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Clinical Trial Results:
A Randomized, Phase III, Open-Label Study of Oral Topotecan Plus Whole-Brain Radiation Therapy (WBRT) Compared with WBRT Alone in Patients with Brain Metastases from Non-Small Cell Lung Cancer.

Summary
EudraCT number	2006-002074-22
Trial protocol	HU SK
Global end of trial date	16 Aug 2013

Results information
Results version number	v1(current)
This version publication date	02 May 2016
First version publication date	26 Apr 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

UM2005/00201/00

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Aug 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Aug 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of treatment with either oral topotecan plus WBRT or WBRT alone in patients with brain metastases due to NSCLC.

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Dec 2006

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 45

Country: Number of subjects enrolled

Poland: 111

Country: Number of subjects enrolled

Russian Federation: 90

Country: Number of subjects enrolled

United States: 45

Country: Number of subjects enrolled

Hungary: 173

Country: Number of subjects enrolled

Slovakia: 8

Worldwide total number of subjects

472

EEA total number of subjects

292

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

358

From 65 to 84 years

114

85 years and over

Subject disposition

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Recruitment details

Screening details

Participants (par.) were randomly assigned to receive either topotecan capsules 1.1 mg/m2/day plus WBRT 3 Gy/day (experimental/chemoradiation arm) or WBRT alone 3 Gy/day over ten days. The randomization was stratified by the number of brain lesions and RPA Class.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemoradiation: Topotecan plus WBRT

Arm description

Participants received topotecan 1.1 milligrams per meters squared per day (mg/m2/day), orally followed approximately 2 hours later by whole-brain radiation therapy (WBRT) 3 Gray (Gy)/day to midline over the course of 10 days. After a 2-week washout period, participants completing chemoradiation and willing to participate in the Continuation Phase of the study received oral topotecan 2.3 mg/m2/day for 5 days, every 21 days, as monotherapy provided the baseline hematologic requirements were met. Monotherapy continued until disease progression or discontinuation. Chemoradiation participants choosing not to participate in the Continuation Phase may have received other chemotherapies or best supportive care, as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

1.1 mg/m2/day

Investigational medicinal product name

whole-brain radiation therapy (WBRT)

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Route of administration not applicable

Dosage and administration details

3 Gy/day

Radiation: WBRT Alone

Arm description

Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.

Arm type

Active comparator

Investigational medicinal product name

whole-brain radiation therapy (WBRT)

Investigational medicinal product code

Other name

Pharmaceutical forms

Kit for radiopharmaceutical preparation

Routes of administration

Route of administration not applicable

Dosage and administration details

3 Gy/day

Number of subjects in period 1	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Started	236	236
Completed	206	204
Not completed	30	32
Consent withdrawn by subject	12	15
Physician decision	-	1
Death	1	-
Ongoing	4	2
Investigator Decision	4	6
Lost to follow-up	7	6
Protocol deviation	2	2

Baseline characteristics

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Reporting group title

Chemoradiation: Topotecan plus WBRT

Reporting group description

Reporting group title

Radiation: WBRT Alone

Reporting group description

Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.

Reporting group values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone	Total
Number of subjects	236	236	472
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.4 ( 8.56 )	57.8 ( 8.65 )	-
Gender categorical
Units: Subjects
Female	84	78	162
Male	152	158	310
Race
Units: Subjects
African American/African Heritage (Her.)	3	1	4
Central/South Asian Heritage	1	0	1
Japanese/East Asian Heritage/South East Asian Her.	0	3	3
Native Hawaiian or other Pacific Islander	1	0	1
White	230	232	462
Asian & White	1	0	1
Race
Units: Subjects
African American/African Heritage (Her.)	3	1	4
Central/South Asian Heritage	1	0	1
Japanese/East Asian Heritage/South East Asian Her.	0	3	3
Native Hawaiian or other Pacific Islander	1	0	1
White	230	232	462
Asian & White	1	0	1

End points

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Reporting group title

Chemoradiation: Topotecan plus WBRT

Reporting group description

Reporting group title

Radiation: WBRT Alone

Reporting group description

Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.

Primary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival is defined as the time from randomization until the date of death due to any cause. The date of last contact was used for those participants who had not died or were lost to follow-up. These participants were classified as having been censored. Intent-to-Treat (ITT) Population: all randomized participants. Participants were analyzed by the treatment to which they were randomized, even if this differed from the treatment they actually received.

End point type

Primary

End point timeframe

From the time of Randomization until the date of death due to any cause (up to 195 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	236 ^[1]	236 ^[2]
Units: months
median (confidence interval 95%)	4 (3.4 to 4.8)	3.6 (3 to 4)

Notes
[1] - ITT Population
[2] - ITT Population

Anaysis 1

Comparison groups

Chemoradiation: Topotecan plus WBRT v Radiation: WBRT Alone

Number of subjects included in analysis

472

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.1862 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.07

Notes
[3] - The hazard ratio is estimated using a Pike estimator. The hazard ratio from a stratified log-rank test is adjusted for RPA class and the number of brain lesions at Screening.
[4] - p-value from a stratified log-rank test is adjusted for Recursive Partitioning Analysis (RPA) class and the number of brain lesions at Screening.

Secondary: Six-month survival

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End point title

Six-month survival

End point description

Six-month survival is defined as the percentage of participants alive at 6 months following randomization. The date of last contact was used for those participants who had not died or were lost to follow-up. These participants were classified as having been censored.

End point type

Secondary

End point timeframe

Month 6

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	236 ^[5]	236 ^[6]
Units: percentage of participants	36	28

Notes
[5] - ITT Population
[6] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with a complete response (CR) or a partial response (PR) (central nervous system [CNS]-radiologic)

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End point title

Number of participants with a complete response (CR) or a partial response (PR) (central nervous system [CNS]-radiologic)

End point description

The number of participants achieving either a CR or PR, per World Health Organization (WHO) Criteria, in the CNS was assessed. CR is defined as the complete disappearance of all known measurable (Must be accurately measured in >=1 dimension) and nonmeasurable disease, without clinical, laboratory, or radiological evidence of recurrence for at least 4 weeks. CR may have been defined in participants with measurable and/or non-measurable disease at Screening. PR is defined as at least a 50% decrease in the sum of the products of the greatest length and perpendicular width of all measurable disease with no clear increase in nonmeasurable disease in participants without measurable disease. In both cases, there must have been no appearance of new disease, and no clinical, laboratory, or radiological evidence of disease progression for at least 4 weeks. Assessment of response was performed by the investigator and was based on unconfirmed responses.

End point type

Secondary

End point timeframe

From the time of Randomization until the time of CR or PR (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	236 ^[7]	236 ^[8]
Units: participants
Complete response	23	11
Partial response	63	61

Notes
[7] - ITT Population
[8] - ITT Population

No statistical analyses for this end point

Secondary: Time to response (TTR) (CNS-radiologic)

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End point title

Time to response (TTR) (CNS-radiologic)

End point description

TTR is defined as the time from Randomization until the first documented evidence of CR or PR in the CNS. CR is defined as the complete disappearance of all known measurable (Must be accurately measured in >=1 dimension) and nonmeasurable disease, without clinical, laboratory, or radiological evidence of recurrence for at least 4 weeks. CR may have been defined in participants with measurable and/or non-measurable disease at Screening. PR is defined as at least a 50% decrease in the sum of the products of the greatest length and perpendicular width of all measurable disease with no clear increase in nonmeasurable disease in participants without measurable disease. In both cases, there must have been no appearance of new disease, and no clinical, laboratory, or radiological evidence of disease progression for at least 4 weeks. Assessment of response was performed by the investigator and was based on unconfirmed responses.

End point type

Secondary

End point timeframe

From the time of Randomization until the first documented evidence of CR or PR (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	173 ^[9]	170 ^[10]
Units: weeks
median (confidence interval 95%)	8 (7.7 to 8.1)	8.1 (6 to 8.1)

Notes
[9] - ITT Population. Only those participants with a CR, PR, or a missing response were assessed.
[10] - ITT Population. Only those participants with a CR, PR, or a missing response were assessed.

