Dose Escalation and Double-blind Study of Veliparib in Combination With Carboplatin and Etoposide in Treatment-naive Extensive Stage Disease Small Cell Lung Cancer
Sponsor
AbbVie (Industry)
Overall Status
Completed
CT.gov ID
NCT02289690
Collaborator
(none)
221
62
4
54.1
3.6
0.1
Study Details
Study Description
Brief Summary
The study seeks to assess the efficacy of veliparib (ABT-888) in combination with carboplatin and etoposide in participants with extensive disease small cell lung cancer (ED SCLC).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
This is a Phase 1, open-label, dose-escalation/Phase 2 randomized double-blind study of veliparib in combination with carboplatin and etoposide and maintenance veliparib monotherapy.
Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen for up to four 21-day cycles based on the observed toxicities. The study design for Phase 1 will follow a traditional "3 + 3" dose-escalation protocol.
Once the veliparib recommended Phase 2 dose (RPTD) and schedule is determined, enrollment into Phase 2 will begin. Participants from the Phase 1 dose-escalation portion of the study are not eligible for enrollment into the Phase 2 portion. Participants in Phase 2 will be randomized in a 1:1:1 ratio to carboplatin, etoposide, placebo followed by placebo maintenance (Arm C), or carboplatin, etoposide, veliparib followed by either veliparib (Arm
- or placebo (Arm B) maintenance. Randomization for Phase 2 will be stratified by baseline lactate dehydrogenase (LDH) level (> upper limit of normal [ULN] vs. ≤ ULN), and gender.
Study Design
Study Type:
Interventional
Actual Enrollment
:
221 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
Double (Participant, Investigator)
Masking Description:
Phase 1 was open-label, phase 2 was conducted in a double-blind manner.
Primary Purpose:
Treatment
Official Title:
A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind Study of Veliparib in Combination With Carboplatin and Etoposide as a Therapy of Treatment-Naïve Extensive Stage Disease Small Cell Lung Cancer
Actual Study Start Date
:
Oct 13, 2014
Actual Primary Completion Date
:
Apr 17, 2019
Actual Study Completion Date
:
Apr 17, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1: Veliparib + Carboplatin + Etoposide Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with carboplatin/etoposide for up to four 21-day cycles. Participants without evidence of disease progression will continue on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
Drug: Veliparib
Capsules administered orally twice a day according to the dosing schedule.
Other Names:
Drug: Carboplatin
Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL*minute.
Drug: Etoposide
Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m².
Other Names:
|
| Experimental: Phase 2: Veliparib + Carboplatin + Etoposide -> Veliparib Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
Drug: Veliparib
Capsules administered orally twice a day according to the dosing schedule.
Other Names:
Drug: Carboplatin
Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL*minute.
Drug: Etoposide
Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m².
Other Names:
|
| Experimental: Phase 2: Veliparib + Carboplatin + Etoposide -> Placebo Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. |
Drug: Veliparib
Capsules administered orally twice a day according to the dosing schedule.
Other Names:
Drug: Carboplatin
Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL*minute.
Drug: Etoposide
Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m².
Other Names:
Drug: Placebo
Placebo to veliparib administered orally twice a day according to the dosing schedule.
|
| Active Comparator: Phase 2: Placebo + Carboplatin + Etoposide -> Placebo Participants will receive placebo in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. |
Drug: Carboplatin
Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL*minute.
Drug: Etoposide
Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m².
Other Names:
Drug: Placebo
Placebo to veliparib administered orally twice a day according to the dosing schedule.
|
Outcome Measures
Primary Outcome Measures
- Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) [Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days)]
A DLT was defined as any of the following drug-related toxicities, graded according to the Common Toxicity Criteria for Adverse Events (CTCAE), V.4.0: Events associated with treatment delay >14 days in initiating Cycle 2 therapy: Grade 4 thrombocytopenia, neutropenia, or febrile neutropenia, or Grade 3 febrile neutropenia with fever for > 7 days Grade ≥ 3 non-hematologic toxicity with ≥ 2 grade increase from baseline and attributed to veliparib treatment, excluding nausea or vomiting for ≤ 48 hours or inadequately treated, electrolyte abnormalities resolving in ≤ 24 hours, hypersensitivity reactions or alopecia Grade 2 non-hematologic toxicity of ≥ 2 grade increase from baseline, attributed to veliparib treatment requiring delay of >14 days in initiation of Cycle 2 Any toxicity of ≥ 2-grade increase from baseline, attributed to veliparib and requiring a dose modification in Cycle 1 or omission of carboplatin, >1 daily etoposide dose, or >30% veliparib doses in Cycle 1
- Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
- Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
- Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods.
- Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration.
- Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. Dose normalized Cmax is calculated as Cmax / veliparib dose in mg.
- Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / veliparib dose in mg.
- Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib [Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose]
The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. Dose normalized AUC(0-12) is calculated as AUC(0-12) / veliparib dose in mg.
- Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.
- Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.
- Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods.
- Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods.
- Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation.
- Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. Dose normalized Cmax is calculated as Cmax / etoposide dose in mg/m².
- Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-t) is calculated as AUC(0-t) / etoposide dose in mg/m².
- Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib [Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.]
The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-∞) is calculated as AUC(0-∞) / etoposide dose in mg/m².
- Phase 2: Progression-free Survival [From randomization up to the date the 126th PFS event was reached; Median time on follow-up was 7.3, 7.1, and 8.9 months in each treatment group respectively.]
Progression-free survival (PFS) is defined as the time from the date of randomization to the date of earliest radiographic disease progression or death provided no radiographic disease progression occurred. If a participant did not have an event of disease progression and had not died on or prior to the cutoff for PFS analysis, the participant's data was censored at the date of their last disease assessment or randomization date provided participant did not have any post-baseline disease assessment. Disease assessments were performed using computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions.
Secondary Outcome Measures
- Phase 2: Overall Survival [From randomization until the end of study; median time on follow-up was 10.0, 8.6, and 11.7 months in each treatment group respectively.]
Overall survival (OS) is defined as the time from the date of randomization to the date of death. If a participant did not die on or prior to the cut-off for OS analysis, the participant's data were censored at the date of their last known alive date, which is defined as the last date of the last survival follow-up visit, the start date of the last AE, the start date or end date of the last dose of any study drugs, the last lab and vital sign collection date, or the last disease assessment date, whichever occurred last.
- Phase 2: Objective Response Rate [Tumor assessments were performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter until disease progression; median time on follow-up was 7.3, 7.1, and 8.9 months in each group respectively.]
Objective response rate (ORR) is defined as the percentage of participants with objective response (confirmed) as assessed by the investigator using RECIST version 1.1. Objective response includes both complete response (CR) and partial response (PR). Response must be confirmed at a subsequent tumor assessment at least 28 days apart. Participants with no post-baseline confirmed response were counted as non-responders. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. No new lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and no new lesions.
- Phase 1: Number of Participants With Adverse Events [From first dose of any study drug to 30 days after the last dose; the median duration of treatment with veliparib across all groups in Phase 1 was 127.5 days.]
The intensity of each adverse event (AE) was assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, and according to the following: Grade 1 (Mild): AE is transient and easily tolerated by the participant; Grade 2 (Moderate): AE causes the participant discomfort and interrupts the participant's usual activities; Grade 3/4 (Severe): The adverse event causes considerable interference with the participant's usual activities and may be incapacitating or life-threatening; Grade 5: Death. Serious adverse events were those that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in congenital anomaly, or persistent or significant disability/incapacity.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 99 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Subject with histologically or cytologically confirmed extensive-stage disease SCLC which is newly diagnosed and chemotherapy naive
-
Phase 1 ONLY: histologically or cytologically confirmed advanced/metastatic solid tumors for which carboplatin/etoposide treatment is considered appropriate.
-
Subject in Phase 2 only: must have measurable disease per RECIST 1.1.
-
Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and biomarker analysis.
-
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
-
Subject must have adequate hematologic, renal and hepatic function.
Exclusion Criteria:
- Phase 1 ONLY: Subject has had any prior anti-cancer therapy other than:
Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2).
One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2).
Adjuvant/neoadjuvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day -2, with field not involving > 10% of bone marrow reserve).
