Study for Participants With Advanced, Not Amenable to Surgery, or Metastatic Lung Cancer Comparing Treatment With Pemetrexed + Cisplatin + Enzastaurin Versus Pemetrexed + Cisplatin + Placebo

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00538681
• Collaborator: (none)
• Enrollment: 35
• Locations: 12
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is intended for participants with advanced, not amenable to surgery, or metastatic lung cancer who have not received any prior chemotherapy. The study will be conducted in 2 parts:

• Part 1 is intended to evaluate safety of pemetrexed + cisplatin + enzastaurin combination chemotherapy

• Part 2 whose main objective is to compare the efficacy of pemetrexed + cisplatin + enzastaurin versus pemetrexed + cisplatin + placebo. Participants to be included in Part 2 are those with Nonsquamous Non-Small Cell Lung Cancer (NSCLC).

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Drug: enzastaurin; Drug: pemetrexed; Drug: cisplatin; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-Blind, Placebo Controlled, Phase 2 Study of Pemetrexed and Cisplatin Plus Enzastaurin Versus Pemetrexed and Cisplatin Plus Placebo in Chemonaive Patients With Advanced, Unresectable, or Metastatic (Stage IIIB or IV) Nonsquamous Non-Small Cell Lung Cancer
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzastaurin + Pemetrexed + Cisplatin	Drug: enzastaurin; 1125 milligrams (mg) loading dose then 500 mg, oral (po), daily (QD), until disease progression; Other Names: LY317615 ; Drug: pemetrexed; 500 milligrams/square meter (mg/m²), intravenously (IV), every 21 days, for each 21-day cycle; Other Names: LY231514 Alimta ; Drug: cisplatin; 75 mg/m², IV, every 21 days, for each 21-day cycle
Placebo Comparator: Placebo + Pemetrexed + Cisplatin	Drug: pemetrexed; 500 milligrams/square meter (mg/m²), intravenously (IV), every 21 days, for each 21-day cycle; Other Names: LY231514 Alimta ; Drug: cisplatin; 75 mg/m², IV, every 21 days, for each 21-day cycle; Drug: placebo; po, QD

Outcome Measures

Primary Outcome Measures

1. Part 1: Evaluate Safety [Toxicity, Serious Adverse Events (SAEs) and Reasons for Participant's Discontinuation] [Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and 30-day follow up]

   Presented are data that evaluates safety based on toxicity using Common Terminology Criteria for Adverse Events (CTCAE v3.0), SAEs, and discontinuations due to SAEs or other non-serious adverse events (AE's) of study participants. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Event module.

2. Part 2: Compare Progression-Free Survival (PFS) Between the 2 Treatment Arms Through the Assessment of Tumor Response [Baseline to measured PD up to 5 months]

   PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause. For participants not known to have died as of the data cut-off date and who did not have objective progressive disease (PD), PFS was censored at the date of the last objective progression-free assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression or death, PFS was censored at the date of last objective progression-free assessment prior to the initiation of post discontinuation anticancer therapy. PFS was calculated and analyzed based on an alternative definition of censoring; for each participant who is not known to have died or who have had objective disease progression as of the data cut-off date, PFS was censored at the date of last prior contact. Zero participants were analyzed in this outcome as study was terminated early.

Secondary Outcome Measures

1. Part 2: To Evaluate the Safety and Toxicity Profile of Study Treatments [Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and 30-day follow-up]

   The safety and toxicity profile for Part 2 was defined as serious adverse events (SAEs) and other non-serious adverse events (AEs). A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Event module.

2. Part 2: Number of Participants With a Complete Response (CR) or Partial Response (PR) (Response Rate) [Baseline to measured progressive disease (PD) up to 5 months]

   Response rate was defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter (LD) of target lesions. Best response was confirmed by a second assessment in ≥28 days. Response rate was defined as the number of participants with best response of CR or PR divided by the total number of treated participants. Zero participants were analyzed in this outcome as study was terminated early.