No statistical analyses for this end point

Secondary: Time to progression (TTP) (CNS-radiologic)

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End point title

Time to progression (TTP) (CNS-radiologic)

End point description

TTP is defined as the time from Randomization until the first documented sign of disease progression in the CNS. Progressive disease (PD) is defined as an increase >=25% in any measurable lesion or, in participants with non-measurable disease only, an estimation of an increase >=25%. In both cases, determination of progression included the appearance of any new lesions, or signification worsening of conditions presumed to be related to malignancy. Participants with clinical or laboratory evidence of possible disease progression were to be evaluated radiologically. TTP was analyzed with censoring for extended loss to follow-up to account for two or more missed assessments before a TTP event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

End point type

Secondary

End point timeframe

From the time of Randomization until the first documented sign of disease progression (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	236 ^[11]	236 ^[12]
Units: weeks
median (confidence interval 95%)	9.7 (8.1 to 13.9)	9.7 (8.3 to 10.9)

Notes
[11] - ITT Population
[12] - ITT Population

No statistical analyses for this end point

Secondary: Time to progression (TTP) (all sites of disease-radiologic)

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End point title

Time to progression (TTP) (all sites of disease-radiologic)

End point description

TTP is defined as the time from Randomization until the first documented sign of disease progression in all sites of disease. Progressive disease (PD) is defined as an increase >=25% in any measurable lesion or, in participants with non-measurable disease only, an estimation of an increase >=25%. In both cases, determination of progression included the appearance of any new lesions, or signification worsening of conditions presumed to be related to malignancy. Participants with clinical or laboratory evidence of possible disease progression were to be evaluated radiologically. TTP was analyzed with censoring for extended loss to follow-up to account for two or more missed assessments before a TTP event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

End point type

Secondary

End point timeframe

From the time of Randomization until the first documented sign of disease progression (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	236 ^[13]	236 ^[14]
Units: weeks
median (confidence interval 95%)	8 (6.7 to 8.7)	7.7 (6.1 to 8.1)

Notes
[13] - ITT Population
[14] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants who ranked each individual indicated neurological sign and symptom as none, mild, moderate, or severe at Months 1 and 3

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End point title

Number of participants who ranked each individual indicated neurological sign and symptom as none, mild, moderate, or severe at Months 1 and 3

End point description

Neurological signs and symptoms data were derived from a participant-reported diary. The participants were asked to assess the following signs and symptoms on a scale of none, mild, moderate, or severe at Months 1 and 3: headache, problems with balance/coordination (PB/C), leg weakness, arm weakness, loss of feeling/numbness (LofF/N), speech difficulty (SD), confusion, loss of memory (LofM), drowsiness, nausea, vomiting, dizziness, visual problems (VP), seizures, leg/ankle swelling (L/AS), heart burn, difficulty sleeping (DS), tiredness, and appetite/weight gain (A/WG). Only those participants who were assessed for the indicated sign and symptom at the indicated time point were analyzed.

End point type

Secondary

End point timeframe

Months 1 and 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	179 ^[15]	189 ^[16]
Units: participants
Headache, Month 1, none, n=179, 189	93	106
Headache, Month 1, mild, n=179, 189	71	68
Headache, Month 1, moderate, 179, 189	11	13
Headache, Month 1, severe, 179, 189	4	2
Headache, Month 3, none, n=109, 111	69	53
Headache, Month 3, mild, n=109, 111	33	41
Headache, Month 3, moderate, n=109, 111	5	14
Headache, Month 3, severe, n=109, 111	2	3
PB/C, Month 1, none, n=179, 188	84	79
PB/C, Month 1, mild, n=179, 188	66	71
PB/C, Month 1, moderate, n=179, 188	22	30
PB/C, Month 1, severe, n=179, 188	7	8
PB/C, Month 3, none, n=109, 111	69	46
PB/C, Month 3, mild, n=109, 111	28	36
PB/C, Month 3, moderate, n=109, 111	10	18
PB/C, Month 3, severe, n=109, 111	2	11
Leg weakness, Month 1, none, n=179, 188	47	59
Leg weakness, Month 1, mild, n=179, 188	73	72
Leg weakness, Month 1, moderate, n=179, 188	41	41
Leg weakness, Month 1, severe, n=179, 188	18	16
Leg weakness, Month 3, none, n=109, 111	28	34
Leg weakness, Month 3, mild, n=109, 111	51	37
Leg weakness, Month 3, moderate, n=109, 111	20	19
Leg weakness, Month 3, severe, n=109, 111	10	21
Arm weakness, Month 1, none, n=179, 188	96	97
Arm weakness, Month 1, mild, n=179, 188	55	60
Arm weakness, Month 1, moderate, n=179, 188	23	18
Arm weakness, Month 1, severe, n=179, 188	5	13
Arm weakness, Month 3, none, n=109, 111	60	53
Arm weakness, Month 3, mild, n=109, 111	39	34
Arm weakness, Month 3, molderate, n=109, 111	8	16
Arm weakness, Month 3, severe, n=109, 111	2	8
LofF/N, Month 1, none, n=179, 188	101	111
LofF/N, Month 1, mild, n=179, 188	53	43
LofF/N, Month 1, moderate, n=179, 188	17	25
LofF/N, Month 1, severe, n=179, 188	8	9
LofF/N, Month 3, none, n=109, 111	73	66
LofF/N, Month 3, mild, n=109, 111	28	27
LofF/N, Month 3, moderate, n=109, 111	3	11
LofF/N, Month 3, severe, n=109, 111	5	7
SD, Month 1, none, n=179, 188	151	137
SD, Month 1, mild, n=179, 188	16	40
SD, Month 1, moderate, n=179, 188	9	9
SD, Month 1, severe, n=179, 188	3	2
SD, Month 3, none, n=109, 110	94	78
SD, Month 3, mild, n=109, 110	11	22
SD, Month 3, moderate, n=109, 110	2	8
SD, Month 3, severe, n=109, 110	2	2
Confusion, Month 1, none, n=179, 188	150	148
Confusion, Month 1, mild, n=179, 188	20	32
Confusion, Month 1, moderate, n=179, 188	6	7
Confusion, Month 1, severe, n=179, 188	3	1
Confusion, Month 3, none, n=109, 110	99	71
Confusion, Month 3, mild, n=109, 110	7	29
Confusion, Month 3, moderate, n=109, 110	2	9
Confusion, Month 3, severe, n=109, 110	1	1
LofM, Month 1, none, n=179, 188	149	141
LofM, Month 1, mild, n=179, 188	20	41
LofM, Month 1, moderate, n=179, 188	8	5
LofM, Month 1, severe, n=179, 188	2	1
LofM, Month 3, none, n=109, 110	93	78
LofM, Month 3, mild, n=109, 110	14	25
LofM, Month 3, moderate, n=109, 110	1	6
LofM, Month 3, severe, n=109, 110	1	1
Drowsiness, Month 1, none, n=179, 188	90	96
Drowsiness, Month 1, mild, n=179, 188	55	59
Drowsiness, Month 1, moderate, n=179, 188	25	26
Drowsiness, Month 1, severe, n=179, 188	9	7
Drowsiness, Month 3, none, n=109, 111	50	44
Drowsiness, Month 3, mild, n=109, 111	42	40
Drowsiness, Month 3, moderate, n=109, 111	15	15
Drowsiness, Month 3, severe, n=109, 111	2	12
Nausea, Month 1, none, n=179, 188	125	142
Nausea, Month 1, mild, n=179, 188	38	36
Nausea, Month 1, moderate, n=179, 188	12	10
Nausea, Month 1, severe, n=179, 188	4	0
Nausea, Month 3, none, n=109, 111	70	73
Nausea, Month 3, mild, n=109, 111	31	29
Nausea, Month 3, moderate, n=109, 111	7	6
Nausea, Month 3, severe, n=109, 111	1	3
Vomiting, Month 1, none, n=179, 188	153	164
Vomiting, Month 1, mild, n=179, 188	20	19
Vomiting, Month 1, moderate, n=179, 188	4	4
Vomiting, Month 1, severe, n=179, 188	2	1
Vomiting, Month 3, none, n=109, 111	89	91
Vomiting, Month 3, mild, n=109, 111	15	15
Vomiting, Month 3, moderate, n=109, 111	4	3
Vomiting, Month 3, severe=109, 111	1	2
Dizziness, Month 1, none, n=179, 188	96	94
Dizziness, Month 1, mild, n=179, 188	58	70
Dizziness, Month 1, moderate, n=179, 188	22	21
Dizziness, Month 1, severe, n=179, 188	3	3
Dizziness, Month 3, none, n=109, 111	64	54
Dizziness, Month 3, mild, n=109, 111	35	36
Dizziness, Month 3, moderate, n=109, 111	7	14
Dizziness, Month 3, severe, n=109, 111	3	7
VP, Month 1, none, n=179, 188	103	117
VP, Month 1, mild, n=179, 188	54	53
VP, Month 1, moderate, n=179, 188	17	16
VP, Month 1, severe, n=179, 188	5	2
VP, Month 3, none, n=109, 111	72	69
VP, Month 3, mild, n=109, 111	29	28
VP, Month 3, moderate, n=109, 111	7	10
VP, Month 3, severe, n=109, 111	1	4
Seizures, Month 1, none, n=179, 188	173	179
Seizures, Month 1, mild, n=179, 188	5	7
Seizures, Month 1, moderate, n=179, 188	1	2
Seizures, Month 1, severe, n=179, 188	0	0
Seizures, Month 3, none, n=109, 110	108	102
Seizures, Month 3, mild, n=109, 110	0	4
Seizures, Month 3, moderate, n=109, 110	1	3
Seizures, Month 3, severe, n=109, 110	0	1
L/AS, Month 1, none, n=179, 188	141	138
L/AS, Month 1, mild, n=179, 188	21	29
L/AS, Month 1, moderate, n=179, 188	12	15
L/AS, Month 1, severe, n=179, 188	5	6
L/AS, Month 3, none, n=109, 111	86	85
L/AS, Month 3, mild, n=109, 111	19	19
L/AS, Month 3, moderate, n=109, 111	3	6
L/AS, Month 3, severe, n=109, 111	1	1
Heartburn, Month 1, none, n=179, 188	142	151
Heartburn, Month 1, mild, n=179, 188	26	27
Heartburn, Month 1, moderate, n=179, 188	9	9
Heartburn, Month 1, severe, n=179, 188	2	1
Heartburn, Month 3, none, n=109, 111	87	86
Heartburn, Month 3, mild, n=109, 111	16	18
Heartburn, Month 3, moderate, n=109, 111	4	6
Heartburn, Month 3, severe, n=109, 111	2	1
DS, Month 1, none, n=179, 188	112	109
DS, Month 1, mild, n=179, 188	41	48
DS, Month 1, moderate, n=179, 188	15	24
DS, Month 1, severe, n=179, 188	11	7
DS, Month 3, none, n=109, 110	78	71
DS, Month 3, mild, n=109, 110	20	23
DS, Month 3, moderate, n=109, 110	8	12
DS, Month 3, severe, n=109, 110	3	4
Tiredness, Month 1, none, n=179, 188	42	42
Tiredness, Month 1, mild, n=179, 188	75	85
Tiredness, Month 1, moderate, n=179, 188	46	44
Tiredness, Month 1, severe, n=179, 188	16	17
Tiredness, Month 3, none, n=109, 111	28	21
Tiredness, Month 3, mild, n=109, 111	52	42
Tiredness, Month 3, moderate, n=109, 111	19	32
Tiredness, Month 3, severe, n=109, 111	10	16
A/WG, Month 1, none, n=179, 188	107	113
A/WG, Month 1, mild, n=179, 188	42	41
A/WG, Month 1, moderate, n=179, 188	19	29
A/WG, Month 1, severe, n=179, 188	11	5
A/WG, Month 3, none, n=108, 111	71	73
A/WG, Month 3, mild, n=108, 111	27	23
A/WG, Month 3, moderate, n=108, 111	4	11
A/WG, Month 3, severe, n=108, 111	6	4