-
Phase 2 ONLY: Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer agents or biologic therapy for the disease under study. Single non-target lesion irradiation with intent of symptom palliation is allowed if ≥ 4 weeks prior Cycle 1 Day -2.
-
Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS or leptomeningeal metastases.
-
Subject has a history of seizures within 12 months of Cycle 1 Day-2 or diagnosed neurological condition placing subject at the increased risk of seizures.
-
Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days prior to Cycle 1 Day-2.
-
Subject has had major surgery within 6 weeks prior to Cycle 1 Day-2 (subjects must have completely recovered from any previous surgery prior Cycle 1 Day-2).
-
Subject has clinically significant and uncontrolled major medical condition(s) including but not limited to:
-
Uncontrolled nausea/vomiting/diarrhea;
-
Active uncontrolled infection;
-
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months, it must be done at screening);
-
History of hepatitis C (HCV) with HCV ribonucleic acid (RNA) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months it must be done at screening);
-
Symptomatic congestive heart failure (Yew York Heart Association [NYHA] class ≥ II);
-
Unstable angina pectoris or cardiac arrhythmia (except atrial fibrillation);
-
Psychiatric illness/social situation that would limit compliance with study requirements;
-
Any other medical condition, which in the opinion of the Investigator, places the subject at an unacceptably high risk for toxicities.
- The subject has a history of another active cancer within the past 3 years except cervical cancer in situ, in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ cancer that is considered cured by the investigator (e.g., in situ prostate cancer, breast DCIS).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic - Scottsdale /ID# 129127 | Scottsdale | Arizona | United States | 85259 |
| 2 | Univ of Colorado Cancer Center /ID# 129220 | Aurora | Colorado | United States | 80045 |
| 3 | Emory University Hospital /ID# 141682 | Atlanta | Georgia | United States | 30322 |
| 4 | Georgia Regents University /ID# 148567 | Augusta | Georgia | United States | 30912 |
| 5 | Northwestern University Feinberg School of Medicine /ID# 137088 | Chicago | Illinois | United States | 60611-2927 |
| 6 | Herbert Herman Cancer Center /ID# 167020 | Lansing | Michigan | United States | 48912 |
| 7 | Gabrail Cancer Center Research /ID# 129216 | Canton | Ohio | United States | 44718 |
| 8 | Allegheny General Hospital /ID# 147328 | Pittsburgh | Pennsylvania | United States | 15212 |
| 9 | University of Texas MD Anderson Cancer Center /ID# 129213 | Houston | Texas | United States | 77030 |
| 10 | Southern Medical Day Care Ctr /ID# 155498 | Wollongong | New South Wales | Australia | 2500 |
| 11 | The Townsville Hospital /ID# 155499 | Douglas | Queensland | Australia | 4814 |
| 12 | Peninsula & South Eastern Haem /ID# 155497 | Frankston | Victoria | Australia | 3199 |
| 13 | Border Medical /ID# 157894 | Wodonga | Victoria | Australia | 3690 |
| 14 | Cliniques Universitaires Saint Luc /ID# 151024 | Woluwe-Saint-Lambert | Bruxelles-Capitale | Belgium | 1200 |
| 15 | CHU de Liege /ID# 151025 | Liège | Liege | Belgium | 4000 |
| 16 | UZ Antwerp /ID# 151026 | Edegem | Belgium | 2650 | |
| 17 | C.H.U.de Mons Borinage /ID# 151023 | Mons | Belgium | 7000 | |
| 18 | CHU UCL Namur /ID# 151022 | Namur | Belgium | 5000 | |
| 19 | University of Calgary /ID# 152544 | Calgary | Alberta | Canada | T2N 4Z6 |
| 20 | Cross Cancer Institute /ID# 132883 | Edmonton | Alberta | Canada | T6G 1Z2 |
| 21 | Juravinski Cancer Clinic /ID# 152543 | Hamilton | Ontario | Canada | L8V 1C3 |
| 22 | Hopital du Sacre Coeur Montreal /ID# 154436 | Montreal | Quebec | Canada | H4J 1C5 |
| 23 | Nemocnice Na Plesi s.r.o. /ID# 149825 | Nová Ves pod Pleší | Pribram | Czechia | 262 04 |
| 24 | Nemocnice Novy Jicin /ID# 149838 | Nový Jičín 1 | Czechia | 741 01 | |
| 25 | Vitkovicka nemocnice a. s. /ID# 149839 | Ostrava | Czechia | 703 84 | |
| 26 | Multiscan s.r.o. /ID# 150887 | Pardubice | Czechia | 530-03 | |
| 27 | CHU Dupuytren /ID# 153622 | Limoges CEDEX 1 | Franche-Comte | France | 87042 |
| 28 | Centre Hospitalier Le Mans /ID# 158103 | Le Mans CEDEX 9 | Sarthe | France | 72037 |
| 29 | Centre Hosp Intercommunal de Creteil /ID# 157970 | Creteil | Val-de-Marne | France | 94000 |
| 30 | Orszagos Koranyi Pulmonologiai Intezet /ID# 151351 | Budapest XII | Budapest | Hungary | 1122 |
| 31 | Markusovszky Egyetemi Oktatókórház /ID# 158806 | Szombathely | Vas | Hungary | 9700 |
| 32 | Debreceni Egyetem Klinikai Központ /ID# 151354 | Debrecen | Hungary | 4032 | |
| 33 | Veszprem Megyei Tudogyogyintez /ID# 158807 | Farkasgyepu | Hungary | 8582 | |
| 34 | Petz Aladar Megyei Oktato Korh /ID# 155352 | Gyor | Hungary | 9023 | |
| 35 | Matrahaza Gyogyintezet /ID# 151355 | Kékesteto | Hungary | 3233 | |
| 36 | Fejer Megyei Szent Gyorgy Korh /ID# 151352 | Szekesfehervar | Hungary | 8000 | |
| 37 | Jasz-Nagykun-Szolnok Megyei /ID# 155090 | Szolnok | Hungary | 5004 | |
| 38 | Dong-A University Hospital /ID# 153187 | Busan | Busan Gwang Yeogsi | Korea, Republic of | 49201 |
| 39 | Chungbuk National Univ Hosp /ID# 153186 | Cheongju | Korea, Republic of | 361-240 | |
| 40 | Chonnam National University Hwasun Hospital /ID# 153188 | Jeonnam | Korea, Republic of | 58128 | |
| 41 | Asan Medical Center /ID# 153185 | Seoul | Korea, Republic of | 05505 | |
| 42 | Universitair Medisch Centrum Groningen /ID# 131252 | Groningen | Netherlands | 9713 GZ | |
| 43 | Ziekenhuis St. Jansdal /ID# 151974 | Harderwijk | Netherlands | 3844 DG | |
| 44 | Atrium-Orbis Zuyderland Medisch Centrum /ID# 149830 | Heerlen | Netherlands | 6419 PC | |
| 45 | Erasmus Medisch Centrum /ID# 131251 | Rotterdam | Netherlands | 3015 CE | |
| 46 | Isala /ID# 151975 | Zwolle | Netherlands | 8025 AB | |
| 47 | S.C. Centrul de Oncologie Sf. Nectarie S.R.L. /ID# 161137 | Craiova | Dolj | Romania | 200347 |
| 48 | Oncocenter Oncologie Clinica S /ID# 151694 | Timisoara | Timis | Romania | 300166 |
| 49 | S.C. Radiotherapy Center Cluj /ID# 165137 | Cluj | Romania | 407280 | |
| 50 | NN Blokhin Russian Cancer /ID# 152329 | Moscow | Moskva | Russian Federation | 115478 |
| 51 | Sverdlovsk Regional Oncology Center Dispensary /ID# 152328 | Ekaterinburg | Sverdlovskaya Oblast | Russian Federation | 620043 |
| 52 | Belgorod Oncology Dispensary /ID# 152330 | Belgorod | Russian Federation | 308001 | |
| 53 | Univercity Headache Clynic,LTD /ID# 161708 | Moscow | Russian Federation | 109028 | |
| 54 | Murmansk RCH P.A. Bayandina /ID# 152331 | Murmansk | Russian Federation | 183047 | |
| 55 | Ogarev Mordovia State Univ /ID# 152327 | Saransk | Russian Federation | 430005 | |
| 56 | Road Hospital Open Joint Stock Company Russian Railways /ID# 152731 | St. Petersburg | Russian Federation | 195271 | |
| 57 | Hospital Stanta Creu i Sant Pau /ID# 151254 | Barcelona | Spain | 08025 | |
| 58 | Hosp Univ Quiron Dexues /ID# 130302 | Barcelona | Spain | 08028 | |
| 59 | Hospital Universitario Gregori /ID# 164982 | Madrid | Spain | 28009 | |
| 60 | Hosp Univ 12 de Octubre /ID# 151252 | Madrid | Spain | 28041 | |
| 61 | Hosp Univ Madrid Sanchinarro /ID# 130301 | Madrid | Spain | 28050 | |
| 62 | Hosp Univ Puerta de Hierro Maj /ID# 151253 | Majadahonda | Spain | 28222 |
Sponsors and Collaborators
- AbbVie
Investigators
- Study Director: AbbVie Inc., AbbVie
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
AbbVie
ClinicalTrials.gov Identifier:
NCT02289690
Other Study ID Numbers:
- M14-361
- 2014-001764-35
First Posted:
Nov 13, 2014
Last Update Posted:
May 14, 2020
Last Verified:
May 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by AbbVie
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 52 study sites located in 12 countries (Australia, Belgium, Canada, Czech Republic, France, Hungary, Korea, the Netherlands, Romania, Russian Federation, Spain, United States). |
|---|---|
| Pre-assignment Detail | Participants in Phase 1 were sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen. Participants in Phase 2 were randomized equally to placebo, carboplatin/etoposide followed by placebo maintenance, or to veliparib, carboplatin/etoposide followed by veliparib or placebo maintenance. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 12 (14 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 12 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to Day 19 (continuous schedule) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
| Period Title: Overall Study | ||||||||||
| STARTED | 4 | 3 | 4 | 3 | 8 | 14 | 4 | 61 | 59 | 61 |
| Received Study Drug | 4 | 3 | 4 | 3 | 8 | 14 | 4 | 60 | 58 | 60 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 4 | 3 | 4 | 3 | 8 | 14 | 4 | 61 | 59 | 61 |
Baseline Characteristics
| Arm/Group Title | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered intravenously (IV) on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease pParticipants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 12 (14 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 12 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to Day 19 (continuous schedule) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Total of all reporting groups |