3. Part 2: Overall Survival (OS) [Baseline to date of death from any cause up to 5 months]

   OS time was defined as the time from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS was censored at the last contact date (last contact for participants in post discontinuation was equal to the last known alive date in mortality status). Zero participants were analyzed in this outcome as study was terminated early.

4. Part 2: Duration of Disease Control (DDC) and Response [Baseline to measured PD up to 5 months]

   DDC and response defined as time from complete response (CR), partial response (PR) or stable disease (SD) to first date of objectively determined progressive disease (PD) or death from any cause using RECIST (v1.0) criteria. CR defined as disappearance of all target lesions. PR defined as having ≥30% decrease in sum of longest diameter (LD) of target lesions. PD defined as having ≥20% increase in the sum of the LD of target lesions. SD defined as small changes not meeting above criteria. Participants not known to have died as of data cut-off date, had no objective PD or were lost to follow-up, DCC was censored at date of last objective progression-free assessment (OPFA). Participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to objective PD or death were censored at date of last OPFA prior to initiation of post discontinuation anticancer therapy. Zero participants were analyzed in this outcome as study was terminated early.

5. Part 2: Time to Worsening of Symptoms (TWS) [Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and 30-day follow-up]

   TWS was measured from the date of study enrollment to the first date of a worsening in any of the 6 Lung Cancer Symptom Scale (LCSS) symptoms (appetite, cough, fatigue, shortness of breath, hemoptysis and pain). Participants marked each symptom on a visual analog scale (VAS) that ranged from 0 millimeter (mm) (as good as it can be/none) to 100 mm (as bad/much as it could be). TWS was also measured individually for each of the 6 symptoms independently and were also measured from the date of enrollment to the first date of worsening in pain. For both measurements, worsening was defined as a 15-mm increase from baseline in the participant-reported score for any symptom. Participants who are not known to have had a worsening TWS were censored at the date of the participant's last LCSS assessment. Zero participants were analyzed in this outcome as study was terminated early.

6. Part 2: To Assess Biomarkers of the Disease State and Their Correlation to Clinical Outcome [Baseline, Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and end of study up to 5 months]

   Presented are data that evaluates of biomarkers relevant to the study drug and the disease state of the participant's clinical outcome. Zero participants were analyzed in this outcome as study was terminated early.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• diagnosis of advanced NSCLC not amenable to curative treatment. Participants enrolling in Part 2 of the study must have the above stated diagnosis of NSCLC that is also of nonsquamous histology.

• no prior systemic therapies [chemotherapy, et cetera (etc.)] or pleurodesis with chemotherapy for this disease

• prior radiotherapy is allowed but must be completed at least 2 weeks before study enrollment and participant must be recovered from the acute toxic effects

• have a good performance status

• participant must sign an informed consent document

Exclusion Criteria:

• participant had myocardial infarction occurring less than 6 months before inclusion, uncontrolled arrhythmia, symptomatic angina pectoris, or cardiac failure not controlled by medications

• participant is unable to swallow tablets

• participant is taking a certain medicine to control seizure activity, called "enzyme inducing antiepileptic drugs" and is not able to stop taking the medicine prior to enrolling in the study

• participant is unable to interrupt aspirin and/or other anti-inflammatory agents

• participant is unwilling or unable to take vitamin supplementation (folic acid and vitamin B12) or medications to prevent side effects

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Leuven		Belgium	3000
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Gauting		Germany	82131
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	GroBhansdorf		Germany	D-22927
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hamburg		Germany	D 21075
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Heidelberg		Germany	69126
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bergamo		Italy	24128
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Catania		Italy	95100
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Padova		Italy	35128
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Trento		Italy	38100
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Otwock		Poland	05-400
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Poznan		Poland	60-569
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bucharest		Romania	022328

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9 AM - 5 PM Eastern time (UCT/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00538681
• Other Study ID Numbers: 10722; H6Q-MC-S021
• First Posted: Oct 3, 2007
• Last Update Posted: Nov 5, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Lung Neoplasms; Pemetrexed