Notes
[15] - ITT Population
[16] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of level of consciousness at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of level of consciousness at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants for the neurological sign and symptom of level of consciousness and assigned each participant to one of the following categories: normal; somnolence or sedation not interfering with function (not intefering); somnolence or sedation interfering with function, but not activities of daily living (ADLs) (interfering); obtundation or stupor, difficult to arouse, inteferring with ADLs (obtundation or stupor); coma. If no data are presented for a particular status at a particular time point, then no participants had that status at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[17]	228 ^[18]
Units: participants
Baseline, normal, n=230, 228	219	216
Month 1, normal, n=178, 180	171	169
Month 3, normal, n=109, 107	102	92
Baseline, not interfering, n=230, 228	7	9
Month 1, not interfering, n=178, 180	5	7
Month 3, not interfering, n=109, 107	3	8
Baseline, interfering, n=230, 228	3	3
Month 1, interfering, n=178, 180	0	4
Month 3, interfering, n=109, 107	3	5
Baseline, obtundation and stupor, n=230, 228	1	0
Month 1, obtundation and stupor, n=178, 180	2	0
Month 3, obtundation and stupor, n=109, 107	1	2

Notes
[17] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[18] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of headache at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of headache at Baseline, Month 1, and Month 3

End point description

The investigator (per Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) assessed par. for headache and assigned each par. to one of the following categories:absent, Grade (G) 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade and time point, then no par. had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[19]	228 ^[20]
Units: participants
Baseline, absent, n=230, 228	141	146
Month 1, absent, n=178, 180	126	127
Month 3, absent, n=109, 107	85	74
Baseline, Grade 1, n=230, 228	62	55
Month 1, Grade 1, n=178, 180	43	38
Month 3, Grade 1, n=109, 107	17	23
Baseline, Grade 2, n=230, 228	25	23
Month 1, Grade 2, n=178, 180	9	14
Month 3, Grade 2, n=109, 107	7	10
Baseline, Grade 3, n=230, 228	2	4
Month 1, Grade 3, n=178, 180	0	1

Notes
[19] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[20] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of dizziness/lightheadedness at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of dizziness/lightheadedness at Baseline, Month 1, and Month 3

End point description

The investigator (per CTCAE, version 3.0) assessed participants for dizziness/lightheadedness and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[21]	228 ^[22]
Units: participants
Baseline, absent, n=230, 228	160	151
Month 1, absent, n=178, 180	124	128
Month 3, absent, n=109, 107	76	76
Baseline, Grade 1, n=230, 228	45	47
Month 1, Grade 1, n=178, 180	44	36
Month 3, Grade 1, n=109, 107	21	20
Baseline, Grade 2, n=230, 228	21	26
Month 1, Grade 2, n=178, 180	7	14
Month 3, Grade 2, n=109, 107	9	9
Baseline, Grade 3, n=230, 228	4	4
Month 1, Grade 3, n=178, 180	3	2
Month 3, Grade 3, n=109, 107	3	2

Notes
[21] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[22] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of vertigo at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of vertigo at Baseline, Month 1, and Month 3

End point description

The investigator (per CTCAE, version 3.0) assessed participants for vertigo and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[23]	228 ^[24]
Units: participants
Baseline, absent, n=230, 228	180	173
Month 1, absent, n=178, 180	148	150
Month 3, absent, n=109, 107	90	86
Baseline, Grade 1, n=230, 228	26	30
Month 1, Grade 1, n=178, 180	19	19
Month 3, Grade 1, n=109, 107	14	13
Baseline, Grade 2, n=230, 228	19	22
Month 1, Grade 2, n=178, 180	7	9
Month 3, Grade 2, n=109, 107	4	6
Baseline, Grade 3, n=230, 228	5	3
Month 1, Grade 3, n=178, 180	3	2
Month 3, Grade 3, n=109, 107	1	2
Month 1, Grade 4, n=178, 180	1	0

Notes
[23] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[24] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of nausea/vomiting at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of nausea/vomiting at Baseline, Month 1, and Month 3

End point description

The investigator (per CTCAE, version 3.0) assessed participants for nausea/vomiting and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[25]	228 ^[26]
Units: participants
Baseline, absent, n=230, 228	203	192
Month 1, absent, n=178, 180	151	162
Month 3, absent, n=109, 107	88	93
Baseline, Grade 1, n=230, 228	19	22
Month 1, Grade 1, n=178, 180	20	15
Month 3, Grade 1, n=109, 107	14	11
Baseline, Grade 2, n=230, 228	7	10
Month 1, Grade 2, n=178, 180	6	3
Month 3, Grade 2, n=109, 107	6	3
Baseline, Grade 3, n=230, 228	1	4
Month 1, Grade 3, n=178, 180	1	0
Month 3, Grade 5, n=109, 107	1	0

Notes
[25] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[26] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of visual problem at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of visual problem at Baseline, Month 1, and Month 3

