteinuria, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.08 | |
| Confidence Interval |
(2-Sided) 95% 0.74 to 1.57 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Pulmonary haemorrhage, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.31 | |
| Confidence Interval |
(2-Sided) 95% 0.28 to 10.79 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Other hemorrhages, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.24 | |
| Confidence Interval |
(2-Sided) 95% 0.88 to 1.74 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 10
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Wound healing complications/ abscesses/ fistulas, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.26 | |
| Confidence Interval |
(2-Sided) 95% 0.47 to 3.57 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Progression-Free Survival (PFS) Time as Determined by Investigator Assessment |
|---|---|
| Description | PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique. |
| Time Frame | Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. |
| Arm/Group Title | BI 695502 | Avastin® US |
|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. |
| Measure Participants | 335 | 328 |
| Median (95% Confidence Interval) [Months] |
8.34
|
9.00
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.22 | |
| Confidence Interval |
(2-Sided) 95% 1.02 to 1.45 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival (OS) Time |
|---|---|
| Description | OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique. |
| Time Frame | From baseline until death due to any cause, ie., up to 35 cycles (105 weeks). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. |
| Arm/Group Title | BI 695502 | Avastin® US |
|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. |
| Measure Participants | 335 | 328 |
| Median (95% Confidence Interval) [Months] |
15.57
|
19.48
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.23 | |
| Confidence Interval |
(2-Sided) 95% 1.00 to 1.51 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Duration of Response (DOR) as Determined by Investigator Assessment |
|---|---|
| Description | DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique. |
| Time Frame | Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Only patients with an objective response were included in the analysis. |
| Arm/Group Title | BI 695502 | Avastin® US |
|---|---|---|
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. |
| Measure Participants | 175 | 187 |
| Median (95% Confidence Interval) [Months] |
7.66
|
8.94
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | BI 695502, Avastin® US |
|---|---|---|
| Comments | Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.14 | |
| Confidence Interval |
(2-Sided) 95% 0.88 to 1.48 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | For Pre-switch period: From first dose of trial drug until 112 days (16 weeks) after the last dose of trial medication, up to 218 days. For post-switch period: From the first dose of Avastin® until end of treatment (EOT) visit, up to 127 days. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | BI 695502 (Pre-switch) | US-licensed Avastin® (Pre-switch) | BI 695502 (Post-switch) | US-licensed Avastin® (Post-switch) | ||||
| Arm/Group Description | Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier. | Patients switched from BI 695502 to receive commercially available Avastin®. | Patients switched from US-licensed Avastin® to receive commercially available Avastin®. | ||||
All Cause Mortality |
||||||||
| BI 695502 (Pre-switch) | US-licensed Avastin® (Pre-switch) | BI 695502 (Post-switch) | US-licensed Avastin® (Post-switch) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 193/335 (57.6%) | 184/328 (56.1%) | 3/42 (7.1%) | 2/46 (4.3%) | ||||
Serious Adverse Events |
||||||||
| BI 695502 (Pre-switch) | US-licensed Avastin® (Pre-switch) | BI 695502 (Post-switch) | US-licensed Avastin® (Post-switch) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 108/335 (32.2%) | 89/328 (27.1%) | 5/42 (11.9%) | 2/46 (4.3%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Febrile neutropenia | 13/335 (3.9%) | 11/328 (3.4%) | 0/42 (0%) | 0/46 (0%) | ||||
| Anaemia | 6/335 (1.8%) | 11/328 (3.4%) | 0/42 (0%) | 0/46 (0%) | ||||
| Neutropenia | 4/335 (1.2%) | 9/328 (2.7%) | 0/42 (0%) | 0/46 (0%) | ||||
| Thrombocytopenia | 4/335 (1.2%) | 5/328 (1.5%) | 0/42 (0%) | 0/46 (0%) | ||||
| Bone marrow failure | 2/335 (0.6%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Leukopenia | 1/335 (0.3%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pancytopenia | 1/335 (0.3%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Disseminated intravascular coagulati | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cardiac disorders | ||||||||
| Acute myocardial infarction | 1/335 (0.3%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Atrial fibrillation | 1/335 (0.3%) | 3/328 (0.9%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cardiac arrest | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cardiac failure acute | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cardiopulmonary failure | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Arrhythmia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cardiac failure | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Coronary artery occlusion | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Sinus tachycardia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cardiac tamponade | 0/335 (0%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Myocardial ischaemia | 0/335 (0%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Myocardial rupture | 0/335 (0%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Congenital, familial and genetic disorders | ||||||||