Study Results

Participant Flow

Arm/Group Title	Part 1- Cohort 1	Part 1- Cohort 2	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 500 milligrams (mg) enzastaurin orally (po) as loading dose on Day 1 and 125 mg orally twice daily (BID) on Days 2 to 28 of 28-day cycle then 500 milligrams per square meter (mg/m²) pemetrexed intravenous (IV) followed by 75 mg/m2 cisplatin IV on Day 8 of a 28-day cycle. Cycles 2 to 6: 125 mg enzastaurin po BID Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: 1125 mg enzastaurin po as loading dose on Day 1 of a 28-day cycle and 250 mg po BID on Days 2 to 28 of 28-day cycle, then 500 mg/m2 pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycles 2 to 6: 250 mg enzastaurin po BID Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: 375 mg enzastaurin po 3 times on Day 1 as a loading dose and 250 mg po BID on Day 2 to 28 of a 28-day cycle, then 500 mg/m² IV followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Period Title: Overall Study
STARTED	9	4	11	11
Received ≥1 Dose of Any Study Drug	9	4	11	11
COMPLETED	0	0	0	0
NOT COMPLETED	9	4	11	11

Baseline Characteristics

Arm/Group Title	Part 1- Cohort 1	Part 1- Cohort 2	Part 2- Enzastaurin	Part 2- Placebo	Other	Total
Arm/Group Description	Cycle 1: 500 mg enzastaurin orally (po) as loading dose on Day 1 and 125 mg orally twice daily (BID) on Days 2 to 28 of 28-day cycle then 500 milligrams per square meter (mg/m²) pemetrexed intravenous (IV) followed by 75 mg/m2 cisplatin IV on Day 8 of a 28-day cycle. Cycles 2 to 6: 125 mg enzastaurin po BID Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: 1125 mg enzastaurin po as loading dose on Day 1 of a 28-day cycle and 250 mg po BID on Days 2 to 28 of 28-day cycle, then 500 mg/m2 pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycles 2 to 6: 250 mg enzastaurin po BID Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: 375 mg enzastaurin po 3 times on Day 1 as a loading dose and 250 mg po BID on Day 2 to 28 of a 28-day cycle, then 500 mg/m² IV followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.	500 mg/m² pemetrexed and 75 mg/m² cisplatin administered intravenously	Total of all reporting groups
Overall Participants	9	4	11	10	1	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (9.32)	61.2 (6.85)	58.6 (9.62)	59.5 (9.39)	49.1 (NA)	58.8 (8.88)
Sex: Female, Male (Count of Participants)
Female	1 11.1%	2 50%	6 54.5%	6 60%	1 100%	16 45.7%
Male	8 88.9%	2 50%	5 45.5%	4 40%	0 0%	19 54.3%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	9 100%	4 100%	11 100%	10 100%	1 100%	35 100%
Region of Enrollment (Count of Participants)
Belgium	4 44.4%	1 25%	1 9.1%	4 40%	0 0%	10 28.6%
Poland	0 0%	0 0%	4 36.4%	4 40%	1 100%	9 25.7%
Germany	5 55.6%	3 75%	6 54.5%	2 20%	0 0%	16 45.7%
Type of Carcinoma (Count of Participants)
Adenocarcinoma: Lung	7 77.8%	3 75%	1 9.1%	4 40%	0 0%	15 42.9%
Carcinoma Large Cell: Lung	1 11.1%	0 0%	3 27.3%	2 20%	0 0%	6 17.1%
Squamous Cell Carcinoma: Lung	1 11.1%	1 25%	0 0%	0 0%	0 0%	2 5.7%
Carcinoma Non-Small Cell: Lung	0 0%	0 0%	2 18.2%	1 10%	0 0%	3 8.6%
Adenocarcinoma, Bronchioalveolar	0 0%	0 0%	5 45.5%	3 30%	1 100%	9 25.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0-Fully Active	1 11.1%	1 25%	4 36.4%	3 30%	0 0%	9 25.7%
1-Ambulatory, work of a light or sedentary nature	8 88.9%	3 75%	7 63.6%	7 70%	1 100%	26 74.3%