End point description

The investigator (per CTCAE, version 3.0) assessed participants for visual problem and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[27]	228 ^[28]
Units: participants
Baseline, absent, n=230, 228	181	189
Month 1, absent, n=178, 180	148	154
Month 3, absent, n=109, 107	93	93
Baseline, Grade 1, n=230, 228	22	25
Month 1, Grade 1, n=178, 180	16	19
Month 3, Grade 1, n=109, 107	12	10
Baseline, Grade 2, n=230, 228	20	13
Month 1, Grade 2, n=178, 180	11	6
Month 3, Grade 2, n=109, 107	4	3
Baseline, Grade 3, n=230, 228	5	1
Month 1, Grade 3, n=178, 180	2	1
Month 3, Grade 3, n=109, 107	0	1
Baseline, Grade 4, n=230, 228	2	0
Month 1, Grade 4, n=178, 180	1	0

Notes
[27] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[28] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of seizure at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of seizure at Baseline, Month 1, and Month 3

End point description

The investigator (per CTCAE, version 3.0) assessed participants for seizure and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[29]	228 ^[30]
Units: participants
Baseline, absent, n=230, 228	218	216
Month 1, absent, n=178, 180	175	178
Month 3, absent, n=109, 107	109	101
Baseline, Grade 1, n=230, 228	4	6
Month 1, Grade 1, n=178, 180	2	1
Month 3, Grade 1, n=109, 107	0	4
Baseline, Grade 2, n=230, 228	6	6
Month 1, Grade 2, n=178, 180	1	1
Month 3, Grade 2, n=109, 107	0	2
Baseline, Grade 3, n=230, 228	1	0
Baseline, Grade 4, n=230, 228	1	0

Notes
[29] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[30] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of other neurological symptoms at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment for the neurological sign and symptom of other neurological symptoms at Baseline, Month 1, and Month 3

End point description

The investigator (per CTCAE, version 3.0) assessed participants for other neurological symptoms and assigned each participant to one of the following categories: absent, G 1, G 2, G 3, G 4, and G 5. Grade refers to the severity of the AE. The CTCAE displays G 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: G 1: mild, asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL; G 4: life-threatening consequences, urgent intervention indicated; G 5: death related to AE. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	229 ^[31]	228 ^[32]
Units: participants
Baseline, absent, n=229, 228	219	214
Month 1, absent, n=177, 180	165	171
Month 3, absent, n=109, 107	99	101
Baseline, Grade 1, n=229, 228	2	5
Month 1, Grade 1, n=177, 180	2	6
Month 3, Grade 1, n=109, 107	6	5
Baseline, Grade 2, n=229, 228	7	8
Month 1, Grade 2, n=177, 180	8	1
Month 3, Grade 2, n=109, 107	3	1
Baseline, Grade 3, n=229, 228	1	1
Month 1, Grade 3, n=177, 180	2	1
Month 1, Grade 4, n=177, 180	0	1
Month 3, Grade 5, n=109, 107	1	0

Notes
[31] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[32] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of cranial nerves II-XII at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of cranial nerves II-XII at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of cranial nerves II-XII and assigned each participant to one of the following categories: normal; present, not interfering with ADLs; present, interfering with ADLs; life threatening, disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	229 ^[33]	225 ^[34]
Units: participants
Baseline, normal, n=229, 225	218	211
Month 1, normal, n=177, 179	172	169
Month 3, normal, n=109, 107	106	102
Baseline, present, not interfering, n=229, 225	11	10
Month 1, present, not interfering, n=177, 179	4	6
Month 3, present, not interfering, n=109, 107	3	2
Baseline, present, interfering, n=229, 225	0	4
Month 1, present, interfering, n=177, 179	1	4
Month 3, present, interfering, n=109, 107	0	3

Notes
[33] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[34] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of language (dysphasia or aphasia) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of language (dysphasia or aphasia) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of language (dysphasia or aphasia) and assigned each participant to one of the following categories: absent; awareness of receptive or expressive aphasia, not impairing ability to communicate (not impaired); receptive or expressive dysphasia, impairing ability to communicate (impaired); inability to communicate (unable). If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[35]	228 ^[36]
Units: participants
Baseline, absent, n=230, 228	211	215
Month 1, absent, n=178, 180	169	173
Month 3, absent, n=109, 107	105	98
Baseline, not impaired, n=230, 228	15	10
Month 1, not impaired, n=178, 180	6	5
Month 3, not impaired, n=109, 107	3	7
Baseline, impaired, n=230, 228	3	3
Month 1, impaired, n=178, 180	3	2
Month 3, impaired, n=109, 107	1	0
Baseline, unable, n=230, 228	1	0
Month 3, unable, n=109, 107	0	2

Notes
[35] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[36] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of strength (right upper extremity) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of strength (right upper extremity) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of strength (right upper extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[37]	228 ^[38]
Units: participants
Baseline, normal, n=230, 228	203	195
Month 1, normal, n=178, 179	153	159
Month 3, normal, n=109, 107	93	89
Baseline, Grade 1, n=230, 228	15	16
Month 1, Grade 1, n=178, 179	13	12
Month 3, Grade 1, n=109, 107	10	10
Baseline, Grade 2, n=230, 228	6	12
Month 1, Grade 2, n=178, 179	6	5
Month 3, Grade 2, n=109, 107	4	5
Baseline, Grade 3, n=230, 228	5	5
Month 1, Grade 3, n=178, 179	4	2
Month 3, Grade 3, n=109, 107	2	3
Baseline, Grade 4, n=230, 228	1	0
Month 1, Grade 4, n=178, 179	2	1

Notes
[37] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[38] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of strength (left upper extremity) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of strength (left upper extremity) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of strength (left upper extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[39]	228 ^[40]
Units: participants
Baseline, normal, n=230, 228	197	202
Month 1, normal, n=178, 179	149	157
Month 3, normal, n=109, 107	90	86
Baseline, Grade 1, n=230, 228	16	13
Month 1, Grade 1, n=178, 179	16	13
Month 3, Grade 1, n=109, 107	10	11
Baseline, Grade 2, n=230, 228	11	8
Month 1, Grade 2, n=178, 179	8	5
Month 3, Grade 2, n=109, 107	6	5
Baseline, Grade 3, n=230, 228	6	4
Month 1, Grade 3, n=178, 179	3	2
Month 3, Grade 3, n=109, 107	3	4
Baseline, Grade 4, n=230, 228	0	1
Month 1, Grade 4, n=178, 179	2	2
Month 3, Grade 4, n=109, 107	0	1

Notes
[39] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[40] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of strength (right lower extremity) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of strength (right lower extremity) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of strength (right lower extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[41]	228 ^[42]
Units: participants
Baseline, normal, n=230, 228	196	189
Month 1, normal, n=178, 180	137	145
Month 3, normal, n=109, 107	81	80
Baseline, Grade 1, n=230, 228	20	19
Month 1, Grade 1, n=178, 180	17	15
Month 3, Grade 1, n=109, 107	12	11
Baseline, Grade 2, n=230, 228	9	16
Month 1, Grade 2, n=178, 180	11	19
Month 3, Grade 2, n=109, 107	11	11
Baseline, Grade 3, n=230, 228	3	4
Month 1, Grade 3, n=178, 180	9	0
Month 3, Grade 3, n=109, 107	4	3
Baseline, Grade 4, n=230, 228	2	0
Month 1, Grade 4, n=178, 180	4	1
Month 3, Grade 4, n=109, 107	1	2

Notes
[41] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[42] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of strength (left lower extremity) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of strength (left lower extremity) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of strength (left lower extremity) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic with weakness on physical examination; Grade 2, symptomatic and interfering with function, but not interfering with ADLs; Grade 3, symptomatic and interfering with ADLs; Grade 4: bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[43]	228 ^[44]
Units: participants
Baseline, normal, n=230, 228	182	190
Month 1, normal, n=178, 179	128	143
Month 3, normal, n=109, 107	76	73
Baseline, Grade 1, n=230, 228	28	18
Month 1, Grade 1, n=178, 179	26	13
Month 3, Grade 1, n=109, 107	11	11
Baseline, Grade 2, n=230, 228	15	15
Month 1, Grade 2, n=178, 179	11	17
Month 3, Grade 2, n=109, 107	14	14
Baseline, Grade 3, n=230, 228	4	3
Month 1, Grade 3, n=178, 179	10	4
Month 3, Grade 3, n=109, 107	6	5
Baseline, Grade 4, n=230, 228	1	2
Month 1, Grade 4, n=178, 179	3	2
Month 3, Grade 4, n=109, 107	2	4

