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Clinical Trial Results:
Karisma II: A randomized, double blinded, six-armed placebo controlled study to investigate optimal dose of tamoxifen with the most favourable side effect spectra and with mammographic density reduction non-inferior to that of 20 mg tamoxifen.

Summary
EudraCT number	2016-000882-22
Trial protocol	SE
Global end of trial date	25 Oct 2019

Results information
Results version number	v1(current)
This version publication date	18 Jul 2021
First version publication date	18 Jul 2021
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

KARISMAII

ISRCTN number

US NCT number

NCT03346200

WHO universal trial number (UTN)

Sponsor organisation name

Karolinska Institutet

Sponsor organisation address

Fatburs Brunnsgata 7, Stockholm, Sweden, SE-118 28

Public contact

Karma Study Center at Södersjukhuset Breast Center, Karolinska Institutet at Södersjukhuset Breast Center, 0046 70750 2110, per.hall@ki.se

Scientific contact

Karma Study Center at Södersjukhuset Breast Center, Karolinska Institutet at Södersjukhuset Breast Center, 0046 70750 2110, per.hall@ki.se

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

20 Apr 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Sep 2019

Global end of trial reached?

Yes

Global end of trial date

25 Oct 2019

Was the trial ended prematurely?

Main objective of the trial

Identify the minimal dose of tamoxifen non-inferior in its ability to reduce mammographic density and with less side effects compared to 20 mg of tamoxifen.

Protection of trial subjects

The study was performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects that were adopted in 1964 by the 18th World Medical Assembly, in Helsinki, Finland, with later revisions and the International Conference on Harmonisation (ICH) Guidelines.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Nov 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 1440

Worldwide total number of subjects

1440

EEA total number of subjects

1440

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)

1096

From 65 to 84 years

344

85 years and over

Subject disposition

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Recruitment details

Study invitations were sent to women invited for mammography in the Swedish mammography screening program. Of 159 027 women invited, 2 314 showed interest of participating and were assessed for eligibility. At study screening 874 did not meet the inclusion/exclusion criteria and eventually 1 440 women were randomized.

Screening details

Exclusion criteria were made to not allowing women with previous cancer or with elevated risk for cardiovascular disorders.

Period 1 title

6 months on IMP (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Assessor, Subject

Are arms mutually exclusive

Yes

Placebo

Arm description

0 mg of IMP (tamoxifen)

Arm type

Placebo

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 6 months.

1 mg of IMP

Arm description

1 mg of IMP (tamoxifen)

Arm type

Experimental

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 6 months.

2,5 mg of IMP

Arm description

2,5 mg of IMP (tamoxifen)

Arm type

Experimental

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 6 months.

5 mg of IMP

Arm description

5 mg of IMP (tamoxifen)

Arm type

Experimental

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 6 months.

10 mg of IMP

Arm description

10 mg of IMP (tamoxifen)

Arm type

Experimental

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 6 months.

20 mg of IMP

Arm description

20 mg of IMP (tamoxifen)

Arm type

Active comparator

Investigational medicinal product name

Tamoxifen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 6 months.

Number of subjects in period 1	Placebo	1 mg of IMP	2,5 mg of IMP	5 mg of IMP	10 mg of IMP	20 mg of IMP
Started	242	239	235	240	243	241
Completed	211	205	200	201	210	203
Not completed	31	34	35	39	33	38
Consent withdrawn by subject	22	22	20	22	19	17
Adverse event, non-fatal	9	12	15	17	14	21

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

0 mg of IMP (tamoxifen)

Reporting group title

1 mg of IMP

Reporting group description

1 mg of IMP (tamoxifen)

Reporting group title

2,5 mg of IMP

Reporting group description

2,5 mg of IMP (tamoxifen)

Reporting group title

5 mg of IMP

Reporting group description

5 mg of IMP (tamoxifen)

Reporting group title

10 mg of IMP

Reporting group description

10 mg of IMP (tamoxifen)

Reporting group title

20 mg of IMP

Reporting group description

20 mg of IMP (tamoxifen)

Reporting group values	Placebo	1 mg of IMP	2,5 mg of IMP	5 mg of IMP	10 mg of IMP	20 mg of IMP	Total
Number of subjects	242	239	235	240	243	241	1440
Age categorical
Age categories, all 1 440 randomized, stratified per dose arm.
Units: Subjects
Adults (18-64 years)	177	193	181	185	179	181	1096
From 65-84 years	65	46	54	55	64	60	344
Gender categorical
Units: Subjects
Female	242	239	235	240	243	241	1440
Male	0	0	0	0	0	0	0

Subject analysis set title

Efficacy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Mean relative dense area change (%) and difference in mean change at six-months in the primary intention to treat population

