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Clinical Trial Results:
A feasibility study to inform the design of a randomised controlled trial to identify the most clinically and cost effective length of Anticoagulation with Low molecular weight heparin In the treatment of Cancer Associated Thrombosis (ALICAT).

Summary
EudraCT number	2012-004117-14
Trial protocol	GB
Global end of trial date	22 Nov 2014

Results information
Results version number	v1(current)
This version publication date	30 Mar 2019
First version publication date	30 Mar 2019
Other versions
Summary report(s)	Full HTA report

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

SPON1037-11

ISRCTN number

ISRCTN37913976

US NCT number

NCT01817257

WHO universal trial number (UTN)

Other trial identifiers

WCTU Number: WCTU062, Sponsors Number: SPON1037-11, NIHR HTA Project Reference Number: 10/145/01

Sponsor organisation name

Cardiff University

Sponsor organisation address

30-36 Newport Road, Cardiff, United Kingdom, CF24 0DE

Public contact

Shaw, Cardiff University, +44 29 2087 5834/9626, shawc3@cardiff.ac.uk

Scientific contact

Shaw, Cardiff University, +44 29 2087 5834/9626, shawc3@cardiff.ac.uk

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

10 Mar 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Nov 2014

Global end of trial reached?

Yes

Global end of trial date

22 Nov 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

To explore the feasibility of conducting a randomised controlled trial (RCT) to identify the use of low molecular weight heparin (LMWH) in the treatment of cancer associated thrombosis (CAT) in patients with locally advanced or metastatic cancer following an initial six months of anticoagulation.

Protection of trial subjects

It was anticipated that participants may prefer one randomization arm to the other. As such participants were asked to participate in qualitative interviews and quality of life questionnaires. Furthermore, as participants would be asked to self-inject, xxxxx were designed to look into participants feelings and preferences relating to this.

Background therapy

Cancer patients are at higher risk of Venous thromboembolism (VTE). It is therefore recommended that patients receive Low molecular weight heparin (LMWH) for six months only.

Evidence for comparator

It is unknown whether treating patients with LMWH for longer would improve patient outcomes, particularly for patients with cancer associated thrombosis (CAT) and ongoing cancer whereby the risk of thrombotic tendency increases.

Actual start date of recruitment

03 Jun 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 5

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The first participants was registered on the 23/12/2013 and the last participant was registered on the 16/06/2014. Participants were registered across 2 UK sites.

Screening details

Index VTE events were identified through primary and secondary care clinical databases and clinical records. Potential participants were screened by a NISCHR (Welsh sites) or NIHR NCRN (English sites) researcher and flagged up to the local PI.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Are arms mutually exclusive

Yes

LMWH 12 months

Arm description

Participants receive 12 months of LMWH.

Arm type

Experimental

Investigational medicinal product name

LMWH

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per local policy. LMWH may include dalteparin (Fragmin®),tinzaparin (Innohep®) and enoxaparin (Clexane®)

LMWH for 6 months

Arm description

Participants receive 6 months of LMWH only.

Arm type

Experimental

Investigational medicinal product name

LMWH

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

As per local policy. Permitted LMWH include dalteparin (Fragmin®), tinzaparin (Innohep®) and enoxaparin (Clexane®)

Number of subjects in period 1	LMWH 12 months	LMWH for 6 months
Started	3	2
Completed	2	1
Not completed	1	1
Patient died	1	1

Baseline characteristics

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Reporting group title

LMWH 12 months

Reporting group description

Participants receive 12 months of LMWH.

Reporting group title

LMWH for 6 months

Reporting group description

Participants receive 6 months of LMWH only.

Reporting group values	LMWH 12 months	LMWH for 6 months	Total
Number of subjects	3	2	5
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Mean age
Units: years
arithmetic mean (standard deviation)	66.67 ( 11.93 )	50.5 ( 21.92 )	-
Gender categorical
Units: Subjects
Female	1	1	2
Male	2	1	3
ECOG Performance status
Units: Subjects
ECOG 0	2	2	4
ECOG 2	1	0	1

Subject analysis set title

Overall Trial

Subject analysis set type

Full analysis

Subject analysis set description

All 5 patients who were randomised.

Subject analysis sets values	Overall Trial
Number of subjects	5
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Mean age
Units: years
arithmetic mean (standard deviation)	( )
Gender categorical
Units: Subjects
Female	2
Male	3
ECOG Performance status
Units: Subjects
ECOG 0	4
ECOG 2	1

End points

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Reporting group title

LMWH 12 months

Reporting group description

Participants receive 12 months of LMWH.