Notes
[43] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[44] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of sensation at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of sensation at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of sensation and assigned each participant to one of the following categories: normal; loss of deep tendon reflexes or paresthesia, but not interfering with function (not interfering with function); objective sensory loss or paresthesia interfering with function, but not interfering with ADLs (interfering with function); sensory loss or paresthesia interfering with ADLs (intefering with ADLs); permanent sensory loss that interferes with function (permanent sensory loss). If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[45]	228 ^[46]
Units: participants
Baseline (BL), normal, n=230, 228	197	192
Month (M) 1, normal, n=178, 180	144	159
Month 3, normal, n=109, 107	100	94
BL, not interfering with function, n=230, 228	26	26
M 1, not interfering with function, n=178, 180	22	15
M 3, not interfering with function, n=109, 107	5	9
BL, interfering with function, n=230, 228	3	6
M 1, interfering with function, n=178, 180	7	4
M 3, interfering with function, n=109, 107	2	2
Baseline, interfering with ADLs, n=230, 228	4	3
Month 1, interfering with ADLs, n=178, 180	5	2
Month 3, interfering with ADLs, n=109, 107	2	2
Baseline, permanent sensory loss, n=230, 228	0	1

Notes
[45] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[46] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of ataxia (right upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of ataxia (right upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of ataxia (right upper extremity: finger to nose testing) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	229 ^[47]	228 ^[48]
Units: participants
Baseline, normal, n=229, 228	206	198
Month 1, normal, n=178, 179	166	166
Month 3, normal, n=109, 107	103	95
Baseline, Grade 1, n=229, 228	13	17
Month 1, Grade 1, n=178, 179	7	6
Month 3, Grade 1, n=109, 107	6	5
Baseline, Grade 2, n=229, 228	5	12
Month 1, Grade 2, n=178, 179	3	6
Month 3, Grade 2, n=109, 107	0	5
Baseline, Grade 3, n=229, 228	3	1
Month 3, Grade 3, n=109, 107	0	1
Baseline, Grade 4, n=229, 228	2	0
Month 1, Grade 4, n=178, 179	2	1
Month 3, Grade 4, n=109, 107	0	1

Notes
[47] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[48] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of ataxia (left upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of ataxia (left upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of ataxia (left upper extremity: finger to nose testing) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[49]	227 ^[50]
Units: participants
Baseline, normal, n=230, 227	199	201
Month 1, normal, n=178, 178	156	162
Month 3, normal, n=109, 107	97	94
Baseline, Grade 1, n=230, 227	15	13
Month 1, Grade 1, n=178, 178	14	9
Month 3, Grade 1, n=109, 107	10	6
Baseline, Grade 2, n=230, 227	8	7
Month 1, Grade 2, n=178, 178	6	3
Month 3, Grade 2, n=109, 107	2	3
Baseline, Grade 3, n=230, 227	8	4
Month 1, Grade 3, n=178, 178	0	3
Month 3, Grade 3, n=109, 107	0	1
Baseline, Grade 4, n=230, 227	0	2
Month 1, Grade 4, n=178, 178	2	1
Month 3, Grade 4, n=109, 107	0	3

Notes
[49] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[50] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of ataxia (gait) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of ataxia (gait) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of ataxia (gait) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[51]	227 ^[52]
Units: participants
Baseline, normal, n=230, 227	172	178
Month 1, normal, n=178, 179	138	147
Month 3, normal, n=108, 107	85	76
Baseline, Grade 1, n=230, 227	13	22
Month 1, Grade 1, n=178, 179	16	13
Month 3, Grade 1, n=108, 107	9	10
Baseline, Grade 2, n=230, 227	37	20
Month 1, Grade 2, n=178, 179	14	14
Month 3, Grade 2, n=108, 107	9	12
Baseline, Grade 3, n=230, 227	6	6
Month 1, Grade 3, n=178, 179	7	3
Month 3, Grade 3, n=108, 107	4	5
Baseline, Grade 4, n=230, 227	2	1
Month 1, Grade 4, n=178, 179	3	2
Month 3, Grade 4, n=108, 107	1	4

Notes
[51] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[52] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated investigator assessment of ataxia (balance) at Baseline, Month 1, and Month 3

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End point title

Number of participants with the indicated investigator assessment of ataxia (balance) at Baseline, Month 1, and Month 3

End point description

The investigator assessed participants' status of ataxia (balance) and assigned each participant to one of the following categories: normal; Grade 1, asymptomatic but abnormal on physical examination, and not interfering with function; Grade 2, mild symptoms interfering with function, but not interfering with ADLs; Grade 3, moderate symptoms interfering with ADLs; Grade 4, bedridden or disabling. If no data are presented for a particular grade at a particular time point, then no participants had an event of that grade at that time point.

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	230 ^[53]	228 ^[54]
Units: participants
Baseline, normal, n=230, 228	153	152
Month 1, normal, n=178, 178	131	128
Month 3, normal, n=108, 107	78	75
Baseline, Grade 1, n=230, 228	37	44
Month 1, Grade 1, n=178, 178	23	28
Month 3, Grade 1, n=108, 107	17	13
Baseline, Grade 2, n=230, 228	27	23
Month 1, Grade 2, n=178, 178	13	16
Month 3, Grade 2, n=108, 107	8	9
Baseline, Grade 3, n=230, 228	10	7
Month 1, Grade 3, n=178, 178	8	5
Month 3, Grade 3, n=108, 107	4	5
Baseline, Grade 4, n=230, 228	3	2
Month 1, Grade 4, n=178, 178	3	1
Month 3, Grade 4, n=108, 107	1	5

Notes
[53] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.
[54] - ITT Population. Only those participants who were assessed at the indicated time point were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with any adverse event (AE; both serious and non-serious) or serious adverse event (SAE)

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End point title

Number of participants with any adverse event (AE; both serious and non-serious) or serious adverse event (SAE)

End point description

An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect. For a list of all SAEs and AEs , see the SAE/AE module of this results summary. Participants were analyzed by the actual treatment received, even if this differed from the treatment to which they were randomized.

End point type

Secondary

End point timeframe

From Randomization until the last clinic visit associated with the study, up until 35 days after the start of the last course of treatment (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	235 ^[55]	233 ^[56]
Units: participants
AE	204	148
SAE	96	43

Notes
[55] - Modified ITT Population: all randomized par. who received at least one dose of randomized therapy.
[56] - Modified ITT Population: all randomized par. who received at least one dose of randomized therapy.

No statistical analyses for this end point

Secondary: Number of participants with the indicated worst-case change from Baseline in the indicated chemistry parameters with respect to the normal range

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End point title

Number of participants with the indicated worst-case change from Baseline in the indicated chemistry parameters with respect to the normal range

End point description

The worst-case change from Baseline in chemistry parameters was measured as decrease to low (DTL), change to normal or no change (CTN/NC), or increase to high (ITH). The worst-case change value could have been measured at any point during the on-therapy period. Participants are counted twice if the participant "Decreased to Low" and "Increased to High" during the on-therapy period. Modified ITT Population. Only those participants with available laboratory values (indicated by the "n" in the category titles) were analyzed. Different participants may have been analyzed for different parameters; therefore, the overall number of participants analyzed reflects everyone in the Modified ITT Population.

End point type

Secondary

End point timeframe

From Randomization until the last clinic visit associated with the study, up until 35 days after the start of the last course of treatment (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	235 ^[57]	233 ^[58]
Units: participants
Chloride, DTL, n=169, 171	32	21
Chloride, CTN/NC, n=169, 171	116	144
Chloride, ITH, n=169, 171	22	6
Creatinine clearance, DTL, n=159, 145	26	9
Creatinine clearance, CTN/NC, n=159, 145	121	134
Creatinine clearance, ITH, n=159, 145	15	2
Lactate dehydrogenase, DTL, n=169, 168	8	1
Lactate dehydrogenase, CTN/NC, n=169, 168	117	127
Lactate dehydrogenase, ITH, n=169, 168	47	40
Total protein, DTL, n=171, 175	48	36
Total protein, CTN/NC, n=171, 175	119	137
Total protein, ITH, n=171, 175	4	2
Urea/blood urea nitrogen, DTL, n=178, 179	7	4
Urea/blood urea nitrogen, CTN/NC, n=178, 179	139	152
Urea/blood urea nitrogen, ITH, n=178, 179	33	24
Uric acid, DTL, n=159, 152	21	12
Uric acid, CTN/NC, n=159, 152	125	134
Uric acid, ITH, n=159, 152	13	6
Basophils, DTL, n=215, 211	7	1
Basophils, CTN/NC, n=215, 211	186	200
Basophils, ITH, n=215, 211	25	10
Eosinophils, DTL, n=214, 211	28	12
Eosinophils, CTN/NC, n=214, 211	182	191
Eosinophils, ITH, n=214, 211	4	8
Hematocrit, DTL, n=215, 212	98	38
Hematocrit, CTN/NC, n=215, 212	117	169
Hematocrit, ITH, n=215, 212	1	6
Monocytes, DTL, n=216, 212	84	17
Monocytes, CTN/NC, n=216, 212	119	161
Monocytes, ITH, n=216, 212	54	37
Red Blood Cell Count, DTL, n=216, 212	103	38
Red Blood Cell Count, CTN/NC, n=216, 212	113	171
Red Blood Cell Count, ITH, n=216, 212	0	4

Notes
[57] - Modified ITT Population
[58] - Modified ITT Population

No statistical analyses for this end point

Secondary: Lesion assessment and measurement

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End point title

Lesion assessment and measurement

End point description

Lesions were assessed per WHO criteria. For lesion assessment data, see the outcome measure entitled "Number of participants with a complete response (CR) or a partial response (PR) (central nervous system [CNS]-radiologic)."