Outcome Measures

1. Primary Outcome

Title	Part 1: Evaluate Safety [Toxicity, Serious Adverse Events (SAEs) and Reasons for Participant's Discontinuation]
Description	Presented are data that evaluates safety based on toxicity using Common Terminology Criteria for Adverse Events (CTCAE v3.0), SAEs, and discontinuations due to SAEs or other non-serious adverse events (AE's) of study participants. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Event module.
Time Frame	Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and 30-day follow up

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Part 1- Cohort 1	Part 1- Cohort 2
Arm/Group Description	Cycle 1: 500 mg enzastaurin orally (po) as loading dose on Day 1 and 125 mg orally twice daily (BID) on Days 2 to 28 of 28-day cycle then 500 milligrams per square meter (mg/m²) pemetrexed intravenous (IV) followed by 75 mg/m2 cisplatin IV on Day 8 of a 28-day cycle. Cycles 2 to 6: 125 mg enzastaurin po BID Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: 1125 mg enzastaurin po as loading dose on Day 1 of a 28-day cycle and 250 mg po BID on Days 2 to 28 of 28-day cycle, then 500 mg/m2 pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycles 2 to 6: 250 mg enzastaurin po BID Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.
Measure Participants	9	4
SAEs	5 55.6%	0 0%
AEs	9 100%	4 100%
Discontinued due to AE	1 11.1%	1 25%

2. Primary Outcome

Title	Part 2: Compare Progression-Free Survival (PFS) Between the 2 Treatment Arms Through the Assessment of Tumor Response
Description	PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause. For participants not known to have died as of the data cut-off date and who did not have objective progressive disease (PD), PFS was censored at the date of the last objective progression-free assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression or death, PFS was censored at the date of last objective progression-free assessment prior to the initiation of post discontinuation anticancer therapy. PFS was calculated and analyzed based on an alternative definition of censoring; for each participant who is not known to have died or who have had objective disease progression as of the data cut-off date, PFS was censored at the date of last prior contact. Zero participants were analyzed in this outcome as study was terminated early.
Time Frame	Baseline to measured PD up to 5 months

Outcome Measure Data

Analysis Population Description

No participant completed a full cycle of therapy and data were not collected for this Outcome Measure.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	0	0

3. Secondary Outcome

Title	Part 2: To Evaluate the Safety and Toxicity Profile of Study Treatments
Description	The safety and toxicity profile for Part 2 was defined as serious adverse events (SAEs) and other non-serious adverse events (AEs). A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Event module.
Time Frame	Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and 30-day follow-up

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose enzastaurin or placebo.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	11	10
SAEs	2 22.2%	4 100%
AEs	8 88.9%	8 200%

4. Secondary Outcome

Title	Part 2: Number of Participants With a Complete Response (CR) or Partial Response (PR) (Response Rate)
Description	Response rate was defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter (LD) of target lesions. Best response was confirmed by a second assessment in ≥28 days. Response rate was defined as the number of participants with best response of CR or PR divided by the total number of treated participants. Zero participants were analyzed in this outcome as study was terminated early.
Time Frame	Baseline to measured progressive disease (PD) up to 5 months

Outcome Measure Data

Analysis Population Description

No participant completed a full cycle of therapy and data were not collected for this Outcome Measure.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	0	0

5. Secondary Outcome

Title	Part 2: Overall Survival (OS)
Description	OS time was defined as the time from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS was censored at the last contact date (last contact for participants in post discontinuation was equal to the last known alive date in mortality status). Zero participants were analyzed in this outcome as study was terminated early.
Time Frame	Baseline to date of death from any cause up to 5 months

Outcome Measure Data

Analysis Population Description

No participant completed a full cycle of therapy and data were not collected for this Outcome Measure.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	0	0

