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A Phase 1 Study in Patients With Solid Tumors

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ClinicalTrials.gov Identifier: NCT01215916
Recruitment Status : Completed
First Posted : October 7, 2010
Results First Posted : March 15, 2019
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Solid Tumors
Interventions Drug: LY573636
Drug: Pemetrexed
Enrollment 39
Recruitment Details  
Pre-assignment Details Study planned for dose-escalation followed by dose-confirmation phase. Enrollment stopped before anyone entered dose-confirmation phase. Participant (pt) Flow presents pt disposition during dose-escalation & provide reasons for pts who discontinued treatment. All pts who received atleast 1dose of study drug were considered to have completed study.
Arm/Group Title LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day 1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4
Hide Arm/Group Description Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL and 500 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 1 and 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Period Title: Overall Study
Started 1 5 3 6 6 4 9 3 2
Received at Least 1 Dose of Either Drug 1 5 3 6 6 4 9 3 2
Completed 0 0 0 0 0 0 0 0 0
Not Completed 1 5 3 6 6 4 9 3 2
Reason Not Completed
Progressive Disease             0             2             1             2             5             4             5             3             1
Adverse Event             1             1             0             1             0             0             3             0             0
Withdrawal by Subject             0             1             1             2             0             0             1             0             0
Death             0             1             0             0             1             0             0             0             1
Physician Decision             0             0             1             1             0             0             0             0             0
Arm/Group Title LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day 1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4 Total
Hide Arm/Group Description Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL and 500 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 1 and 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met Participants received a combination of 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Total of all reporting groups
Overall Number of Baseline Participants 1 5 3 6 6 4 9 3 2 39
Hide Baseline Analysis Population Description
All enrolled participants: those who received 1 or more doses of LY573636 or pemetrexed.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1 participants 5 participants 3 participants 6 participants 6 participants 4 participants 9 participants 3 participants 2 participants 39 participants
62.63 [1]   (NA) 63.13  (11.54) 60.36  (9.39) 60.91  (10.47) 59.52  (11.00) 58.26  (6.22) 50.50  (14.55) 65.26  (5.80) 68.27  (0.07) 59.02  (11.25)
[1]
Only one participant was involved in this group, the SD is not applicable
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1 participants 5 participants 3 participants 6 participants 6 participants 4 participants 9 participants 3 participants 2 participants 39 participants
Female
1
 100.0%
5
 100.0%
1
  33.3%
4
  66.7%
4
  66.7%
4
 100.0%
5
  55.6%
2
  66.7%
0
   0.0%
26
  66.7%
Male
0
   0.0%
0
   0.0%
2
  66.7%
2
  33.3%
2
  33.3%
0
   0.0%
4
  44.4%
1
  33.3%
2
 100.0%
13
  33.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1 participants 5 participants 3 participants 6 participants 6 participants 4 participants 9 participants 3 participants 2 participants 39 participants
African
0
   0.0%
0
   0.0%
0
   0.0%
1
  16.7%
0
   0.0%
0
   0.0%
2
  22.2%
1
  33.3%
0
   0.0%
4
  10.3%
Caucasian
1
 100.0%
5
 100.0%
3
 100.0%
5
  83.3%
6
 100.0%
3
  75.0%
7
  77.8%
2
  66.7%
2
 100.0%
34
  87.2%
East Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.6%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 1 participants 5 participants 3 participants 6 participants 6 participants 4 participants 9 participants 3 participants 2 participants 39 participants
1
 100.0%
5
 100.0%
3
 100.0%
6
 100.0%
6
 100.0%
4
 100.0%
9
 100.0%
3
 100.0%
2
 100.0%
39
 100.0%
1.Primary Outcome
Title Recommended Phase 2 Dose
Hide Description Based on maximum tolerated dose (MTD) in Cycle 1: highest dose where <33% participants (pts) had dose-limiting toxicity (DLT). DLTs were adverse events (AE) possibly related to study drug or AEs that met any of National Cancer Institute's (NCI) Common Terminology Criteria for AEs (CTAE): Grade (G) 4 neutropenia lasting ≥5 days; G4 neutropenia with fever, G4 thrombocytopenia, G3 thrombocytopenia with bleeding, ≥G3 non-hematologic toxicity (except nausea/vomiting and diarrhea controlled by medication; electrolyte toxicity resolved with standard replacement treatment; alopecia; and elevated alanine aminotransferase or aspartate aminotransferase with preexisting hepatic metastasis, if agreed by investigator). Investigators, with sponsor, could declare a DLT if pt experienced increasing toxicity during treatment and it was clear that further treatment would expose pt to excessive risk. Enrollment was stopped during the dose-escalation phase, thus further dose-escalation was not explored.
Time Frame Baseline to toxicity [up to end of Cycle 1 (cycle = 21 or 28 days)]
Hide Outcome Measure Data
Hide Analysis Population Description
Enrollment was stopped during the dose-escalation phase and it was too early to assess the recommended dose for Phase 2 or to estimate the MTD, therefore zero participants were analyzed.
Arm/Group Title Pemetrexed Followed by LY573636 LY573636 Followed by Pemetrexed LY573636 and Pemetrexed on Day 1
Hide Arm/Group Description:

Pemetrexed on Day 1 and LY573636 on Day 4.

LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 micrograms per milliliter (ug/mL) up to 360 µg/mL. Intravenous dosing was completed once each 28-day cycle.

Pemetrexed: 375 milligrams per square meter (mg/m^2) to 500 mg/m^2; intravenous dosing was completed once each 28-day cycle.

Participants were pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent].

Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.

LY573636 on Day 1 and pemetrexed on Day 4.

LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 ug/mL up to 360 µg/mL. Intravenous dosing was completed once each 28-day cycle.

Pemetrexed: 375 mg/m^2 to 500 mg/m^2; intravenous dosing was completed once each 28-day cycle.

Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).

Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.

LY573636 and pemetrexed on Day 1.

LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 ug/mL up to 360 µg/mL. Intravenous dosing was completed once each 21-day cycle.

Pemetrexed: 375 mg/m^2 to 500 mg/m^2. Intravenous dosing was completed once each 21-day cycle.

Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).

Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.

Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
2.Secondary Outcome
Title Number of Participants With Clinically Significant Effects
Hide Description Clinically significant effects were defined as serious and other non-serious adverse events (AEs) regardless of causality. A summary of serious and all other non-serious AEs is located in the Reported Adverse Events module.
Time Frame Baseline to end of study (up to 1 year of treatment plus 30-day follow-up)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants: those who received 1 or more doses of LY573636 or pemetrexed.
Arm/Group Title LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day 1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4
Hide Arm/Group Description:
Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL and 500 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 1 and 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
Overall Number of Participants Analyzed 1 5 3 6 6 4 9 3 2
Measure Type: Count of Participants
Unit of Measure: Participants
Serious AEs 1 4 2 4 3 3 4 3 2
Non-Serious AEs 1 5 3 6 6 4 9 3 2
3.Secondary Outcome
Title Percentage of Participants With a Tumor Response
Hide Description Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and confirmed by repeat assessment. Complete Response (CR) was defined as the disappearance of all target lesions and the normalization of tumor marker levels for non-target lesions; Partial Response (PR) was defined as at least a 30% decrease in the sum of the longest diameter of target lesions. Percentage of participants with a tumor response = (number of participants with CR or PR/number of enrolled participants)*100.
Time Frame Baseline to progressive disease (up to 1 year of treatment plus 30-day follow-up)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants: those who received 1 or more doses of LY573636 or pemetrexed.
Arm/Group Title Pemetrexed Followed by LY573636 LY573636 Followed by Pemetrexed LY573636 and Pemetrexed on Day 1
Hide Arm/Group Description:

Pemetrexed on Day 1 and LY573636 on Day 4.

LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 micrograms per milliliter (ug/mL) up to 360 µg/mL. Intravenous dosing was completed once each 28-day cycle.