End point type

Secondary

End point timeframe

From the time of Randomization until the time of CR or PR (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	0 ^[59]	0 ^[60]
Units: participants

Notes
[59] - ITT Population
[60] - ITT Population

No statistical analyses for this end point

Secondary: Brain symptoms

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End point title

Brain symptoms

End point description

Brain symptoms were assessed as the number of participants with neurological signs and symptoms. For brain symptom data, see the outcome measures entitled "Number of participants with the indicated investigator assessment for the neurological sign and symptom of X at Baseline, Month 1, and Month 3."

End point type

Secondary

End point timeframe

Baseline, Month 1, and Month 3

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	0 ^[61]	0 ^[62]
Units: participants

Notes
[61] - ITT Population
[62] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants who died or progressed

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End point title

Number of participants who died or progressed

End point description

Disease-related events were measured as the number of participants who died or progressed. Progressive disease (PD) is defined as an increase >=25% in any measurable lesion or, in participants with non-measurable disease only, an estimation of an increase >=25%. In both cases, determination of progression included the appearance of any new lesions, or signification worsening of conditions presumed to be related to malignancy. Participants with clinical or laboratory evidence of possible disease progression were to be evaluated radiologically. Data were analyzed with censoring for extended loss to follow-up to account for two or more missed assessments before an event. The date of the last adequate CNS assessment before extended loss to follow-up was used for censored participants.

End point type

Secondary

End point timeframe

From Randomization until the last clinic visit associated with the study, up until 35 days after the start of the last course of treatment (up to 75 weeks)

End point values	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Number of subjects analysed	235 ^[63]	233 ^[64]
Units: participants	179	161

Notes
[63] - mITT Population
[64] - mITT Population

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment AEs

Adverse event reporting additional description

Serious adverse events (SAEs) and non-serious AEs were collected in members of the Modified Intent-to-Treat Population, comprised of all randomized participants (par.) who received at least one dose of randomized therapy. Par. were analyzed by the actual treatment received, even if it differed from the treatment to which they were randomized.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Chemoradiation: Topotecan plus WBRT

Reporting group description

Reporting group title

Radiation: WBRT Alone

Reporting group description

Participants received WBRT 3 Gy/day for 10 days. Participants may have received other chemotherapies or best supportive care, as determined by the investigator.