6. Secondary Outcome

Title	Part 2: Duration of Disease Control (DDC) and Response
Description	DDC and response defined as time from complete response (CR), partial response (PR) or stable disease (SD) to first date of objectively determined progressive disease (PD) or death from any cause using RECIST (v1.0) criteria. CR defined as disappearance of all target lesions. PR defined as having ≥30% decrease in sum of longest diameter (LD) of target lesions. PD defined as having ≥20% increase in the sum of the LD of target lesions. SD defined as small changes not meeting above criteria. Participants not known to have died as of data cut-off date, had no objective PD or were lost to follow-up, DCC was censored at date of last objective progression-free assessment (OPFA). Participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to objective PD or death were censored at date of last OPFA prior to initiation of post discontinuation anticancer therapy. Zero participants were analyzed in this outcome as study was terminated early.
Time Frame	Baseline to measured PD up to 5 months

Outcome Measure Data

Analysis Population Description

No participant completed a full cycle of therapy and data were not collected for this Outcome Measure.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	0	0

7. Secondary Outcome

Title	Part 2: Time to Worsening of Symptoms (TWS)
Description	TWS was measured from the date of study enrollment to the first date of a worsening in any of the 6 Lung Cancer Symptom Scale (LCSS) symptoms (appetite, cough, fatigue, shortness of breath, hemoptysis and pain). Participants marked each symptom on a visual analog scale (VAS) that ranged from 0 millimeter (mm) (as good as it can be/none) to 100 mm (as bad/much as it could be). TWS was also measured individually for each of the 6 symptoms independently and were also measured from the date of enrollment to the first date of worsening in pain. For both measurements, worsening was defined as a 15-mm increase from baseline in the participant-reported score for any symptom. Participants who are not known to have had a worsening TWS were censored at the date of the participant's last LCSS assessment. Zero participants were analyzed in this outcome as study was terminated early.
Time Frame	Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and 30-day follow-up

Outcome Measure Data

Analysis Population Description

No participant completed a full cycle of therapy and data were not collected for this Outcome Measure.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	0	0

8. Secondary Outcome

Title	Part 2: To Assess Biomarkers of the Disease State and Their Correlation to Clinical Outcome
Description	Presented are data that evaluates of biomarkers relevant to the study drug and the disease state of the participant's clinical outcome. Zero participants were analyzed in this outcome as study was terminated early.
Time Frame	Baseline, Cycle 1 (28-day cycle), Cycles 2, 3, 4, 5, and 6 (21-day cycles) and end of study up to 5 months

Outcome Measure Data

Analysis Population Description

No participant completed a full cycle of therapy and data were not collected for this Outcome Measure.