| Overall Participants | 4 | 3 | 4 | 3 | 8 | 14 | 4 | 61 | 59 | 61 | 221 |
| Age (years) [Median (Full Range) ] | |||||||||||
| Phase 1 |
74.0
|
69.0
|
62.5
|
54.0
|
52.0
|
66.0
|
59.0
|
62.5
|
|||
| Phase 2 |
62.0
|
64.0
|
63.0
|
63.0
|
|||||||
| Sex: Female, Male (Count of Participants) | |||||||||||
| Female |
3
75%
|
0
0%
|
2
50%
|
1
33.3%
|
2
25%
|
5
35.7%
|
1
25%
|
21
34.4%
|
21
35.6%
|
23
37.7%
|
79
35.7%
|
| Male |
1
25%
|
3
100%
|
2
50%
|
2
66.7%
|
6
75%
|
9
64.3%
|
3
75%
|
40
65.6%
|
38
64.4%
|
38
62.3%
|
142
64.3%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||||||||
| White |
4
100%
|
3
100%
|
4
100%
|
3
100%
|
8
100%
|
14
100%
|
4
100%
|
55
90.2%
|
51
86.4%
|
52
85.2%
|
198
89.6%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
3.3%
|
1
1.7%
|
1
1.6%
|
4
1.8%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
4
6.6%
|
7
11.9%
|
7
11.5%
|
18
8.1%
|
| Missing |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
1.6%
|
1
0.5%
|
| Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants) | |||||||||||
| 0 - Fully active |
1
25%
|
1
33.3%
|
1
25%
|
1
33.3%
|
2
25%
|
3
21.4%
|
2
50%
|
21
34.4%
|
16
27.1%
|
23
37.7%
|
71
32.1%
|
| 1 - Restricted but ambulatory |
3
75%
|
2
66.7%
|
3
75%
|
2
66.7%
|
5
62.5%
|
11
78.6%
|
1
25%
|
39
63.9%
|
42
71.2%
|
37
60.7%
|
145
65.6%
|
| Missing |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
12.5%
|
0
0%
|
1
25%
|
1
1.6%
|
1
1.7%
|
1
1.6%
|
5
2.3%
|
Outcome Measures
| Title | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) |
|---|---|
| Description | A DLT was defined as any of the following drug-related toxicities, graded according to the Common Toxicity Criteria for Adverse Events (CTCAE), V.4.0: Events associated with treatment delay >14 days in initiating Cycle 2 therapy: Grade 4 thrombocytopenia, neutropenia, or febrile neutropenia, or Grade 3 febrile neutropenia with fever for > 7 days Grade ≥ 3 non-hematologic toxicity with ≥ 2 grade increase from baseline and attributed to veliparib treatment, excluding nausea or vomiting for ≤ 48 hours or inadequately treated, electrolyte abnormalities resolving in ≤ 24 hours, hypersensitivity reactions or alopecia Grade 2 non-hematologic toxicity of ≥ 2 grade increase from baseline, attributed to veliparib treatment requiring delay of >14 days in initiation of Cycle 2 Any toxicity of ≥ 2-grade increase from baseline, attributed to veliparib and requiring a dose modification in Cycle 1 or omission of carboplatin, >1 daily etoposide dose, or >30% veliparib doses in Cycle 1 |
| Time Frame | Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 12 (14 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 12 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to Day 19 (continuous schedule) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
| Measure Participants | 4 | 3 | 4 | 3 | 8 | 14 | 4 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
12.5%
|
0
0%
|
1
25%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide, Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | A primary objective of Phase 1 was to establish the recommended phase 2 dose (RP2D) for veliparib combined with carboplatin and etoposide. The RP2D was determined by the rate of DLTs and overall tolerability of veliparib plus carboplatin and etoposide. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | RP2D for veliparib in mg BID for 14 days |
| Estimated Value | 240 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The RP2D for veliparib was determined to be 240 mg BID for 14 days with carboplatin (AUC 5 mg/mL*min) on Day 1 and etoposide (100 mg/m²) on Days 1 to 3 during 21-day cycles for 4 cycles. | |
| Title | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib |
|---|---|
| Description | Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom Cmax could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 3 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [μg/mL] |
0.620
(17)
|
1.00
(31)
|
1.39
(29)
|
1.44
(10)
|
1.99
(25)
|
| Title | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib |
|---|---|
| Description | Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom Tmax could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 3 | 22 |
| Median (Full Range) [hours] |
2.0
|
1.0
|
1.5
|
2.0
|
1.0
|
| Title | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-8) could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 2 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL] |
3.18
(14)
|
4.24
(25)
|
7.51
(28)
|
6.66
(4)
|
9.29
(37)
|
| Title | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-12) could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 3 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL] |
4.07
(15)
|
5.25
(27)
|
9.71
(31)
|
8.35
(6)
|
11.6
(40)
|
| Title | Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib |
|---|---|
| Description | Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. Dose normalized Cmax is calculated as Cmax / veliparib dose in mg. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom Cmax could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 3 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [(ng/mL)/mg] |
7.75
(16)
|
8.35
(31)
|
8.66
(29)
|
7.19
(10)
|
8.31
(25)
|
| Title | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / veliparib dose in mg. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-8) could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 2 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/mg] |
39.8
(14)
|
35.3
(25)
|
46.9
(28)
|
33.3
(4)
|
38.7
(37)
|
| Title | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. Dose normalized AUC(0-12) is calculated as AUC(0-12) / veliparib dose in mg. |
| Time Frame | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-12) could be calculated. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide |
|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. | Participants received 240 mg veliparib orally BID (Days -2 to 5 for 7-day schedule, Days -2 to 12 for 14-day schedule or Days -2 to 19 for continuous dosing) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. |
| Measure Participants | 4 | 3 | 4 | 3 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/mg] |
50.9
(15)
|
43.8
(27)
|
60.7
(31)
|
41.7
(6)
|
48.5
(40)
|
| Title | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib |
|---|---|
| Description | Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom Cmax could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group and participants whose etoposide dose was reduced in Cycle 2 are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 37 | 23 |
| Geometric Mean (Geometric Coefficient of Variation) [μg/mL] |
16.9
(18)
|
16.4
(21)
|
| Title | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib |
|---|---|
| Description | Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom Tmax could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 37 | 28 |
| Median (Full Range) [hours] |
0.9
|
0.9
|
| Title | Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group and participants whose etoposide dose was reduced in Cycle 2 are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 35 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL] |
102
(23)
|
94.7
(18)
|
| Title | Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group and participants whose etoposide dose was reduced in Cycle 2 are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 35 | 22 |
| Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL] |
112
(56)
|
99.5
(18)
|
| Title | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib |
|---|---|
| Description | The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation. |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in Phase 1 who received at least 1 dose of study drug and had at least 1 reported PK sample concentration for each time point and for whom t1/2 could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 35 | 27 |
| Mean (Standard Deviation) [hours] |
5.7
(1.5)
|
5.0
(1.2)
|
| Title | Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib |
|---|---|
| Description | Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. Dose normalized Cmax is calculated as Cmax / etoposide dose in mg/m². |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom Cmax could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 37 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [(ng/mL)/(mg/m²)] |
169
(18)
|
170
(20)
|
| Title | Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-t) is calculated as AUC(0-t) / etoposide dose in mg/m². |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 35 | 27 |
| Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/(mg/m²)] |
1020
(23)
|
952
(21)
|
| Title | Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib |
|---|---|
| Description | The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-∞) is calculated as AUC(0-∞) / etoposide dose in mg/m². |
| Time Frame | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis. |
| Arm/Group Title | Etoposide Cycle 1 Day 1 (With Veliparib) | Etoposide Cycle 2 Day 1 (No Veliparib) |
|---|---|---|
| Arm/Group Description | Phase 1 participants received 100 mg/m² etoposide intravenously with carboplatin target AUC 5.0 mg*min/mL and veliparib 80 to 240 mg BID on Cycle 1 Day 1. | Phase 1 participants received etoposide 100 mg/m² and carboplatin target AUC 5.0 mg*min/mL on Day 1 of Cycle 2. No veliparib was administered. |