| Pyloric stenosis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Ear and labyrinth disorders | ||||||||
| Deafness bilateral | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Eye disorders | ||||||||
| Retinal artery occlusion | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Vision blurred | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Vomiting | 4/335 (1.2%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Nausea | 3/335 (0.9%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Diarrhoea | 2/335 (0.6%) | 6/328 (1.8%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Anal incontinence | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Constipation | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Diverticular perforation | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Diverticulum intestinal | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Duodenal perforation | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Duodenal ulcer | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Gastric ulcer | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Gastrointestinal perforation | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Lower gastrointestinal haemorrhage | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Upper gastrointestinal haemorrhage | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Colitis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Dyspepsia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Dysphagia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Ileus paralytic | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Small intestinal obstruction | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Oesophageal perforation | 0/335 (0%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Oesophagobronchial fistula | 0/335 (0%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| General disorders | ||||||||
| Chest pain | 3/335 (0.9%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pyrexia | 2/335 (0.6%) | 5/328 (1.5%) | 0/42 (0%) | 0/46 (0%) | ||||
| Death | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Non-cardiac chest pain | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pain | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Sudden cardiac death | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Sudden death | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Asthenia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Fatigue | 0/335 (0%) | 3/328 (0.9%) | 0/42 (0%) | 0/46 (0%) | ||||
| General physical health deterioratio | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hepatobiliary disorders | ||||||||
| Bile duct obstruction | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cholecystitis acute | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hepatitis toxic | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hepatocellular injury | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hyperbilirubinaemia | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Jaundice cholestatic | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cholelithiasis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Drug-induced liver injury | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hepatic failure | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Liver injury | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Immune system disorders | ||||||||
| Anaphylactic reaction | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Anaphylactic shock | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Drug hypersensitivity | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypersensitivity | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Infections and infestations | ||||||||
| Pneumonia | 9/335 (2.7%) | 9/328 (2.7%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Lung infection | 2/335 (0.6%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Peritonitis | 2/335 (0.6%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pyelonephritis | 2/335 (0.6%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Anal abscess | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Anorectal infection | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Appendicitis perforated | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Klebsiella infection | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Lower respiratory tract infection | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Lung abscess | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Osteomyelitis | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pulmonary mycosis | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Respiratory tract infection | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Urinary tract infection | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Bronchitis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Campylobacter gastroenteritis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Diverticulitis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Gastroenteritis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Herpes zoster | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Infectious pleural effusion | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pneumonia bacterial | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Respiratory tract infection bacteria | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Subcutaneous abscess | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Upper respiratory tract infection | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Urosepsis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Sepsis | 0/335 (0%) | 0/328 (0%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Clavicle fracture | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Femoral neck fracture | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Infusion related reaction | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Procedural pneumothorax | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Fall | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hip fracture | 0/335 (0%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Meniscus injury | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Spinal compression fracture | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Investigations | ||||||||