Arm/Group Title	Part 2- Enzastaurin	Part 2- Placebo
Arm/Group Description	Cycle 1: 375 milligrams (mg) enzastaurin orally (po) 3 times on Day 1 as a loading dose and 250 mg po twice daily (BID) on Day 2 to 28 of a 28-day cycle, then 500 milligrams per square meter (mg/m²) intravenous (IV) followed by 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2 to 6: 250 mg enzastaurin po BID on Days 1 to 21 of each 21-day cycle, then 500 mg/m² pemetrexed IV followed by 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.	Cycle 1: Placebo was administered po 3 times on Day 1 and BID on Days 2 to 28 of a 28-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 8 of 28-day cycle. Cycle 2 to 6: Placebo was administered po BID on Days 1 to 21 of each 21-day cycle then 500 mg/m² pemetrexed followed by 75 mg/m² cisplatin administered IV on Day 1 of each 21-day cycle.
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	Study-specific clinical outcomes due to progressive disease (PD) were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Arm/Group Title	Part 1- Cohort 1		Part 1- Cohort 2		Part 2- Enzastaurin		Part 2- Placebo		Part 2- Pemetrexed + Cisplatin
Arm/Group Description	Cycle 1: 500 mg Enzastaurin orally as loading dose on Day 1 of a 28-day cycle and 125 mg orally twice daily, plus 500 mg/m2 pemetrexed intravenous (IV) and 75 mg/m2 cisplatin IV on Day 8 of a 28-day cycle. Cycles 2-6: 125 mg Enzastaurin orally twice daily, with 500 mg/m2 pemetrexed IV and 75 mg/m2 cisplatin IV on Day 1 of each 21-day cycle.		Cycle 1: 1125 mg Enzastaurin orally as loading dose on Day 1 of a 28-day cycle and 250 mg orally twice daily starting on Day 2, plus 500 mg/m2 pemetrexed IV and 75 mg/m2 cisplatin IV on Day 8 of a 28-day cycle. Cycles 2-6: 250 mg Enzastaurin orally twice daily, with 500 mg/m2 pemetrexed IV and 75 mg/m2 cisplatin IV on Day 1 of each 21-day cycle.		Cycle 1: 375 mg Enzastaurin orally 3 times on Day 1 of a 28-day cycle and 250 mg orally twice daily starting on Day 2, plus 500 mg/m² pemetrexed intravenously (IV) and 75 mg/m² cisplatin IV on Day 8 of a 28-day cycle. Cycle 2-6: 250 mg Enzastaurin orally twice daily on Days 1 to 21 (21-day cycles) with 500 mg/m² pemetrexed IV and 75 mg/m² cisplatin IV on day 1 of each 21-day cycle.		Cycle 1: Placebo was administered orally 3 times on Day 1 and 2 times a day on Days 2-28 (28-day cycle) plus 500 mg/m² pemetrexed IV and 75 mg/m² cisplatin IV on Day 8 of cycle (28-day cycle). Cycle 2-6: Placebo was administered orally 2 time a day on Days 1 to 21 (21-day cycles) plus 500 mg/m² pemetrexed IV and 75 mg/m² cisplatin IV on Day 1 of each 21-day cycle.		Participant was not randomized to Arm A or Arm B but received 500 mg/m² pemetrexed and 75 mg/m² cisplatin administered intravenously but not randomized
All Cause Mortality
	Part 1- Cohort 1		Part 1- Cohort 2		Part 2- Enzastaurin		Part 2- Placebo		Part 2- Pemetrexed + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1- Cohort 1		Part 1- Cohort 2		Part 2- Enzastaurin		Part 2- Placebo		Part 2- Pemetrexed + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/9 (55.6%)		0/4 (0%)		2/11 (18.2%)		4/10 (40%)		0/1 (0%)
Cardiac disorders
Pericardial effusion	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Tachyarrhythmia	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Duodenal ulcer	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Ileus paralytic	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Infections and infestations
Appendicitis	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Candidiasis	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Lung infection	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Investigations
Blood amylase increased	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Renal and urinary disorders
Haematuria	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Dyspnoea exertional	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Pleural effusion	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Pulmonary embolism	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Vascular disorders
Venous thrombosis limb	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	Part 1- Cohort 1		Part 1- Cohort 2		Part 2- Enzastaurin		Part 2- Placebo		Part 2- Pemetrexed + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		4/4 (100%)		8/11 (72.7%)		8/10 (80%)		1/1 (100%)
Blood and lymphatic system disorders
Anaemia	1/9 (11.1%)	1	0/4 (0%)	0	2/11 (18.2%)	3	0/10 (0%)	0	0/1 (0%)	0
Leukopenia	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	1/1 (100%)	2
Neutropenia	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	1/10 (10%)	1	1/1 (100%)	1
Cardiac disorders
Cardiac failure	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Ear and labyrinth disorders
Deafness	2/9 (22.2%)	2	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Tinnitus	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Eye disorders
Abnormal sensation in eye	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Dry eye	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Eyelid oedema	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Lacrimation increased	1/9 (11.1%)	1	1/4 (25%)	1	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Photopsia	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Visual disturbance	0/9 (0%)	0	2/4 (50%)	2	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Abdominal pain	1/9 (11.1%)	2	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Abdominal pain upper	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	2/10 (20%)	2	0/1 (0%)	0
Constipation	2/9 (22.2%)	2	3/4 (75%)	5	3/11 (27.3%)	3	0/10 (0%)	0	0/1 (0%)	0