| Measure Participants | 35 | 27 |
| Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/(mg/m²)] |
1120
(56)
|
1020
(20)
|
| Title | Phase 2: Progression-free Survival |
|---|---|
| Description | Progression-free survival (PFS) is defined as the time from the date of randomization to the date of earliest radiographic disease progression or death provided no radiographic disease progression occurred. If a participant did not have an event of disease progression and had not died on or prior to the cutoff for PFS analysis, the participant's data was censored at the date of their last disease assessment or randomization date provided participant did not have any post-baseline disease assessment. Disease assessments were performed using computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions. |
| Time Frame | From randomization up to the date the 126th PFS event was reached; Median time on follow-up was 7.3, 7.1, and 8.9 months in each treatment group respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 2 |
| Arm/Group Title | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo |
|---|---|---|---|
| Arm/Group Description | Participants in Arm A received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants in Arm B received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants in Arm C received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
| Measure Participants | 61 | 59 | 61 |
| Median (80% Confidence Interval) [months] |
5.8
|
5.7
|
5.6
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | The primary efficacy analysis in the Phase 2 portion of the study was the comparison of PFS among participants who received veliparib in combination with carboplatin and etoposide followed by veliparib maintenance monotherapy (Arm A) vs. placebo in combination with carboplatin and etoposide followed by placebo maintenance monotherapy (Arm C). Statistical significance was determined by a two-sided p-value ≤ 0.2 | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.059 |
| Comments | ||
| Method | Log Rank | |
| Comments | Two-sided log-rank test stratified by lactate dehydrogenase (LDH) level | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.665 | |
| Confidence Interval |
(2-Sided) 80% 0.503 to 0.880 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio estimate was obtained from a Cox proportional hazards model stratified by LDH level. A hazard ratio < 1 favors veliparib in combination with carboplatin and etoposide followed by veliparib maintenance monotherapy (Arm A). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints: OS (Arm A vs Arm C) PFS (Arms B vs Arm C) OS (Arm B vs Arm C) ORR (Arm A vs Arm C) ORR (Arm B vs Arm C) If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.924 |
| Comments | ||
| Method | Log Rank | |
| Comments | Two-sided log-rank test stratified by lactate dehydrogenase (LDH) level | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.979 | |
| Confidence Interval |
(2-Sided) 80% 0.744 to 1.288 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio estimate was obtained from a Cox proportional hazards model stratified by LDH level. A hazard ratio of < 1 favors veliparib in combination with carboplatin and etoposide followed by placebo maintenance monotherapy (Arm B). | |
| Title | Phase 2: Overall Survival |
|---|---|
| Description | Overall survival (OS) is defined as the time from the date of randomization to the date of death. If a participant did not die on or prior to the cut-off for OS analysis, the participant's data were censored at the date of their last known alive date, which is defined as the last date of the last survival follow-up visit, the start date of the last AE, the start date or end date of the last dose of any study drugs, the last lab and vital sign collection date, or the last disease assessment date, whichever occurred last. |
| Time Frame | From randomization until the end of study; median time on follow-up was 10.0, 8.6, and 11.7 months in each treatment group respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 2 |
| Arm/Group Title | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo |
|---|---|---|---|
| Arm/Group Description | Participants in Arm A received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants in Arm B received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants in Arm C received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
| Measure Participants | 61 | 59 | 61 |
| Median (80% Confidence Interval) [months] |
10.1
|
10.0
|
12.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints: OS (Arm A vs Arm C) PFS (Arms B vs Arm C) OS (Arm B vs Arm C) ORR (Arm A vs Arm C) ORR (Arm B vs Arm C) If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.088 |
| Comments | ||
| Method | Log Rank | |
| Comments | Two-sided log rank test stratified by LDH level. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.432 | |
| Confidence Interval |
(2-Sided) 80% 1.092 to 1.879 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio estimate was obtained from a Cox proportional hazards model stratified by LDH level. A hazard ratio of < 1 favors veliparib in combination with carboplatin and etoposide followed by veliparib maintenance monotherapy (Arm A). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints: OS (Arm A vs Arm C) PFS (Arms B vs Arm C) OS (Arm B vs Arm C) ORR (Arm A vs Arm C) ORR (Arm B vs Arm C) If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.083 |
| Comments | ||
| Method | Log Rank | |
| Comments | Two-sided log rank test stratified by LDH level. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.460 | |
| Confidence Interval |
(2-Sided) 80% 1.104 to 1.931 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio estimate was obtained from a Cox proportional hazards model stratified by LDH level. A hazard ratio of < 1 favors veliparib in combination with carboplatin and etoposide followed by placebo maintenance monotherapy (Arm B). | |
| Title | Phase 2: Objective Response Rate |
|---|---|
| Description | Objective response rate (ORR) is defined as the percentage of participants with objective response (confirmed) as assessed by the investigator using RECIST version 1.1. Objective response includes both complete response (CR) and partial response (PR). Response must be confirmed at a subsequent tumor assessment at least 28 days apart. Participants with no post-baseline confirmed response were counted as non-responders. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. No new lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and no new lesions. |
| Time Frame | Tumor assessments were performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter until disease progression; median time on follow-up was 7.3, 7.1, and 8.9 months in each group respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 2 |
| Arm/Group Title | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo |
|---|---|---|---|
| Arm/Group Description | Participants in Arm A received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants in Arm B received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants in Arm C received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. |
| Measure Participants | 61 | 59 | 61 |
| Number (80% Confidence Interval) [percentage of participants] |
77.0
1925%
|
59.3
1976.7%
|
63.9
1597.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints: OS (Arm A vs Arm C) PFS (Arms B vs Arm C) OS (Arm B vs Arm C) ORR (Arm A vs Arm C) ORR (Arm B vs Arm C) If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.115 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | Cochran-Mantel-Haenszel test stratified by LDH level. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.9 | |
| Confidence Interval |
(2-Sided) 80% 1.1 to 3.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Odds ratio was from a Cochran-Mantel-Haenszel test stratified by LDH level. An odds ratio of > 1 favors veliparib in combination with carboplatin and etoposide followed by veliparib maintenance monotherapy (Arm A). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide, Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide |
|---|---|---|
| Comments | If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints: OS (Arm A vs Arm C) PFS (Arms B vs Arm C) OS (Arm B vs Arm C) ORR (Arm A vs Arm C) ORR (Arm B vs Arm C) If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.604 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | Cochran-Mantel-Haenszel test stratified by LDH level. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.8 | |
| Confidence Interval |
(2-Sided) 80% 0.5 to 1.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Odds ratio was from a Cochran-Mantel-Haenszel test stratified by LDH level. An odds ratio of > 1 favors veliparib in combination with carboplatin and etoposide followed by placebo maintenance monotherapy (Arm B). | |
| Title | Phase 1: Number of Participants With Adverse Events |
|---|---|