Serious adverse events	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Total subjects affected by serious adverse events
subjects affected / exposed	96 / 235 (40.85%)	43 / 233 (18.45%)
number of deaths (all causes)	212	205
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Vascular disorders
Arterial thrombosis limb
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Deep vein thrombosis
subjects affected / exposed	3 / 235 (1.28%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Performance status decreased
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Fatigue
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	5 / 235 (2.13%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	5 / 235 (2.13%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	3 / 5	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 235 (0.43%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	0 / 235 (0.00%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 3
Pulmonary haemorrhage
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Aspiration
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Bronchial obstruction
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Hypoxia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Oropharyngeal pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	3 / 235 (1.28%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	3 / 235 (1.28%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Face injury
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation pneumonitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac failure acute
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Coronary artery insufficiency
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Myocardial ischaemia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pericarditis
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Syncope
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Paraplegia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	13 / 235 (5.53%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	13 / 13	0 / 0
deaths causally related to treatment / all	2 / 2	0 / 0
Pancytopenia
subjects affected / exposed	6 / 235 (2.55%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Agranulocytosis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	8 / 235 (3.40%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	8 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	16 / 235 (6.81%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	15 / 17	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	22 / 235 (9.36%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	23 / 23	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Thrombocytopenia
subjects affected / exposed	22 / 235 (9.36%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	25 / 25	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	6 / 235 (2.55%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	5 / 6	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Nausea
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Intestinal perforation
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Oesophageal stenosis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Oropharyngitis fungal
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peridiverticular abscess
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	7 / 235 (2.98%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	2 / 7	0 / 6
deaths causally related to treatment / all	1 / 3	0 / 3
Sepsis
subjects affected / exposed	4 / 235 (1.70%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	1 / 2	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	5 / 235 (2.13%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	2 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Chemoradiation: Topotecan plus WBRT	Radiation: WBRT Alone
Total subjects affected by non serious adverse events
subjects affected / exposed	192 / 235 (81.70%)	139 / 233 (59.66%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	3 / 235 (1.28%)	3 / 233 (1.29%)
occurrences all number	3	3
Tumour pain
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Non-small cell lung cancer
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	2	0
Lung neoplasm malignant
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Metastases to skin
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Vascular disorders
Hypotension
subjects affected / exposed	6 / 235 (2.55%)	0 / 233 (0.00%)
occurrences all number	7	0
Hypertension
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Flushing
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Phlebitis
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Haematoma
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Hot flush
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Orthostatic hypotension
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Thrombophlebitis superficial
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Deep vein thrombosis
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	2
General disorders and administration site conditions
Fatigue
subjects affected / exposed	39 / 235 (16.60%)	37 / 233 (15.88%)
occurrences all number	40	38
Asthenia
subjects affected / exposed	29 / 235 (12.34%)	19 / 233 (8.15%)
occurrences all number	29	21
Oedema peripheral
subjects affected / exposed	15 / 235 (6.38%)	15 / 233 (6.44%)
occurrences all number	16	16
Pyrexia
subjects affected / exposed	13 / 235 (5.53%)	5 / 233 (2.15%)
occurrences all number	14	5
Mucosal inflammation
subjects affected / exposed	7 / 235 (2.98%)	0 / 233 (0.00%)
occurrences all number	9	0
Gait disturbance
subjects affected / exposed	2 / 235 (0.85%)	4 / 233 (1.72%)
occurrences all number	2	4
Chest pain
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	3
Face oedema
subjects affected / exposed	1 / 235 (0.43%)	3 / 233 (1.29%)
occurrences all number	1	3
Pain
subjects affected / exposed	1 / 235 (0.43%)	3 / 233 (1.29%)
occurrences all number	1	3
Chills
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Non-cardiac chest pain
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Spinal pain
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Chest discomfort
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Early satiety
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Gravitational oedema
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Hyperthermia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Influenza like illness
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Local swelling
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Localised oedema
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Malaise
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Mucosal erosion
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Oedema
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Swelling
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Reproductive system and breast disorders
Epididymitis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Prostatitis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	31 / 235 (13.19%)	20 / 233 (8.58%)
occurrences all number	32	21
Cough
subjects affected / exposed	26 / 235 (11.06%)	17 / 233 (7.30%)
occurrences all number	29	18
Epistaxis
subjects affected / exposed	8 / 235 (3.40%)	2 / 233 (0.86%)
occurrences all number	9	2
Haemoptysis
subjects affected / exposed	3 / 235 (1.28%)	7 / 233 (3.00%)
occurrences all number	3	7
Oropharyngeal pain
subjects affected / exposed	5 / 235 (2.13%)	3 / 233 (1.29%)
occurrences all number	5	3
Hiccups
subjects affected / exposed	3 / 235 (1.28%)	2 / 233 (0.86%)
occurrences all number	3	2
Dyspnoea exertional
subjects affected / exposed	1 / 235 (0.43%)	3 / 233 (1.29%)
occurrences all number	1	3
Hypoxia
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	3	1
Productive cough
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	2
Dysphonia
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Lung infiltration
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Pleural effusion
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Pulmonary embolism
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Upper-airway cough syndrome
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Wheezing
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Bronchitis chronic
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Hydrothorax
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Increased upper airway secretion
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Laryngeal inflammation
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Pharyngeal inflammation
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Pneumothorax
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Pulmonary hypertension
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Rales
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Respiratory failure
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Respiratory tract congestion
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Rhinorrhoea
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	17 / 235 (7.23%)	19 / 233 (8.15%)
occurrences all number	17	20
Confusional state
subjects affected / exposed	7 / 235 (2.98%)	11 / 233 (4.72%)
occurrences all number	7	11
Anxiety
subjects affected / exposed	4 / 235 (1.70%)	1 / 233 (0.43%)
occurrences all number	4	1
Depression
subjects affected / exposed	2 / 235 (0.85%)	2 / 233 (0.86%)
occurrences all number	2	2
Mood altered
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Nervousness
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Sleep disorder
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	2
Delusion
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Depressed mood
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Disorientation
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Initial insomnia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Mental disorder
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Staring
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Investigations
Weight decreased
subjects affected / exposed	18 / 235 (7.66%)	8 / 233 (3.43%)
occurrences all number	21	8
Blood lactate dehydrogenase increased
subjects affected / exposed	3 / 235 (1.28%)	2 / 233 (0.86%)
occurrences all number	3	2
Platelet count decreased
subjects affected / exposed	4 / 235 (1.70%)	1 / 233 (0.43%)
occurrences all number	4	1
Haemoglobin decreased
subjects affected / exposed	3 / 235 (1.28%)	1 / 233 (0.43%)
occurrences all number	3	1
Alanine aminotransferase increased
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Weight increased
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Blood glucose increased
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Neutrophil count decreased
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
White blood cell count decreased
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Bacterial test positive
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Blood bilirubin increased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Blood creatinine increased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Blood magnesium increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Blood phosphorus decreased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Blood phosphorus increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Blood urea increased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Blood uric acid increased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Body temperature increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Breath sounds abnormal
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
International normalised ratio increased
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Thermal burn
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Contusion
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Incision site pain
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Overdose
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Radiation skin injury
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Skin wound
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	3 / 235 (1.28%)	2 / 233 (0.86%)
occurrences all number	3	2
Tachycardia
subjects affected / exposed	2 / 235 (0.85%)	3 / 233 (1.29%)
occurrences all number	2	3
Cardiac failure
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Palpitations
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Angina pectoris
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Cardiac failure congestive
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Sinus tachycardia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Supraventricular extrasystoles
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Nervous system disorders
Headache
subjects affected / exposed	27 / 235 (11.49%)	28 / 233 (12.02%)
occurrences all number	33	32
Dizziness
subjects affected / exposed	27 / 235 (11.49%)	19 / 233 (8.15%)
occurrences all number	29	22
Somnolence
subjects affected / exposed	14 / 235 (5.96%)	14 / 233 (6.01%)
occurrences all number	14	15
Hypoaesthesia
subjects affected / exposed	6 / 235 (2.55%)	11 / 233 (4.72%)
occurrences all number	6	12
Ataxia
subjects affected / exposed	8 / 235 (3.40%)	6 / 233 (2.58%)
occurrences all number	8	6
Coordination abnormal
subjects affected / exposed	7 / 235 (2.98%)	4 / 233 (1.72%)
occurrences all number	7	4
Tremor
subjects affected / exposed	6 / 235 (2.55%)	4 / 233 (1.72%)
occurrences all number	6	4
Paraesthesia
subjects affected / exposed	5 / 235 (2.13%)	4 / 233 (1.72%)
occurrences all number	5	4
Amnesia
subjects affected / exposed	2 / 235 (0.85%)	6 / 233 (2.58%)
occurrences all number	2	6
Dysgeusia
subjects affected / exposed	6 / 235 (2.55%)	2 / 233 (0.86%)
occurrences all number	6	2
Aphasia
subjects affected / exposed	1 / 235 (0.43%)	6 / 233 (2.58%)
occurrences all number	1	6
Balance disorder
subjects affected / exposed	0 / 235 (0.00%)	7 / 233 (3.00%)
occurrences all number	0	7
Convulsion
subjects affected / exposed	4 / 235 (1.70%)	1 / 233 (0.43%)
occurrences all number	5	2
Epilepsy
subjects affected / exposed	1 / 235 (0.43%)	3 / 233 (1.29%)
occurrences all number	1	6
Neuropathy peripheral
subjects affected / exposed	2 / 235 (0.85%)	2 / 233 (0.86%)
occurrences all number	2	2
Peripheral sensory neuropathy
subjects affected / exposed	2 / 235 (0.85%)	2 / 233 (0.86%)
occurrences all number	2	2
Speech disorder
subjects affected / exposed	1 / 235 (0.43%)	3 / 233 (1.29%)
occurrences all number	1	3
Syncope
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Brain oedema
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Convulsions local
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Hemiparesis
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Hemiplegia
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Hypersomnia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	2
Loss of consciousness
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Memory impairment
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Psychomotor hyperactivity
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Ageusia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Alcoholic seizure
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Burning sensation
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Cognitive disorder
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Dysarthria
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Facial paresis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Hypotonia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Mental impairment
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Monoplegia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Neuritis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Paresis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Partial seizures
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Peripheral motor neuropathy
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Polyneuropathy
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Sciatica
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Visual field defect
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 235 (2.98%)	1 / 233 (0.43%)
occurrences all number	7	1
Thrombocytopenia
subjects affected / exposed	5 / 235 (2.13%)	1 / 233 (0.43%)
occurrences all number	5	1
Neutropenia
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences all number	4	0
Leukopenia
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Coagulopathy
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Febrile neutropenia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Pancytopenia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	4 / 235 (1.70%)	3 / 233 (1.29%)
occurrences all number	4	3
Tinnitus
subjects affected / exposed	4 / 235 (1.70%)	0 / 233 (0.00%)
occurrences all number	4	0
Ear pain
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Ear pruritus
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Auricular swelling
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Deafness
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Hearing impaired
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Hypoacusis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Eye disorders
Vision blurred
subjects affected / exposed	4 / 235 (1.70%)	8 / 233 (3.43%)
occurrences all number	4	8
Visual acuity reduced
subjects affected / exposed	3 / 235 (1.28%)	2 / 233 (0.86%)
occurrences all number	3	2
Visual impairment
subjects affected / exposed	2 / 235 (0.85%)	2 / 233 (0.86%)
occurrences all number	2	3
Asthenopia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Blindness
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Conjunctivitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Eye inflammation
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Eye pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Myopia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Retinal vascular disorder
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	64 / 235 (27.23%)	30 / 233 (12.88%)
occurrences all number	84	32
Vomiting
subjects affected / exposed	37 / 235 (15.74%)	24 / 233 (10.30%)
occurrences all number	46	29
Dyspepsia
subjects affected / exposed	17 / 235 (7.23%)	10 / 233 (4.29%)
occurrences all number	17	11
Diarrhoea
subjects affected / exposed	19 / 235 (8.09%)	8 / 233 (3.43%)
occurrences all number	19	8
Constipation
subjects affected / exposed	8 / 235 (3.40%)	10 / 233 (4.29%)
occurrences all number	8	10
Abdominal pain
subjects affected / exposed	4 / 235 (1.70%)	6 / 233 (2.58%)
occurrences all number	5	6
Stomatitis
subjects affected / exposed	7 / 235 (2.98%)	1 / 233 (0.43%)
occurrences all number	7	1
Abdominal pain upper
subjects affected / exposed	2 / 235 (0.85%)	3 / 233 (1.29%)
occurrences all number	2	3
Dysphagia
subjects affected / exposed	2 / 235 (0.85%)	3 / 233 (1.29%)
occurrences all number	2	3
Dry mouth
subjects affected / exposed	2 / 235 (0.85%)	2 / 233 (0.86%)
occurrences all number	2	2
Abdominal distension
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	2	1
Flatulence
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	3	0
Gastrooesophageal reflux disease
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences all number	3	0
Glossodynia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	2	0
Mouth ulceration
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Rectal haemorrhage
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Abdominal discomfort
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Aphthous stomatitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Ascites
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Breath odour
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Faecal incontinence
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Faeces discoloured
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Gastritis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Gingival pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Haematochezia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Haemorrhoids
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Hyperchlorhydria
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Oesophageal pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Oral pain
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Retching
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	4 / 235 (1.70%)	1 / 233 (0.43%)
occurrences all number	4	1
Pruritus
subjects affected / exposed	5 / 235 (2.13%)	0 / 233 (0.00%)
occurrences all number	5	0
Rash
subjects affected / exposed	2 / 235 (0.85%)	3 / 233 (1.29%)
occurrences all number	2	3
Dry skin
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	2
Ecchymosis
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	2
Swelling face
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	2
Acne
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Night sweats
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Skin disorder
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Skin ulcer
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Dermatitis allergic
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Haemorrhage subcutaneous
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Increased tendency to bruise
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Petechiae
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Rash papular
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Skin exfoliation
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Alopecia
subjects affected / exposed	21 / 235 (8.94%)	17 / 233 (7.30%)
occurrences all number	21	17
Renal and urinary disorders
Haematuria
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Dysuria
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Pollakiuria
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Chromaturia
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Incontinence
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Nephrolithiasis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Proteinuria
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Urinary bladder haemorrhage
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Urinary incontinence
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Urinary retention
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Endocrine disorders
Cushingoid
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	29 / 235 (12.34%)	22 / 233 (9.44%)
occurrences all number	41	29
Pain in extremity
subjects affected / exposed	8 / 235 (3.40%)	6 / 233 (2.58%)
occurrences all number	9	6
Arthralgia
subjects affected / exposed	6 / 235 (2.55%)	6 / 233 (2.58%)
occurrences all number	6	6
Back pain
subjects affected / exposed	4 / 235 (1.70%)	4 / 233 (1.72%)
occurrences all number	4	4
Muscle spasms
subjects affected / exposed	4 / 235 (1.70%)	2 / 233 (0.86%)
occurrences all number	5	2
Musculoskeletal pain
subjects affected / exposed	4 / 235 (1.70%)	1 / 233 (0.43%)
occurrences all number	4	1
Myalgia
subjects affected / exposed	2 / 235 (0.85%)	2 / 233 (0.86%)
occurrences all number	2	2
Joint swelling
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Neck pain
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Bone pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Extremity contracture
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Groin pain
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Muscle atrophy
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Osteoarthritis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	3 / 235 (1.28%)	4 / 233 (1.72%)
occurrences all number	4	4
Oral candidiasis
subjects affected / exposed	5 / 235 (2.13%)	2 / 233 (0.86%)
occurrences all number	5	2
Candidiasis
subjects affected / exposed	3 / 235 (1.28%)	2 / 233 (0.86%)
occurrences all number	3	2
Oral fungal infection
subjects affected / exposed	2 / 235 (0.85%)	3 / 233 (1.29%)
occurrences all number	2	3
Oropharyngitis fungal
subjects affected / exposed	1 / 235 (0.43%)	3 / 233 (1.29%)
occurrences all number	1	3
Upper respiratory tract infection
subjects affected / exposed	3 / 235 (1.28%)	1 / 233 (0.43%)
occurrences all number	3	1
Nasopharyngitis
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	2
Rhinitis
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Bronchitis
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Cystitis
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Herpes zoster
subjects affected / exposed	0 / 235 (0.00%)	2 / 233 (0.86%)
occurrences all number	0	2
Influenza
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Oesophageal candidiasis
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Oral herpes
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Oropharyngeal candidiasis
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Pharyngitis
subjects affected / exposed	2 / 235 (0.85%)	0 / 233 (0.00%)
occurrences all number	2	0
Anal fungal infection
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Fungal infection
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Fungal oesophagitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Furuncle
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Herpes simplex
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Infection
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Mastoiditis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Orchitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Otitis media
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Rash pustular
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Respiratory tract infection
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Soft tissue infection
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Tonsillitis
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Tracheobronchitis
subjects affected / exposed	0 / 235 (0.00%)	1 / 233 (0.43%)
occurrences all number	0	1
Vaginal infection
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Pneumonia
subjects affected / exposed	4 / 235 (1.70%)	4 / 233 (1.72%)
occurrences all number	4	4
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	9 / 235 (3.83%)	3 / 233 (1.29%)
occurrences all number	9	4
Increased appetite
subjects affected / exposed	7 / 235 (2.98%)	6 / 233 (2.58%)
occurrences all number	7	6
Hyperglycaemia
subjects affected / exposed	4 / 235 (1.70%)	3 / 233 (1.29%)
occurrences all number	5	3
Dehydration
subjects affected / exposed	2 / 235 (0.85%)	4 / 233 (1.72%)
occurrences all number	2	4
Hyponatraemia
subjects affected / exposed	3 / 235 (1.28%)	1 / 233 (0.43%)
occurrences all number	3	1
Cachexia
subjects affected / exposed	2 / 235 (0.85%)	1 / 233 (0.43%)
occurrences all number	2	1
Hypoalbuminaemia
subjects affected / exposed	3 / 235 (1.28%)	0 / 233 (0.00%)
occurrences all number	3	0
Hypomagnesaemia
subjects affected / exposed	1 / 235 (0.43%)	2 / 233 (0.86%)
occurrences all number	1	2
Hypocalcaemia
subjects affected / exposed	1 / 235 (0.43%)	1 / 233 (0.43%)
occurrences all number	1	1
Hyperkalaemia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Malnutrition
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Polydipsia
subjects affected / exposed	1 / 235 (0.43%)	0 / 233 (0.00%)
occurrences all number	1	0
Decreased appetite
subjects affected / exposed	28 / 235 (11.91%)	17 / 233 (7.30%)
occurrences all number	28	17