Subject analysis sets values	Efficacy
Number of subjects	1230
Age categorical
Age categories, all 1 440 randomized, stratified per dose arm.
Units: Subjects
Adults (18-64 years)	982
From 65-84 years	248
Age continuous
Units:
	±
Gender categorical
Units: Subjects
Female	1230
Male	0

End points

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Reporting group title

Placebo

Reporting group description

0 mg of IMP (tamoxifen)

Reporting group title

1 mg of IMP

Reporting group description

1 mg of IMP (tamoxifen)

Reporting group title

2,5 mg of IMP

Reporting group description

2,5 mg of IMP (tamoxifen)

Reporting group title

5 mg of IMP

Reporting group description

5 mg of IMP (tamoxifen)

Reporting group title

10 mg of IMP

Reporting group description

10 mg of IMP (tamoxifen)

Reporting group title

20 mg of IMP

Reporting group description

20 mg of IMP (tamoxifen)

Subject analysis set title

Efficacy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Mean relative dense area change (%) and difference in mean change at six-months in the primary intention to treat population

Primary: Efficacy

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End point title

Efficacy

End point description

Mean relative dense area change (%) and difference in mean change at six-months in the primary intention to treat population

End point type

Primary

End point timeframe

Evaluated after 6 months on IMP.

End point values	Placebo	1 mg of IMP	2,5 mg of IMP	5 mg of IMP	10 mg of IMP	20 mg of IMP	Efficacy
Number of subjects analysed	211 ^[1]	205	200	201	210	203	1230
Units: Absolute numbers	211	205	200	201	210	203	1230

Attachments

Efficacy figure

Notes
[1] - Absolute difference in mammographic density

Intention to treat

Statistical analysis description

For primary efficacy endpoint, evaluating the primary intention to treat population (N=1,230) the difference in mean change (compared with the 20 mg treatment group) at six-months, stratified by menopausal status and tamoxifen dose.

Comparison groups

Placebo v 1 mg of IMP v 2,5 mg of IMP v 5 mg of IMP v 10 mg of IMP v 20 mg of IMP v Efficacy

Number of subjects included in analysis

2460

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

< 0.025 ^[3]

Method

Wald tests

Parameter type

Mean difference (net)

Confidence interval

level

97.5%

sides

1-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Notes
[2] - Non-inferiority was declared if the corrected p-values were less than 0.025. We reported one-sided 97.5% normal-based confidence intervals.
[3] - For the primary endpoint, we calculated one-sided p-values for non-inferiority using Wald tests.

Adverse events

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Timeframe for reporting adverse events

During the 6 months of participation.

Adverse event reporting additional description

Safety and adverse events were assessed by study personnel available through study center phone, a phone app for spontaneous reports, and through scheduled questionnaires at month 1, 3, and 6.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

All participants

Reporting group description

Serious adverse events	All participants
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 1440 (0.76%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	3 / 1440 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Monoclonal gammopathy
subjects affected / exposed	1 / 1440 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Squamous cell carcinoma of head and neck
subjects affected / exposed	1 / 1440 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Vascular disorders
Varicophlebitis
subjects affected / exposed	1 / 1440 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nervous system disorders
Meningioma benign
subjects affected / exposed	1 / 1440 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Transient ischaemic attack
Additional description: Suspicion of Transient ischaemic attack
subjects affected / exposed	1 / 1440 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Peptic ulcer haemorrhage
subjects affected / exposed	1 / 1440 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Pyelonephritis acute
subjects affected / exposed	2 / 1440 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	All participants
Total subjects affected by non serious adverse events
subjects affected / exposed	342 / 1440 (23.75%)
Vascular disorders
Hot flush
subjects affected / exposed	140 / 1440 (9.72%)
occurrences all number	193
Night sweats
subjects affected / exposed	109 / 1440 (7.57%)
occurrences all number	189
Reproductive system and breast disorders
Vaginal discharge
subjects affected / exposed	93 / 1440 (6.46%)
occurrences all number	121

More information

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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

http://www.ncbi.nlm.nih.gov/pubmed/33734864

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Clinical trials

Clinical Trial Results:
Karisma II: A randomized, double blinded, six-armed placebo controlled study to investigate optimal dose of tamoxifen with the most favourable side effect spectra and with mammographic density reduction non-inferior to that of 20 mg tamoxifen.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Efficacy

Primary: Efficacy

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Karisma II: A randomized, double blinded, six-armed placebo controlled study to investigate optimal dose of tamoxifen with the most favourable side effect spectra and with mammographic density reduction non-inferior to that of 20 mg tamoxifen.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Efficacy

Primary: Efficacy

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Karisma II: A randomized, double blinded, six-armed placebo controlled study to investigate optimal dose of tamoxifen with the most favourable side effect spectra and with mammographic density reduction non-inferior to that of 20 mg tamoxifen.