| Description | The intensity of each adverse event (AE) was assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, and according to the following: Grade 1 (Mild): AE is transient and easily tolerated by the participant; Grade 2 (Moderate): AE causes the participant discomfort and interrupts the participant's usual activities; Grade 3/4 (Severe): The adverse event causes considerable interference with the participant's usual activities and may be incapacitating or life-threatening; Grade 5: Death. Serious adverse events were those that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in congenital anomaly, or persistent or significant disability/incapacity. |
| Time Frame | From first dose of any study drug to 30 days after the last dose; the median duration of treatment with veliparib across all groups in Phase 1 was 127.5 days. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in Phase 1 who received at least 1 dose of study drug. |
| Arm/Group Title | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received 80 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered intravenously (IV) on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg twice a day until disease progression or unacceptable toxicity. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID until disease progression or unacceptable toxicity. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID until disease progression or unacceptable toxicity. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 12 (14 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 12 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to Day 19 (continuous schedule) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID until disease progression or unacceptable toxicity. |
| Measure Participants | 4 | 3 | 4 | 3 | 8 | 14 | 4 |
| Any adverse event |
4
100%
|
3
100%
|
4
100%
|
3
100%
|
8
100%
|
14
100%
|
4
100%
|
| Any AE Grade 3/4 |
4
100%
|
3
100%
|
4
100%
|
3
100%
|
7
87.5%
|
14
100%
|
4
100%
|
| Any serious adverse event |
3
75%
|
1
33.3%
|
3
75%
|
2
66.7%
|
3
37.5%
|
6
42.9%
|
3
75%
|
| Any fatal adverse event |
0
0%
|
0
0%
|
1
25%
|
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
Adverse Events
| Time Frame | All-cause mortality is reported from enrollment to the end of study, maximum time on follow-up was 26 months. Treatment-emergent adverse events and serious adverse events were collected from first dose of study drug until 30 days after the last dose of study drug; Maximum duration of treatment in Phase 1 was 541 days and maximum duration of treatment in Phase 2 was 654 days. | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | All-cause mortality is reported for all participants enrolled in Phase 1 and randomized in Phase 2. Adverse events are reported for all participants who received at least 1 dose of study drug. | |||||||||||||||||||
| Arm/Group Title | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo | ||||||||||
| Arm/Group Description | Participants received 80 mg veliparib orally twice a day (BID) on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered intravenously (IV) on Day 1 at a target area under the curve (AUC) 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to 12 (14 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 12 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received 240 mg veliparib orally BID on Days -2 to Day 19 (continuous schedule) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | Participants received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles. Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | ||||||||||
All Cause Mortality |
||||||||||||||||||||
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/4 (0%) | 0/3 (0%) | 1/4 (25%) | 1/3 (33.3%) | 0/8 (0%) | 0/14 (0%) | 0/4 (0%) | 50/61 (82%) | 45/59 (76.3%) | 41/61 (67.2%) | ||||||||||
Serious Adverse Events |
||||||||||||||||||||
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/4 (75%) | 1/3 (33.3%) | 3/4 (75%) | 2/3 (66.7%) | 3/8 (37.5%) | 6/14 (42.9%) | 3/4 (75%) | 33/60 (55%) | 39/58 (67.2%) | 27/60 (45%) | ||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||
| ANAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 3/58 (5.2%) | 3 | 2/60 (3.3%) | 3 |
| FEBRILE NEUTROPENIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 5/60 (8.3%) | 5 | 7/58 (12.1%) | 7 | 3/60 (5%) | 3 |
| LEUKOPENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NEUTROPENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 4/58 (6.9%) | 5 | 2/60 (3.3%) | 2 |
| PANCYTOPENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 3 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| THROMBOCYTOPENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 6/58 (10.3%) | 9 | 2/60 (3.3%) | 2 |
| Cardiac disorders | ||||||||||||||||||||
| ACUTE MYOCARDIAL INFARCTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| ATRIAL FIBRILLATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 2/60 (3.3%) | 2 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| CARDIAC FAILURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| CARDIO-RESPIRATORY ARREST | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MYOCARDIAL INFARCTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| SINUS NODE DYSFUNCTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 2 | 0/60 (0%) | 0 |
| VENTRICULAR TACHYCARDIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Endocrine disorders | ||||||||||||||||||||
| DIABETES INSIPIDUS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| Gastrointestinal disorders | ||||||||||||||||||||
| ABDOMINAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| COLITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| DIARRHOEA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| DUODENAL ULCER PERFORATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| DYSPHAGIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| GASTRIC PERFORATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| GASTRITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| GASTROINTESTINAL INFLAMMATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| HAEMATEMESIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| ILEUS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INTESTINAL ISCHAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MOUTH HAEMORRHAGE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NAUSEA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 2 | 2/58 (3.4%) | 2 | 0/60 (0%) | 0 |
| PALATAL OEDEMA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| VOMITING | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| General disorders | ||||||||||||||||||||
| ASTHENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| CHEST PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DEATH | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| DISEASE PROGRESSION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FATIGUE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| GENERAL PHYSICAL HEALTH DETERIORATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 2 | 0/60 (0%) | 0 |
| MALAISE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NON-CARDIAC CHEST PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| OEDEMA PERIPHERAL | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 0/60 (0%) | 0 |
| PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PYREXIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 0/60 (0%) | 0 |
| SUDDEN CARDIAC DEATH | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| SUDDEN DEATH | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||||||||
| HEPATIC FAILURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Infections and infestations | ||||||||||||||||||||
| ABDOMINAL SEPSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| ANAL ABSCESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| BRONCHITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| CELLULITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| DEVICE RELATED INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| ENCEPHALITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| IMPLANT SITE CELLULITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 1/60 (1.7%) | 1 |
| ORCHITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PLEURAL INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PNEUMONIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 7/60 (11.7%) | 10 | 3/58 (5.2%) | 3 | 1/60 (1.7%) | 1 |
| PNEUMONIA INFLUENZAL | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PNEUMONIA LEGIONELLA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 2 |
| RESPIRATORY TRACT INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| SEPSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| SEPTIC SHOCK | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| URINARY TRACT INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 2/58 (3.4%) | 2 | 1/60 (1.7%) | 1 |
| Injury, poisoning and procedural complications | ||||||||||||||||||||
| VASCULAR PROCEDURE COMPLICATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Investigations | ||||||||||||||||||||
| PLATELET COUNT DECREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| TRANSAMINASES INCREASED | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||||||||