Pemetrexed: 375 milligrams per square meter (mg/m^2) to 500 mg/m^2; intravenous dosing was completed once each 28-day cycle.

Participants were pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent].

Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.

LY573636 on Day 1 and pemetrexed on Day 4.

LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 ug/mL up to 360 µg/mL. Intravenous dosing was completed once each 28-day cycle.

Pemetrexed: 375 mg/m^2 to 500 mg/m^2; intravenous dosing was completed once each 28-day cycle.

Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).

Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.

LY573636 and pemetrexed on Day 1.

LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 ug/mL up to 360 µg/mL. Intravenous dosing was completed once each 21-day cycle.

Pemetrexed: 375 mg/m^2 to 500 mg/m^2. Intravenous dosing was completed once each 21-day cycle.

Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).

Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.

Overall Number of Participants Analyzed 18 15 6
Measure Type: Number
Unit of Measure: percentage of participants
0.0 13.3 0.0
4.Secondary Outcome
Title Pharmacokinetics, Concentration Maximum (Cmax) of LY573636
Hide Description [Not Specified]
Time Frame Cycles 1 and 2 on Day 4 (prior to and at the end of LY573636 infusion, 2 and 4 hours post LY573636 infusion), Day 8 (anytime), Day 15 (anytime)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had at least 1 evaluable Cmax pharmacokinetic sample.
Arm/Group Title All Enrolled Participants
Hide Arm/Group Description:
Participants who received 1 or more doses of LY573636.
Overall Number of Participants Analyzed 37
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms per milliliter (µg/mL)
Cycle 1 Number Analyzed 37 participants
264.285
(18.465%)
Cycle 2 Number Analyzed 27 participants
225.588
(24.061%)
5.Secondary Outcome
Title Pharmacokinetics, Area Under the Curve (AUC) of LY573636
Hide Description Area under the concentration-time curve above the albumin corrected threshold (AUCalb) is provided for LY573636, which has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636.
Time Frame Cycles 1 and 2 on Day 4 (prior to and at the end of LY573636 infusion, 2 and 4 hours post LY573636 infusion), Day 8 (anytime), Day 15 (anytime)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who had at least 1 evaluable AUCalb pharmacokinetic sample.
Arm/Group Title All Enrolled Participants
Hide Arm/Group Description:
Participants who received 1 or more doses of LY573636.
Overall Number of Participants Analyzed 36
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour*micrograms per milliliter (h*µg/mL)
Cycle 1 Number Analyzed 36 participants
132.783
(265.75%)
Cycle 2 Number Analyzed 23 participants
68.813
(1840.9%)
Time Frame Baseline to end of study (up to 1 year of treatment plus 30-day follow-up)
Adverse Event Reporting Description Deaths due to progressive disease were not considered serious adverse events and are provided in the Participant Flow.
 