Diarrhoea	1/9 (11.1%)	1	1/4 (25%)	1	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Dyspepsia	1/9 (11.1%)	1	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Dysphagia	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Faeces discoloured	2/9 (22.2%)	2	2/4 (50%)	2	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Gastritis	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Gastrooesophageal reflux disease	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Large intestinal haemorrhage	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Nausea	5/9 (55.6%)	8	3/4 (75%)	11	3/11 (27.3%)	5	5/10 (50%)	7	0/1 (0%)	0
Stomatitis	2/9 (22.2%)	2	0/4 (0%)	0	2/11 (18.2%)	2	1/10 (10%)	1	0/1 (0%)	0
Vomiting	4/9 (44.4%)	7	2/4 (50%)	4	3/11 (27.3%)	4	2/10 (20%)	3	0/1 (0%)	0
General disorders
Asthenia	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Chest pain	5/9 (55.6%)	5	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Face oedema	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Fatigue	7/9 (77.8%)	7	3/4 (75%)	3	3/11 (27.3%)	3	0/10 (0%)	0	0/1 (0%)	0
General physical health deterioration	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Local swelling	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Mucosal inflammation	1/9 (11.1%)	1	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Oedema peripheral	6/9 (66.7%)	7	1/4 (25%)	1	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Pain	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Pyrexia	0/9 (0%)	0	1/4 (25%)	1	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Infections and infestations
Bronchitis	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Candidiasis	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Nasopharyngitis	1/9 (11.1%)	1	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Rash pustular	0/9 (0%)	0	1/4 (25%)	1	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Respiratory tract infection	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Investigations
Blood creatinine increased	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Blood glucose increased	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Blood sodium decreased	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Haemoglobin	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	1/10 (10%)	1	0/1 (0%)	0
Neutrophil count	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Oxygen saturation decreased	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Platelet count decreased	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	3	0/1 (0%)	0
Urine colour abnormal	1/9 (11.1%)	1	2/4 (50%)	2	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Weight decreased	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
White blood cell count decreased	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Metabolism and nutrition disorders
Anorexia	3/9 (33.3%)	4	1/4 (25%)	1	1/11 (9.1%)	1	2/10 (20%)	2	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	2/9 (22.2%)	2	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Back pain	3/9 (33.3%)	4	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Muscle spasms	1/9 (11.1%)	1	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Musculoskeletal pain	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Myalgia	2/9 (22.2%)	2	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Nervous system disorders
Dizziness	1/9 (11.1%)	1	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Headache	1/9 (11.1%)	1	1/4 (25%)	1	2/11 (18.2%)	2	0/10 (0%)	0	0/1 (0%)	0
Hemiparesis	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Neuropathy peripheral	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Paraesthesia	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Polyneuropathy	2/9 (22.2%)	2	2/4 (50%)	2	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Psychiatric disorders
Anxiety	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Confusional state	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Dysphonia	0/9 (0%)	0	1/4 (25%)	1	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Dyspnoea	2/9 (22.2%)	2	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Dyspnoea exertional	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Epistaxis	2/9 (22.2%)	2	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Haemoptysis	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Hiccups	1/9 (11.1%)	1	0/4 (0%)	0	1/11 (9.1%)	2	0/10 (0%)	0	0/1 (0%)	0
Productive cough	1/9 (11.1%)	1	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Pulmonary embolism	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Rhinorrhoea	1/9 (11.1%)	1	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	2/9 (22.2%)	2	1/4 (25%)	1	1/11 (9.1%)	1	2/10 (20%)	2	1/1 (100%)	1
Dermatitis	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Drug eruption	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Dry skin	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Night sweats	1/9 (11.1%)	1	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Pruritus	0/9 (0%)	0	0/4 (0%)	0	1/11 (9.1%)	2	0/10 (0%)	0	0/1 (0%)	0
Rash	0/9 (0%)	0	0/4 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/1 (0%)	0
Vascular disorders
Arterial occlusive disease	0/9 (0%)	0	1/4 (25%)	1	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0
Hypertension	1/9 (11.1%)	1	0/4 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/1 (0%)	0
Phlebitis	2/9 (22.2%)	2	0/4 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/1 (0%)	0

Limitations/Caveats

This trial was terminated due to lack of efficacy demonstrated in relevant participant population in other clinical trials.

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Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.