| DECREASED APPETITE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| DEHYDRATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| HYPOKALAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| HYPOMAGNESAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 2 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HYPONATRAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 3/58 (5.2%) | 3 | 0/60 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||
| ARTHRALGIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| BACK PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| BURSITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| FLANK PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MUSCULOSKELETAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PAIN IN EXTREMITY | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||
| CANCER PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MALIGNANT NEOPLASM PROGRESSION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 5/60 (8.3%) | 6 | 5/58 (8.6%) | 6 | 5/60 (8.3%) | 5 |
| METASTASES TO CENTRAL NERVOUS SYSTEM | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 4/58 (6.9%) | 4 | 0/60 (0%) | 0 |
| Nervous system disorders | ||||||||||||||||||||
| CEREBRAL ISCHAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DIZZINESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| HEADACHE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| ISCHAEMIC STROKE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MIGRAINE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| MOTOR DYSFUNCTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| TOXIC NEUROPATHY | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||||||||
| DEPRESSION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||||||
| ACUTE KIDNEY INJURY | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||
| ACUTE RESPIRATORY DISTRESS SYNDROME | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 2 |
| ACUTE RESPIRATORY FAILURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| ATELECTASIS | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| CHRONIC OBSTRUCTIVE PULMONARY DISEASE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DYSPNOEA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| EPISTAXIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 2 | 0/60 (0%) | 0 |
| HAEMOPTYSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PLEURAL EFFUSION | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 3/58 (5.2%) | 4 | 0/60 (0%) | 0 |
| PNEUMONIA ASPIRATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PNEUMONITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PULMONARY EMBOLISM | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 2/58 (3.4%) | 2 | 1/60 (1.7%) | 1 |
| PULMONARY HAEMORRHAGE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 2 | 0/60 (0%) | 0 |
| RESPIRATORY FAILURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Vascular disorders | ||||||||||||||||||||
| AORTITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| HAEMORRHAGE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| HYPOTENSION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| PERIPHERAL ARTERY THROMBOSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| PERIPHERAL EMBOLISM | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| SUPERIOR VENA CAVA SYNDROME | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| VENA CAVA THROMBOSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||||||||||||||
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/4 (100%) | 3/3 (100%) | 4/4 (100%) | 3/3 (100%) | 8/8 (100%) | 14/14 (100%) | 4/4 (100%) | 57/60 (95%) | 53/58 (91.4%) | 53/60 (88.3%) | ||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||
| ANAEMIA | 1/4 (25%) | 3 | 1/3 (33.3%) | 1 | 2/4 (50%) | 9 | 1/3 (33.3%) | 3 | 4/8 (50%) | 11 | 7/14 (50%) | 18 | 2/4 (50%) | 6 | 35/60 (58.3%) | 104 | 35/58 (60.3%) | 105 | 26/60 (43.3%) | 55 |
| DISSEMINATED INTRAVASCULAR COAGULATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FEBRILE NEUTROPENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 1/4 (25%) | 1 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| LEUKOPENIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 2/8 (25%) | 3 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 7/60 (11.7%) | 15 | 12/58 (20.7%) | 27 | 3/60 (5%) | 13 |
| NEUTROPENIA | 1/4 (25%) | 4 | 0/3 (0%) | 0 | 2/4 (50%) | 8 | 0/3 (0%) | 0 | 4/8 (50%) | 11 | 8/14 (57.1%) | 34 | 2/4 (50%) | 6 | 36/60 (60%) | 94 | 33/58 (56.9%) | 86 | 28/60 (46.7%) | 71 |
| THROMBOCYTOPENIA | 1/4 (25%) | 2 | 1/3 (33.3%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 3/8 (37.5%) | 6 | 5/14 (35.7%) | 16 | 1/4 (25%) | 3 | 22/60 (36.7%) | 58 | 23/58 (39.7%) | 62 | 12/60 (20%) | 22 |
| Cardiac disorders | ||||||||||||||||||||
| ATRIAL FIBRILLATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 5/58 (8.6%) | 5 | 1/60 (1.7%) | 1 |
| LEFT VENTRICULAR FAILURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PALPITATIONS | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 4 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| TACHYCARDIA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| Ear and labyrinth disorders | ||||||||||||||||||||
| EAR DISCOMFORT | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HYPOACUSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| OTOTOXICITY | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| TINNITUS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Endocrine disorders | ||||||||||||||||||||
| INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Eye disorders | ||||||||||||||||||||
| BLINDNESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DRY EYE | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| EYE IRRITATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| EYE PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| LACRIMATION INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| VITREOUS DETACHMENT | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||||||||
| ABDOMINAL DISCOMFORT | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| ABDOMINAL DISTENSION | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 2 | 1/4 (25%) | 1 | 2/60 (3.3%) | 2 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| ABDOMINAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/4 (50%) | 3 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 2/14 (14.3%) | 2 | 0/4 (0%) | 0 | 4/60 (6.7%) | 4 | 1/58 (1.7%) | 1 | 3/60 (5%) | 3 |
| ABDOMINAL PAIN UPPER | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 3/8 (37.5%) | 3 | 2/14 (14.3%) | 2 | 1/4 (25%) | 3 | 2/60 (3.3%) | 2 | 0/58 (0%) | 0 | 2/60 (3.3%) | 2 |
| ANAL INFLAMMATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| ASCITES | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| CONSTIPATION | 2/4 (50%) | 2 | 1/3 (33.3%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 3/8 (37.5%) | 4 | 3/14 (21.4%) | 4 | 0/4 (0%) | 0 | 14/60 (23.3%) | 17 | 13/58 (22.4%) | 19 | 11/60 (18.3%) | 15 |
| DIARRHOEA | 1/4 (25%) | 1 | 1/3 (33.3%) | 1 | 2/4 (50%) | 4 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 7/14 (50%) | 11 | 1/4 (25%) | 1 | 8/60 (13.3%) | 11 | 11/58 (19%) | 21 | 11/60 (18.3%) | 12 |
| DIVERTICULUM | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DRY MOUTH | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/8 (25%) | 2 | 4/14 (28.6%) | 5 | 1/4 (25%) | 1 | 1/60 (1.7%) | 1 | 3/58 (5.2%) | 4 | 0/60 (0%) | 0 |
| DYSPEPSIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/8 (25%) | 2 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 7/60 (11.7%) | 8 | 2/58 (3.4%) | 3 | 4/60 (6.7%) | 5 |
| DYSPHAGIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| ENTEROVESICAL FISTULA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| ERUCTATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 2/14 (14.3%) | 3 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FLATULENCE | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 2/14 (14.3%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 0/60 (0%) | 0 |
| GASTRITIS | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| GASTROOESOPHAGEAL REFLUX DISEASE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 2 | 2/58 (3.4%) | 2 | 3/60 (5%) | 3 |
| HAEMATOCHEZIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HAEMORRHOIDS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| LOWER GASTROINTESTINAL HAEMORRHAGE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NAUSEA | 1/4 (25%) | 1 | 2/3 (66.7%) | 4 | 2/4 (50%) | 7 | 2/3 (66.7%) | 4 | 5/8 (62.5%) | 8 | 9/14 (64.3%) | 16 | 1/4 (25%) | 1 | 29/60 (48.3%) | 57 | 23/58 (39.7%) | 47 | 21/60 (35%) | 29 |
| OESOPHAGITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 2 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| ORAL DISCOMFORT | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PROCTALGIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PROCTITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| RETCHING | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| STOMATITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/8 (12.5%) | 1 | 2/14 (14.3%) | 3 | 0/4 (0%) | 0 | 3/60 (5%) | 4 | 2/58 (3.4%) | 2 | 3/60 (5%) | 4 |
| VOMITING | 2/4 (50%) | 2 | 2/3 (66.7%) | 2 | 3/4 (75%) | 4 | 1/3 (33.3%) | 2 | 1/8 (12.5%) | 2 | 2/14 (14.3%) | 3 | 1/4 (25%) | 1 | 13/60 (21.7%) | 20 | 10/58 (17.2%) | 12 | 8/60 (13.3%) | 9 |
| General disorders | ||||||||||||||||||||
| ASTHENIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 2/14 (14.3%) | 8 | 0/4 (0%) | 0 | 9/60 (15%) | 16 | 11/58 (19%) | 26 | 2/60 (3.3%) | 3 |
| CHEST PAIN | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 2 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 3/58 (5.2%) | 3 | 2/60 (3.3%) | 2 |
| CREPITATIONS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| CRYING | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FACE OEDEMA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FATIGUE | 2/4 (50%) | 3 | 3/3 (100%) | 5 | 1/4 (25%) | 2 | 2/3 (66.7%) | 4 | 6/8 (75%) | 6 | 9/14 (64.3%) | 20 | 1/4 (25%) | 1 | 15/60 (25%) | 23 | 16/58 (27.6%) | 17 | 10/60 (16.7%) | 12 |
| FEELING ABNORMAL | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FEELING COLD | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 3 | 0/60 (0%) | 0 |
| GAIT DISTURBANCE | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| INFLUENZA LIKE ILLNESS | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/4 (25%) | 4 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 2/60 (3.3%) | 2 |
| INJECTION SITE EXTRAVASATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INJECTION SITE HAEMATOMA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INJECTION SITE PHLEBITIS | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| LOSS OF CONTROL OF LEGS | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MALAISE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 2 | 2/14 (14.3%) | 3 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 3/58 (5.2%) | 3 | 0/60 (0%) | 0 |
| MUCOSAL INFLAMMATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 2/58 (3.4%) | 2 | 3/60 (5%) | 3 |
| NECROSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NON-CARDIAC CHEST PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 2/58 (3.4%) | 2 | 4/60 (6.7%) | 4 |
| OEDEMA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 3 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| OEDEMA PERIPHERAL | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 2/14 (14.3%) | 3 | 0/4 (0%) | 0 | 2/60 (3.3%) | 3 | 6/58 (10.3%) | 7 | 5/60 (8.3%) | 5 |
| PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 4/60 (6.7%) | 4 | 3/58 (5.2%) | 3 | 3/60 (5%) | 3 |
| PYREXIA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 3/14 (21.4%) | 3 | 1/4 (25%) | 1 | 6/60 (10%) | 9 | 2/58 (3.4%) | 2 | 8/60 (13.3%) | 10 |
| SWELLING | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| SWELLING FACE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 0/60 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||||||||
| HEPATIC PAIN | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Immune system disorders | ||||||||||||||||||||
| DRUG HYPERSENSITIVITY | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Infections and infestations | ||||||||||||||||||||
| BRONCHITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 3/58 (5.2%) | 3 | 1/60 (1.7%) | 1 |
| CLOSTRIDIUM DIFFICILE COLITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| CYSTITIS | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| DEVICE RELATED INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| GASTROENTERITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NASOPHARYNGITIS | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 2/58 (3.4%) | 3 | 0/60 (0%) | 0 |
| ORAL CANDIDIASIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 2 | 4/58 (6.9%) | 4 | 0/60 (0%) | 0 |
| ORAL FUNGAL INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PNEUMONIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 5/60 (8.3%) | 5 | 0/58 (0%) | 0 | 3/60 (5%) | 3 |
| RESPIRATORY TRACT INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 1/60 (1.7%) | 1 | 3/58 (5.2%) | 3 | 0/60 (0%) | 0 |
| RHINITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 2 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 2/60 (3.3%) | 2 |
| TOOTH ABSCESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| UPPER RESPIRATORY TRACT INFECTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 2/14 (14.3%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 2/60 (3.3%) | 2 |
| URINARY TRACT INFECTION | 2/4 (50%) | 2 | 0/3 (0%) | 0 | 1/4 (25%) | 2 | 1/3 (33.3%) | 2 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 2/58 (3.4%) | 3 | 1/60 (1.7%) | 1 |
| Injury, poisoning and procedural complications | ||||||||||||||||||||
| CHEMICAL PHLEBITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FOREARM FRACTURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INFUSION RELATED REACTION | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| MUSCLE RUPTURE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MUSCLE STRAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| POST PROCEDURAL COMPLICATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PROCEDURAL HEADACHE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PROCEDURAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| SKIN ABRASION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Investigations | ||||||||||||||||||||
| ALANINE AMINOTRANSFERASE INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 1/4 (25%) | 1 | 5/60 (8.3%) | 5 | 3/58 (5.2%) | 6 | 2/60 (3.3%) | 10 |
| ASPARTATE AMINOTRANSFERASE INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 1/4 (25%) | 2 | 5/60 (8.3%) | 6 | 3/58 (5.2%) | 4 | 2/60 (3.3%) | 3 |
| BLOOD BILIRUBIN INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 2 | 2/60 (3.3%) | 2 | 0/58 (0%) | 0 | 1/60 (1.7%) | 3 |
| BLOOD CREATININE INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 4/60 (6.7%) | 4 | 1/58 (1.7%) | 1 | 2/60 (3.3%) | 2 |
| BLOOD LACTATE DEHYDROGENASE INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| GAMMA-GLUTAMYLTRANSFERASE INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| HLA MARKER STUDY POSITIVE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INTERNATIONAL NORMALISED RATIO INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| LYMPHOCYTE COUNT DECREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NEUTROPHIL COUNT DECREASED | 0/4 (0%) | 0 | 1/3 (33.3%) | 5 | 1/4 (25%) | 1 | 1/3 (33.3%) | 2 | 1/8 (12.5%) | 2 | 6/14 (42.9%) | 20 | 2/4 (50%) | 8 | 1/60 (1.7%) | 2 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PLATELET COUNT DECREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 5/14 (35.7%) | 11 | 1/4 (25%) | 3 | 1/60 (1.7%) | 2 | 1/58 (1.7%) | 6 | 0/60 (0%) | 0 |
| TRANSAMINASES INCREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| URINE OUTPUT DECREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| WEIGHT DECREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 1/3 (33.3%) | 3 | 0/8 (0%) | 0 | 5/14 (35.7%) | 13 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 2/58 (3.4%) | 2 | 7/60 (11.7%) | 11 |
| WEIGHT INCREASED | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 2/4 (50%) | 3 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 3 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| WHITE BLOOD CELL COUNT DECREASED | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 2/14 (14.3%) | 2 | 2/4 (50%) | 3 | 1/60 (1.7%) | 5 | 1/58 (1.7%) | 2 | 0/60 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||||||||
| DECREASED APPETITE | 2/4 (50%) | 3 | 2/3 (66.7%) | 4 | 3/4 (75%) | 3 | 0/3 (0%) | 0 | 3/8 (37.5%) | 5 | 7/14 (50%) | 16 | 2/4 (50%) | 2 | 17/60 (28.3%) | 20 | 12/58 (20.7%) | 14 | 14/60 (23.3%) | 16 |
| DEHYDRATION | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 3/58 (5.2%) | 3 | 1/60 (1.7%) | 1 |
| HYPERGLYCAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/8 (25%) | 2 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 6/58 (10.3%) | 6 | 6/60 (10%) | 7 |
| HYPERKALAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 2/60 (3.3%) | 2 | 2/58 (3.4%) | 2 | 3/60 (5%) | 6 |
| HYPOCALCAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 3/58 (5.2%) | 3 | 1/60 (1.7%) | 1 |
| HYPOGLYCAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| HYPOKALAEMIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 2 | 1/4 (25%) | 3 | 5/60 (8.3%) | 5 | 9/58 (15.5%) | 13 | 7/60 (11.7%) | 8 |
| HYPOMAGNESAEMIA | 1/4 (25%) | 1 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/8 (25%) | 3 | 4/14 (28.6%) | 5 | 1/4 (25%) | 1 | 10/60 (16.7%) | 24 | 7/58 (12.1%) | 9 | 9/60 (15%) | 12 |
| HYPONATRAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 3 | 1/4 (25%) | 1 | 6/60 (10%) | 8 | 7/58 (12.1%) | 7 | 4/60 (6.7%) | 5 |
| HYPOPHOSPHATAEMIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 5/60 (8.3%) | 6 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||
| ARTHRALGIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 2/8 (25%) | 3 | 1/14 (7.1%) | 4 | 0/4 (0%) | 0 | 6/60 (10%) | 8 | 2/58 (3.4%) | 6 | 0/60 (0%) | 0 |
| BACK PAIN | 2/4 (50%) | 2 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 2/3 (66.7%) | 2 | 2/8 (25%) | 3 | 6/14 (42.9%) | 6 | 0/4 (0%) | 0 | 9/60 (15%) | 11 | 7/58 (12.1%) | 7 | 9/60 (15%) | 9 |
| BONE PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 2/8 (25%) | 2 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 3/60 (5%) | 3 | 1/58 (1.7%) | 1 | 3/60 (5%) | 3 |
| COCCYDYNIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| FLANK PAIN | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 1/4 (25%) | 1 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 2/60 (3.3%) | 2 |