| Neutrophil count decreased | 5/335 (1.5%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Platelet count decreased | 2/335 (0.6%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Alanine aminotransferase increased | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Aspartate aminotransferase increased | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Blood creatinine increased | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Blood magnesium decreased | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| White blood cell count decreased | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Hyponatraemia | 4/335 (1.2%) | 3/328 (0.9%) | 0/42 (0%) | 0/46 (0%) | ||||
| Dehydration | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypokalaemia | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Decreased appetite | 0/335 (0%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Electrolyte imbalance | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hyperkalaemia | 0/335 (0%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypoalbuminaemia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypocalcaemia | 0/335 (0%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypochloraemia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypomagnesaemia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Back pain | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Exposed bone in jaw | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Intervertebral disc protrusion | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Muscular weakness | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Myalgia | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Osteonecrosis of jaw | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Bone pain | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Musculoskeletal pain | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Bladder transitional cell carcinoma | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Brain neoplasm | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Intracranial tumour haemorrhage | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Nervous system disorders | ||||||||
| Cerebral infarction | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Headache | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hemiparesis | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Intracranial pressure increased | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Neuropathy peripheral | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Spinal cord compression | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Transient ischaemic attack | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Brain oedema | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Cerebrovascular accident | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Seizure | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Psychiatric disorders | ||||||||
| Delirium | 3/335 (0.9%) | 3/328 (0.9%) | 0/42 (0%) | 0/46 (0%) | ||||
| Anxiety | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Suicide attempt | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Confusional state | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Bladder obstruction | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hydronephrosis | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Renal impairment | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Acute kidney injury | 0/335 (0%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Renal failure | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Urinary retention | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Reproductive system and breast disorders | ||||||||
| Benign prostatic hyperplasia | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Pulmonary embolism | 11/335 (3.3%) | 5/328 (1.5%) | 0/42 (0%) | 0/46 (0%) | ||||
| Dyspnoea | 6/335 (1.8%) | 4/328 (1.2%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pneumothorax | 5/335 (1.5%) | 7/328 (2.1%) | 0/42 (0%) | 0/46 (0%) | ||||
| Respiratory failure | 5/335 (1.5%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Haemoptysis | 3/335 (0.9%) | 2/328 (0.6%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pulmonary haemorrhage | 3/335 (0.9%) | 1/328 (0.3%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Acquired tracheo-oesophageal fistula | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Bronchial fistula | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Chronic obstructive pulmonary diseas | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pneumonia aspiration | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Aspiration | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Atelectasis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Bronchospasm | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Epistaxis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Idiopathic pulmonary fibrosis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pulmonary necrosis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Hyperhidrosis | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Vascular disorders | ||||||||
| Deep vein thrombosis | 4/335 (1.2%) | 6/328 (1.8%) | 0/42 (0%) | 0/46 (0%) | ||||