Arm/Group Title LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4
Hide Arm/Group Description Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL and 500 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 1 and 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met. Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
All-Cause Mortality
LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4
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   1/1 (100.00%)      4/5 (80.00%)      2/3 (66.67%)      4/6 (66.67%)      3/6 (50.00%)      3/4 (75.00%)      4/9 (44.44%)      3/3 (100.00%)      2/2 (100.00%)    
Blood and lymphatic system disorders                   
Anaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Leukopenia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Neutropenia  1  1/1 (100.00%)  2 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Thrombocytopenia  1  0/1 (0.00%)  0 2/5 (40.00%)  2 0/3 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Cardiac disorders                   
Atrial fibrillation  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Cardiac arrest  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Tachycardia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Gastrointestinal disorders                   
Abdominal pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Colonic obstruction  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Diarrhoea  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Gastrointestinal haemorrhage  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Ileus  1  1/1 (100.00%)  2 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Intestinal obstruction  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0
Lower gastrointestinal haemorrhage  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Nausea  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Small intestinal obstruction  1  0/1 (0.00%)  0 1/5 (20.00%)  2 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  2 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Upper gastrointestinal haemorrhage  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
General disorders                   
Asthenia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Malaise  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Mucosal inflammation  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Multi-organ failure  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1
Pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pyrexia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 2/4 (50.00%)  2 1/9 (11.11%)  1 2/3 (66.67%)  2 0/2 (0.00%)  0
Infections and infestations                   
Cellulitis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Clostridial infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Enterobacter sepsis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pneumonia  1  1/1 (100.00%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 2/4 (50.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Sepsis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Investigations                   
Alanine aminotransferase increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Aspartate aminotransferase increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Blood alkaline phosphatase increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  3 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hepatic enzyme increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Metabolism and nutrition disorders                   
Dehydration  1  0/1 (0.00%)  0 1/5 (20.00%)  1 1/3 (33.33%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Hyperglycaemia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypoalbuminaemia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nervous system disorders                   
Cerebrovascular accident  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Psychiatric disorders                   
Depression  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Renal and urinary disorders                   
Nephrolithiasis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Renal failure acute  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                   
Dyspnoea  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Hiccups  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypoxia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pleural effusion  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Respiratory failure  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Vascular disorders                   
Hypotension  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day1 LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1 LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4 LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4 Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4
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   1/1 (100.00%)      5/5 (100.00%)      3/3 (100.00%)      6/6 (100.00%)      6/6 (100.00%)      4/4 (100.00%)      9/9 (100.00%)      3/3 (100.00%)      2/2 (100.00%)    
Blood and lymphatic system disorders                   
Anaemia  1  1/1 (100.00%)  2 0/5 (0.00%)  0 2/3 (66.67%)  5 2/6 (33.33%)  5 2/6 (33.33%)  10 0/4 (0.00%)  0 3/9 (33.33%)  9 1/3 (33.33%)  2 0/2 (0.00%)  0
Febrile neutropenia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Iron deficiency anaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Leukopenia  1  1/1 (100.00%)  2 2/5 (40.00%)  5 1/3 (33.33%)  2 0/6 (0.00%)  0 1/6 (16.67%)  3 0/4 (0.00%)  0 3/9 (33.33%)  4 0/3 (0.00%)  0 0/2 (0.00%)  0
Lymphopenia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2
Neutropenia  1  0/1 (0.00%)  0 4/5 (80.00%)  9 1/3 (33.33%)  1 0/6 (0.00%)  0 2/6 (33.33%)  6 0/4 (0.00%)  0 2/9 (22.22%)  3 0/3 (0.00%)  0 0/2 (0.00%)  0
Thrombocytopenia  1  1/1 (100.00%)  2 2/5 (40.00%)  3 1/3 (33.33%)  1 0/6 (0.00%)  0 2/6 (33.33%)  6 0/4 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 1/2 (50.00%)  1
Cardiac disorders                   