| GROIN PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 2/14 (14.3%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INTERVERTEBRAL DISC PROTRUSION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MUSCLE SPASMS | 0/4 (0%) | 0 | 1/3 (33.3%) | 2 | 2/4 (50%) | 2 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MUSCULAR WEAKNESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 2/58 (3.4%) | 2 | 0/60 (0%) | 0 |
| MUSCULOSKELETAL CHEST PAIN | 1/4 (25%) | 1 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 5/60 (8.3%) | 5 | 3/58 (5.2%) | 7 | 0/60 (0%) | 0 |
| MUSCULOSKELETAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 2/14 (14.3%) | 3 | 1/4 (25%) | 1 | 3/60 (5%) | 3 | 2/58 (3.4%) | 2 | 2/60 (3.3%) | 2 |
| MUSCULOSKELETAL STIFFNESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MYALGIA | 3/4 (75%) | 3 | 1/3 (33.3%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 2 | 2/14 (14.3%) | 2 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 2/58 (3.4%) | 8 | 4/60 (6.7%) | 4 |
| MYOSITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NECK PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 4 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| PAIN IN EXTREMITY | 1/4 (25%) | 1 | 2/3 (66.7%) | 2 | 2/4 (50%) | 2 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 4/14 (28.6%) | 6 | 1/4 (25%) | 1 | 1/60 (1.7%) | 2 | 4/58 (6.9%) | 4 | 2/60 (3.3%) | 2 |
| PAIN IN JAW | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| SPINAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| TENDON PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||
| CANCER PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| MALIGNANT NEOPLASM PROGRESSION | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| METASTASES TO CENTRAL NERVOUS SYSTEM | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Nervous system disorders | ||||||||||||||||||||
| ATAXIA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DISTURBANCE IN ATTENTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 2 |
| DIZZINESS | 1/4 (25%) | 2 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 4 | 3/14 (21.4%) | 6 | 2/4 (50%) | 2 | 5/60 (8.3%) | 6 | 9/58 (15.5%) | 13 | 3/60 (5%) | 4 |
| DYSARTHRIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DYSGEUSIA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 3/14 (21.4%) | 3 | 2/4 (50%) | 2 | 2/60 (3.3%) | 2 | 4/58 (6.9%) | 6 | 2/60 (3.3%) | 2 |
| HEAD DISCOMFORT | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HEADACHE | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 2/8 (25%) | 2 | 3/14 (21.4%) | 3 | 0/4 (0%) | 0 | 10/60 (16.7%) | 11 | 9/58 (15.5%) | 11 | 7/60 (11.7%) | 7 |
| MEMORY IMPAIRMENT | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| MUSCLE CONTRACTIONS INVOLUNTARY | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NEUROPATHY PERIPHERAL | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PERIPHERAL MOTOR NEUROPATHY | 2/4 (50%) | 2 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PERIPHERAL SENSORY NEUROPATHY | 2/4 (50%) | 2 | 2/3 (66.7%) | 2 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| POLYNEUROPATHY | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PRESYNCOPE | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| SOMNOLENCE | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 1/4 (25%) | 2 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| TREMOR | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| Product Issues | ||||||||||||||||||||
| DEVICE OCCLUSION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||||||||
| ANXIETY | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 2/8 (25%) | 2 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 4/58 (6.9%) | 4 | 0/60 (0%) | 0 |
| CONFUSIONAL STATE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| DELIRIUM | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 2 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| DEPRESSION | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HALLUCINATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| INSOMNIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 3/8 (37.5%) | 3 | 7/14 (50%) | 11 | 1/4 (25%) | 1 | 4/60 (6.7%) | 5 | 5/58 (8.6%) | 6 | 4/60 (6.7%) | 4 |
| RESTLESSNESS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| TENSION | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||||||
| DYSURIA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 2/60 (3.3%) | 2 |
| NOCTURIA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PNEUMATURIA | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| POST MICTURITION DRIBBLE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| TUBULOINTERSTITIAL NEPHRITIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| URINARY HESITATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| URINARY INCONTINENCE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| URINARY RETENTION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 2 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| Reproductive system and breast disorders | ||||||||||||||||||||
| PERINEAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 6 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||
| ASTHMA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| COUGH | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 2/4 (50%) | 2 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 5/14 (35.7%) | 6 | 2/4 (50%) | 2 | 6/60 (10%) | 6 | 5/58 (8.6%) | 5 | 7/60 (11.7%) | 7 |
| DYSPHONIA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 1/4 (25%) | 1 | 2/60 (3.3%) | 2 | 3/58 (5.2%) | 4 | 1/60 (1.7%) | 1 |
| DYSPNOEA | 2/4 (50%) | 4 | 1/3 (33.3%) | 1 | 1/4 (25%) | 2 | 1/3 (33.3%) | 1 | 1/8 (12.5%) | 1 | 5/14 (35.7%) | 5 | 2/4 (50%) | 2 | 12/60 (20%) | 16 | 9/58 (15.5%) | 11 | 7/60 (11.7%) | 10 |
| EPISTAXIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 1/14 (7.1%) | 1 | 1/4 (25%) | 3 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 2/60 (3.3%) | 2 |
| HAEMOPTYSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 2/58 (3.4%) | 2 | 3/60 (5%) | 3 |
| HICCUPS | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 2 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 1/60 (1.7%) | 1 |
| OROPHARYNGEAL PAIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 3/58 (5.2%) | 3 | 2/60 (3.3%) | 2 |
| PRODUCTIVE COUGH | 1/4 (25%) | 2 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 4/58 (6.9%) | 6 | 3/60 (5%) | 3 |
| PULMONARY EMBOLISM | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 3/60 (5%) | 3 | 2/58 (3.4%) | 2 | 1/60 (1.7%) | 1 |
| RHINITIS ALLERGIC | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| RHINORRHOEA | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 3/58 (5.2%) | 3 | 3/60 (5%) | 4 |
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||
| ALOPECIA | 2/4 (50%) | 2 | 1/3 (33.3%) | 1 | 2/4 (50%) | 3 | 2/3 (66.7%) | 2 | 3/8 (37.5%) | 5 | 8/14 (57.1%) | 12 | 1/4 (25%) | 3 | 22/60 (36.7%) | 27 | 17/58 (29.3%) | 19 | 18/60 (30%) | 20 |
| DRY SKIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| ECCHYMOSIS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| ECZEMA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HYPERHIDROSIS | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 3/14 (21.4%) | 4 | 1/4 (25%) | 1 | 1/60 (1.7%) | 1 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| NIGHT SWEATS | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 1/60 (1.7%) | 1 |
| PETECHIAE | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PIGMENTATION DISORDER | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| PRURITUS | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 1/58 (1.7%) | 2 | 2/60 (3.3%) | 2 |
| RASH | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 4/60 (6.7%) | 4 | 1/58 (1.7%) | 1 | 2/60 (3.3%) | 2 |
| RASH MACULAR | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/8 (12.5%) | 1 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| SKIN ULCER | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 1/58 (1.7%) | 1 | 0/60 (0%) | 0 |
| STICKY SKIN | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| Vascular disorders | ||||||||||||||||||||
| HAEMATOMA | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 1/4 (25%) | 1 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
| HOT FLUSH | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 3/58 (5.2%) | 3 | 0/60 (0%) | 0 |
| HYPERTENSION | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 4/14 (28.6%) | 6 | 0/4 (0%) | 0 | 2/60 (3.3%) | 2 | 1/58 (1.7%) | 3 | 3/60 (5%) | 3 |
| HYPOTENSION | 1/4 (25%) | 1 | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 1/14 (7.1%) | 1 | 0/4 (0%) | 0 | 1/60 (1.7%) | 1 | 5/58 (8.6%) | 5 | 2/60 (3.3%) | 2 |
| INTERMITTENT CLAUDICATION | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/8 (0%) | 0 | 0/14 (0%) | 0 | 0/4 (0%) | 0 | 0/60 (0%) | 0 | 0/58 (0%) | 0 | 0/60 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
Results Point of Contact
| Name/Title | Global Medical Services |
|---|---|
| Organization | AbbVie |
| Phone | 800-633-9110 |
| abbvieclinicaltrials@abbvie.com |
Responsible Party:
AbbVie
ClinicalTrials.gov Identifier:
NCT02289690
Other Study ID Numbers:
- M14-361
- 2014-001764-35
First Posted:
Nov 13, 2014
Last Update Posted:
May 14, 2020
Last Verified:
May 1, 2020