| Shock haemorrhagic | 3/335 (0.9%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypotension | 2/335 (0.6%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Hypertensive crisis | 1/335 (0.3%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Internal haemorrhage | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Microembolism | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Peripheral embolism | 1/335 (0.3%) | 0/328 (0%) | 0/42 (0%) | 0/46 (0%) | ||||
| Arterial thrombosis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Embolism venous | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Vascular stenosis | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Vasoconstriction | 0/335 (0%) | 1/328 (0.3%) | 0/42 (0%) | 0/46 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| BI 695502 (Pre-switch) | US-licensed Avastin® (Pre-switch) | BI 695502 (Post-switch) | US-licensed Avastin® (Post-switch) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 293/335 (87.5%) | 288/328 (87.8%) | 20/42 (47.6%) | 22/46 (47.8%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 112/335 (33.4%) | 84/328 (25.6%) | 2/42 (4.8%) | 4/46 (8.7%) | ||||
| Neutropenia | 61/335 (18.2%) | 52/328 (15.9%) | 0/42 (0%) | 2/46 (4.3%) | ||||
| Thrombocytopenia | 44/335 (13.1%) | 47/328 (14.3%) | 1/42 (2.4%) | 4/46 (8.7%) | ||||
| Leukopenia | 18/335 (5.4%) | 23/328 (7%) | 0/42 (0%) | 2/46 (4.3%) | ||||
| Gastrointestinal disorders | ||||||||
| Nausea | 73/335 (21.8%) | 75/328 (22.9%) | 2/42 (4.8%) | 1/46 (2.2%) | ||||
| Diarrhoea | 60/335 (17.9%) | 45/328 (13.7%) | 1/42 (2.4%) | 1/46 (2.2%) | ||||
| Vomiting | 56/335 (16.7%) | 37/328 (11.3%) | 1/42 (2.4%) | 1/46 (2.2%) | ||||
| Constipation | 51/335 (15.2%) | 44/328 (13.4%) | 1/42 (2.4%) | 1/46 (2.2%) | ||||
| General disorders | ||||||||
| Fatigue | 54/335 (16.1%) | 53/328 (16.2%) | 2/42 (4.8%) | 1/46 (2.2%) | ||||
| Asthenia | 22/335 (6.6%) | 29/328 (8.8%) | 1/42 (2.4%) | 2/46 (4.3%) | ||||
| Malaise | 19/335 (5.7%) | 13/328 (4%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pyrexia | 17/335 (5.1%) | 21/328 (6.4%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Investigations | ||||||||
| Platelet count decreased | 41/335 (12.2%) | 33/328 (10.1%) | 0/42 (0%) | 0/46 (0%) | ||||
| Neutrophil count decreased | 39/335 (11.6%) | 42/328 (12.8%) | 0/42 (0%) | 0/46 (0%) | ||||
| White blood cell count decreased | 30/335 (9%) | 19/328 (5.8%) | 0/42 (0%) | 0/46 (0%) | ||||
| Alanine aminotransferase increased | 24/335 (7.2%) | 32/328 (9.8%) | 0/42 (0%) | 2/46 (4.3%) | ||||
| Gamma-glutamyltransferase increased | 22/335 (6.6%) | 31/328 (9.5%) | 1/42 (2.4%) | 6/46 (13%) | ||||
| Weight decreased | 21/335 (6.3%) | 22/328 (6.7%) | 2/42 (4.8%) | 1/46 (2.2%) | ||||
| Blood cholesterol increased | 20/335 (6%) | 16/328 (4.9%) | 1/42 (2.4%) | 3/46 (6.5%) | ||||
| Aspartate aminotransferase increased | 19/335 (5.7%) | 30/328 (9.1%) | 1/42 (2.4%) | 3/46 (6.5%) | ||||
| Blood alkaline phosphatase increased | 17/335 (5.1%) | 25/328 (7.6%) | 0/42 (0%) | 3/46 (6.5%) | ||||
| Haemoglobin decreased | 5/335 (1.5%) | 17/328 (5.2%) | 0/42 (0%) | 0/46 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 54/335 (16.1%) | 54/328 (16.5%) | 2/42 (4.8%) | 4/46 (8.7%) | ||||
| Hyperglycaemia | 21/335 (6.3%) | 28/328 (8.5%) | 0/42 (0%) | 4/46 (8.7%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 40/335 (11.9%) | 35/328 (10.7%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Myalgia | 38/335 (11.3%) | 29/328 (8.8%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Back pain | 22/335 (6.6%) | 14/328 (4.3%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Musculoskeletal pain | 18/335 (5.4%) | 10/328 (3%) | 0/42 (0%) | 0/46 (0%) | ||||
| Pain in extremity | 12/335 (3.6%) | 18/328 (5.5%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Nervous system disorders | ||||||||
| Neuropathy peripheral | 62/335 (18.5%) | 59/328 (18%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Peripheral sensory neuropathy | 56/335 (16.7%) | 53/328 (16.2%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Headache | 26/335 (7.8%) | 25/328 (7.6%) | 1/42 (2.4%) | 2/46 (4.3%) | ||||
| Paraesthesia | 20/335 (6%) | 19/328 (5.8%) | 0/42 (0%) | 0/46 (0%) | ||||
| Dysgeusia | 13/335 (3.9%) | 17/328 (5.2%) | 0/42 (0%) | 0/46 (0%) | ||||
| Psychiatric disorders | ||||||||
| Insomnia | 15/335 (4.5%) | 18/328 (5.5%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Proteinuria | 51/335 (15.2%) | 46/328 (14%) | 8/42 (19%) | 6/46 (13%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 38/335 (11.3%) | 32/328 (9.8%) | 0/42 (0%) | 5/46 (10.9%) | ||||
| Epistaxis | 38/335 (11.3%) | 32/328 (9.8%) | 0/42 (0%) | 0/46 (0%) | ||||
| Dyspnoea | 22/335 (6.6%) | 31/328 (9.5%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Haemoptysis | 17/335 (5.1%) | 10/328 (3%) | 0/42 (0%) | 1/46 (2.2%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Alopecia | 155/335 (46.3%) | 149/328 (45.4%) | 0/42 (0%) | 0/46 (0%) | ||||
| Rash | 17/335 (5.1%) | 16/328 (4.9%) | 1/42 (2.4%) | 0/46 (0%) | ||||
| Vascular disorders | ||||||||
| Hypertension | 49/335 (14.6%) | 51/328 (15.5%) | 3/42 (7.1%) | 1/46 (2.2%) | ||||
Limitations/Caveats
From 21 December 2017, after Week 18 primary analysis data cut-off, the Sponsor recommended to switch patients from BI 695502/US-licensed Avastin® to Avastin®. The main analyses to report all endpoint and AE results was the pre-switch period.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
| Name/Title | Boehringer Ingelheim, Call Centre |
|---|---|
| Organization | Boehringer Ingelheim |
| Phone | 1-800-243-0127 |
| clintriage.rdg@boehringer-ingelheim.com |
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT02272413
Other Study ID Numbers:
- 1302.5
- 2014-002161-30
First Posted:
Oct 23, 2014
Last Update Posted:
Jan 13, 2020
Last Verified:
Dec 1, 2019