Atrial fibrillation  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Cardiac failure  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Palpitations  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Sinus tachycardia  1  1/1 (100.00%)  2 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  5 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Tachycardia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 2/6 (33.33%)  7 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Eye disorders                   
Dry eye  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Lacrimation increased  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  5 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Gastrointestinal disorders                   
Abdominal distension  1  0/1 (0.00%)  0 1/5 (20.00%)  1 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Abdominal pain  1  1/1 (100.00%)  2 1/5 (20.00%)  1 2/3 (66.67%)  5 0/6 (0.00%)  0 2/6 (33.33%)  6 2/4 (50.00%)  4 0/9 (0.00%)  0 2/3 (66.67%)  3 1/2 (50.00%)  3
Abdominal pain lower  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Abdominal pain upper  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Abnormal faeces  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Anal inflammation  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Ascites  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  4 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Constipation  1  0/1 (0.00%)  0 2/5 (40.00%)  3 2/3 (66.67%)  5 3/6 (50.00%)  3 3/6 (50.00%)  9 0/4 (0.00%)  0 2/9 (22.22%)  4 1/3 (33.33%)  2 0/2 (0.00%)  0
Diarrhoea  1  1/1 (100.00%)  2 3/5 (60.00%)  4 2/3 (66.67%)  4 2/6 (33.33%)  4 1/6 (16.67%)  5 1/4 (25.00%)  2 2/9 (22.22%)  3 0/3 (0.00%)  0 0/2 (0.00%)  0
Dry mouth  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 1/6 (16.67%)  5 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Dyspepsia  1  0/1 (0.00%)  0 2/5 (40.00%)  3 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Dysphagia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  3 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Epigastric discomfort  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Flatulence  1  0/1 (0.00%)  0 0/5 (0.00%)  0 2/3 (66.67%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Gastritis  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Gastrooesophageal reflux disease  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  3 0/3 (0.00%)  0 0/2 (0.00%)  0
Glossitis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Haemorrhoids  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Impaired gastric emptying  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  2 0/2 (0.00%)  0
Mucous stools  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nausea  1  1/1 (100.00%)  2 3/5 (60.00%)  5 3/3 (100.00%)  3 1/6 (16.67%)  3 1/6 (16.67%)  3 2/4 (50.00%)  4 5/9 (55.56%)  7 0/3 (0.00%)  0 1/2 (50.00%)  1
Odynophagia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Oral pain  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Periproctitis  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Stomatitis  1  0/1 (0.00%)  0 2/5 (40.00%)  2 1/3 (33.33%)  2 2/6 (33.33%)  3 1/6 (16.67%)  2 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Vomiting  1  1/1 (100.00%)  2 2/5 (40.00%)  2 0/3 (0.00%)  0 1/6 (16.67%)  2 2/6 (33.33%)  2 0/4 (0.00%)  0 3/9 (33.33%)  3 0/3 (0.00%)  0 0/2 (0.00%)  0
General disorders                   
Asthenia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  2 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Axillary pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Chest pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  4 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Chills  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0
Device malfunction  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Early satiety  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  11 0/6 (0.00%)  0 1/6 (16.67%)  4 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Face oedema  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Fatigue  1  1/1 (100.00%)  2 4/5 (80.00%)  11 2/3 (66.67%)  11 4/6 (66.67%)  11 3/6 (50.00%)  8 2/4 (50.00%)  4 5/9 (55.56%)  11 1/3 (33.33%)  3 0/2 (0.00%)  0
Influenza like illness  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  5 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Injection site reaction  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Malaise  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  4 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Mucosal inflammation  1  0/1 (0.00%)  0 2/5 (40.00%)  2 1/3 (33.33%)  3 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  2 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Oedema  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 1/6 (16.67%)  3 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Oedema peripheral  1  1/1 (100.00%)  1 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 2/6 (33.33%)  7 2/4 (50.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  3 0/6 (0.00%)  0 1/6 (16.67%)  3 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Pyrexia  1  0/1 (0.00%)  0 3/5 (60.00%)  4 1/3 (33.33%)  2 1/6 (16.67%)  4 1/6 (16.67%)  1 0/4 (0.00%)  0 2/9 (22.22%)  2 1/3 (33.33%)  1 1/2 (50.00%)  1
Spinal pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hepatobiliary disorders                   
Hyperbilirubinaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  2 1/3 (33.33%)  1 0/2 (0.00%)  0
Immune system disorders                   
Seasonal allergy  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Infections and infestations                   