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results: A Randomized, Phase III, Open-Label Study of Oral Topotecan Plus Whole-Brain Radiation Therapy (WBRT) Compared with WBRT Alone in Patients with Brain Metastases from Non-Small Cell Lung Cancer.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Survival

Primary: Overall Survival

Secondary: Six-month survival

Secondary: Six-month survival

Secondary: Number of participants with a complete response (CR) or a partial response (PR) (central nervous system [CNS]-radiologic)

Secondary: Number of participants with a complete response (CR) or a partial response (PR) (central nervous system [CNS]-radiologic)

Secondary: Time to response (TTR) (CNS-radiologic)

Secondary: Time to response (TTR) (CNS-radiologic)

Secondary: Time to progression (TTP) (CNS-radiologic)

Secondary: Time to progression (TTP) (CNS-radiologic)

Secondary: Time to progression (TTP) (all sites of disease-radiologic)

Secondary: Time to progression (TTP) (all sites of disease-radiologic)

Secondary: Number of participants who ranked each individual indicated neurological sign and symptom as none, mild, moderate, or severe at Months 1 and 3

Secondary: Number of participants who ranked each individual indicated neurological sign and symptom as none, mild, moderate, or severe at Months 1 and 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of level of consciousness at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of level of consciousness at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of headache at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of headache at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of dizziness/lightheadedness at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of dizziness/lightheadedness at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of vertigo at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of vertigo at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of nausea/vomiting at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of nausea/vomiting at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of visual problem at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of visual problem at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of seizure at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of seizure at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of other neurological symptoms at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment for the neurological sign and symptom of other neurological symptoms at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of cranial nerves II-XII at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of cranial nerves II-XII at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of language (dysphasia or aphasia) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of language (dysphasia or aphasia) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (right upper extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (right upper extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (left upper extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (left upper extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (right lower extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (right lower extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (left lower extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of strength (left lower extremity) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of sensation at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of sensation at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (right upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (right upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (left upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (left upper extremity: finger to nose testing) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (gait) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (gait) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (balance) at Baseline, Month 1, and Month 3

Secondary: Number of participants with the indicated investigator assessment of ataxia (balance) at Baseline, Month 1, and Month 3

Secondary: Number of participants with any adverse event (AE; both serious and non-serious) or serious adverse event (SAE)

Secondary: Number of participants with any adverse event (AE; both serious and non-serious) or serious adverse event (SAE)

Secondary: Number of participants with the indicated worst-case change from Baseline in the indicated chemistry parameters with respect to the normal range

Secondary: Number of participants with the indicated worst-case change from Baseline in the indicated chemistry parameters with respect to the normal range

Secondary: Lesion assessment and measurement

Secondary: Lesion assessment and measurement

Secondary: Brain symptoms

Secondary: Brain symptoms

Secondary: Number of participants who died or progressed

Secondary: Number of participants who died or progressed

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, Phase III, Open-Label Study of Oral Topotecan Plus Whole-Brain Radiation Therapy (WBRT) Compared with WBRT Alone in Patients with Brain Metastases from Non-Small Cell Lung Cancer.