Device related infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Fungal infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  3 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Herpes zoster  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nasopharyngitis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Oral fungal infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Oral herpes  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Sepsis  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Sinusitis  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Upper respiratory tract infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Urinary tract infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  3 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 2/9 (22.22%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Vulvovaginal mycotic infection  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/1 (0.00%)  0 0/4 (0.00%)  0 1/4 (25.00%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/2 (0.00%)  0 0/0  0
Injury, poisoning and procedural complications                   
Laceration  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Radiation skin injury  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Investigations                   
Activated partial thromboplastin time prolonged  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  5 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Alanine aminotransferase increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 3/6 (50.00%)  10 1/4 (25.00%)  1 2/9 (22.22%)  4 0/3 (0.00%)  0 0/2 (0.00%)  0
Aspartate aminotransferase increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 2/6 (33.33%)  8 1/4 (25.00%)  1 1/9 (11.11%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Blood albumin decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 2/4 (50.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Blood alkaline phosphatase increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 3/6 (50.00%)  9 1/4 (25.00%)  3 2/9 (22.22%)  5 0/3 (0.00%)  0 1/2 (50.00%)  3
Blood phosphorus decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Blood sodium decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Creatinine renal clearance decreased  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Haemoglobin decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  5 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Heart rate increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Neutrophil count decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 2/6 (33.33%)  4 0/4 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Platelet count decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Transaminases increased  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Urine colour abnormal  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Weight increased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
White blood cell count decreased  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 1/6 (16.67%)  4 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Metabolism and nutrition disorders                   
Alkalosis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Decreased appetite  1  0/1 (0.00%)  0 2/5 (40.00%)  2 2/3 (66.67%)  10 3/6 (50.00%)  6 1/6 (16.67%)  2 1/4 (25.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Dehydration  1  1/1 (100.00%)  2 3/5 (60.00%)  3 2/3 (66.67%)  2 1/6 (16.67%)  6 2/6 (33.33%)  3 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 1/2 (50.00%)  1
Hyperglycaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 2/6 (33.33%)  7 0/6 (0.00%)  0 0/4 (0.00%)  0 4/9 (44.44%)  7 0/3 (0.00%)  0 0/2 (0.00%)  0
Hyperkalaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypoalbuminaemia  1  0/1 (0.00%)  0 1/5 (20.00%)  1 1/3 (33.33%)  13 2/6 (33.33%)  5 2/6 (33.33%)  6 0/4 (0.00%)  0 3/9 (33.33%)  5 2/3 (66.67%)  5 1/2 (50.00%)  3
Hypocalcaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  3 2/6 (33.33%)  2 0/4 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypoglycaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0
Hypokalaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 2/6 (33.33%)  4 1/6 (16.67%)  1 2/4 (50.00%)  4 3/9 (33.33%)  7 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypomagnesaemia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 2/6 (33.33%)  4 1/6 (16.67%)  2 1/4 (25.00%)  3 2/9 (22.22%)  4 0/3 (0.00%)  0 0/2 (0.00%)  0
Hyponatraemia  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 1/6 (16.67%)  3 2/6 (33.33%)  6 0/4 (0.00%)  0 2/9 (22.22%)  7 1/3 (33.33%)  3 0/2 (0.00%)  0
Hypophosphataemia  1  0/1 (0.00%)  0 2/5 (40.00%)  3 1/3 (33.33%)  1 2/6 (33.33%)  5 2/6 (33.33%)  2 0/4 (0.00%)  0 4/9 (44.44%)  8 1/3 (33.33%)  2 1/2 (50.00%)  1
Metabolic alkalosis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Musculoskeletal and connective tissue disorders                   
Arthralgia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  8 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Back pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  7 1/4 (25.00%)  3 1/9 (11.11%)  4 1/3 (33.33%)  2 0/2 (0.00%)  0
Flank pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Limb discomfort  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Muscle spasms  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  3 0/2 (0.00%)  0
Muscular weakness  1  1/1 (100.00%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Musculoskeletal chest pain  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  2 1/3 (33.33%)  2 0/2 (0.00%)  0
Musculoskeletal pain  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  4 0/3 (0.00%)  0 1/2 (50.00%)  1
Myalgia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pain in extremity  1  0/1 (0.00%)  0 0/5 (0.00%)  0 2/3 (66.67%)  5 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pain in jaw  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nervous system disorders                   
Dizziness  1  0/1 (0.00%)  0 0/5 (0.00%)  0 3/3 (100.00%)  8 0/6 (0.00%)  0 3/6 (50.00%)  3 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Dysgeusia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  3 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Headache  1  0/1 (0.00%)  0 2/5 (40.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 1/4 (25.00%)  3 2/9 (22.22%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Memory impairment  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Neuropathy peripheral  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  3 0/3 (0.00%)  0 0/2 (0.00%)  0
Paraesthesia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 1/6 (16.67%)  9 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Restless legs syndrome  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Sinus headache  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Psychiatric disorders                   
Agitation  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Anxiety  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 1/6 (16.67%)  7 1/4 (25.00%)  2 1/9 (11.11%)  2 1/3 (33.33%)  2 0/2 (0.00%)  0
Confusional state  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Depression  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  12 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0
Insomnia  1  0/1 (0.00%)  0 1/5 (20.00%)  2 2/3 (66.67%)  2 1/6 (16.67%)  3 1/6 (16.67%)  1 0/4 (0.00%)  0 2/9 (22.22%)  5 0/3 (0.00%)  0 0/2 (0.00%)  0
Mental status changes  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Renal and urinary disorders                   
Dysuria  1  0/1 (0.00%)  0 1/5 (20.00%)  1 1/3 (33.33%)  3 0/6 (0.00%)  0 1/6 (16.67%)  3 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Haematuria  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  5 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1
Micturition urgency  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nocturia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pollakiuria  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  3 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Urinary hesitation  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Urinary incontinence  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Reproductive system and breast disorders                   
Vaginal discharge  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/1 (100.00%)  3 0/4 (0.00%)  0 0/4 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  4 0/2 (0.00%)  0 0/0  0
Vaginal haemorrhage  1  1/1 (100.00%)  1 0/5 (0.00%)  0 0/1 (0.00%)  0 0/4 (0.00%)  0 0/4 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/2 (0.00%)  0 0/0  0
Vulvovaginal discomfort  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/1 (0.00%)  0 0/4 (0.00%)  0 0/4 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/2 (0.00%)  0 0/0  0
Respiratory, thoracic and mediastinal disorders                   
Aspiration  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Bronchial hyperreactivity  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Cough  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  3 2/6 (33.33%)  8 0/4 (0.00%)  0 2/9 (22.22%)  5 0/3 (0.00%)  0 0/2 (0.00%)  0
Dysphonia  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  7 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Dyspnoea  1  0/1 (0.00%)  0 0/5 (0.00%)  0 2/3 (66.67%)  3 2/6 (33.33%)  6 2/6 (33.33%)  3 2/4 (50.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Epistaxis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hiccups  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nasal congestion  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Oropharyngeal pain  1  0/1 (0.00%)  0 1/5 (20.00%)  1 0/3 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Pleural effusion  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  5 2/6 (33.33%)  10 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pneumonia aspiration  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Pulmonary oedema  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Wheezing  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Skin and subcutaneous tissue disorders                   
Alopecia  1  0/1 (0.00%)  0 2/5 (40.00%)  7 1/3 (33.33%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Dermatitis  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Dermatitis acneiform  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Dry skin  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Erythema  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Exfoliative rash  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 2/6 (33.33%)  3 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hyperhidrosis  1  0/1 (0.00%)  0 1/5 (20.00%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Night sweats  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Pruritus  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 1/6 (16.67%)  1 2/4 (50.00%)  2 1/9 (11.11%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0
Rash  1  0/1 (0.00%)  0 2/5 (40.00%)  3 0/3 (0.00%)  0 2/6 (33.33%)  3 1/6 (16.67%)  1 0/4 (0.00%)  0 1/9 (11.11%)  4 0/3 (0.00%)  0 1/2 (50.00%)  1
Rash erythematous  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Rash pruritic  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Skin hyperpigmentation  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  5 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Surgical and medical procedures                   
Abdominal hernia repair  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Nephrostomy tube placement  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Stent placement  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0
Vascular disorders                   
Deep vein thrombosis  1  0/1 (0.00%)  0 1/5 (20.00%)  7 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Flushing  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hot flush  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  3 0/6 (0.00%)  0 0/6 (0.00%)  0 1/4 (25.00%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypertension  1  0/1 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/4 (0.00%)  0 1/9 (11.11%)  5 0/3 (0.00%)  0 0/2 (0.00%)  0
Hypotension  1  0/1 (0.00%)  0 0/5 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  2 0/6 (0.00%)  0 0/4 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0
Indicat