Reporting group title

LMWH for 6 months

Reporting group description

Participants receive 6 months of LMWH only.

Subject analysis set title

Overall Trial

Subject analysis set type

Full analysis

Subject analysis set description

All 5 patients who were randomised.

Primary: (i) Number of eligible patients

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End point title

(i) Number of eligible patients ^[1]

End point description

A screening log will be kept in each recruitment site to identify patients potentially meeting the inclusion criteria. Eligible patients who are approached about the trial and given the participant information sheet (PIS) will be anonymously registered on a central database. This will help to inform the design of a Phase III study.

End point type

Primary

End point timeframe

The sites were open for recruitment for 6 months between December 2013 and June 2014

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only 5 out of 32 (15.6%) eligible patients agreed to be randomised. The study was closed early the primary outcome was feasibility of randomisation.

End point values	Overall Trial
Number of subjects analysed	32 ^[2]
Units: Patients	32

Notes
[2] - 32 patients were registered as potentially eligible.

No statistical analyses for this end point

Primary: (ii) Number of recruited patients

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End point title

(ii) Number of recruited patients ^[3]

End point description

Patients meeting the inclusion criteria will be invited to participate in the study as outlined. The number of eligible participants consenting to randomisation shall be recorded.

End point type

Primary

End point timeframe

The sites were open for recruitment for 6 months between December 2013 and June 2014

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only 5 out of 32 (15.6%) eligible patients agreed to be randomised. The study was closed early the primary outcome was feasibility of randomisation.

End point values	Overall Trial
Number of subjects analysed	5 ^[4]
Units: Patients	5

Notes
[4] - 5 patients were randomised

No statistical analyses for this end point

Primary: (iii) Proportion of randomised participants with recurrent VTEs during follow-up

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End point title

(iii) Proportion of randomised participants with recurrent VTEs during follow-up ^[5]

End point description

The number of randomised patients experiencing recurrent symptomatic VTE shall be recorded and used to inform the sample size required for a full RCT.

End point type

Primary

End point timeframe

6 month trial follow-up period

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only 5 out of 32 (15.6%) eligible patients agreed to be randomised. The study was closed early the primary outcome was feasibility of randomisation.

End point values	Overall Trial
Number of subjects analysed	32 ^[6]
Units: Number of patients randomised
randomised	5
not randomised	27

Notes
[6] - 32 patients registered.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious adverse events were reported from time of signature of informed consent, throughout the treatment period up to, and including 30 days after the participant receives their last dose of the IMP.

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

4.03

Reporting group title

Patients treated with LMWH for 12 months

Reporting group description

Reporting group title

Patients treated with LMWH for 6 months

Reporting group description

Serious adverse events	Patients treated with LMWH for 12 months	Patients treated with LMWH for 6 months
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	1 / 2 (50.00%)
number of deaths (all causes)	1	1
number of deaths resulting from adverse events	0	0
General disorders and administration site conditions
Fall
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Colonic obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary tract obstruction
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Community acquired pneumonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Patients treated with LMWH for 12 months	Patients treated with LMWH for 6 months
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	1 / 2 (50.00%)
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	1
Vascular disorders
Superior vena cava syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	1
General disorders and administration site conditions
Fever
subjects affected / exposed	2 / 3 (66.67%)	0 / 2 (0.00%)
occurrences all number	2	0
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	0 / 2 (0.00%)
occurrences all number	4	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Transient elevation of liver transaminases
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	1
Raised Gamma GT
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Rash, urticarial, Pruritus
subjects affected / exposed	2 / 3 (66.67%)	0 / 2 (0.00%)
occurrences all number	2	0
Subcataneous haematoma at injection site
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences all number	1	0
Sore mouth
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	2
Renal and urinary disorders
Urinary retention
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences all number	1	0
urinary catheter
subjects affected / exposed	0 / 3 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	1
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 2 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

17 Mar 2014

The ALICAT Protocol was updated from V2.0 21 March 2013 to V2.1 20 November 2013 to reflect changes to the WCTU’s generic pharmacovigilance management, assessment and reporting procedures in response to a Statutory GCP Systems Inspection (INSPECTION No: Insp GCP 21323/8955167-0001) of the WCTU conducted by the MHRA 20-22 August 2013. Other minor typographical amendments to the protocol were addressed at the same time.

17 Mar 2014

Addition of new site(s) and/or investigator(s)

27 May 2014

Amendment of the ALICAT Protocol from V2.1 to V3.0; Comments/ explanation/ reasons for substantial amendment: 1. Remove reference to recruitment of patients to the RCT and qualitative interviews from the primary care setting, i.e. GP sites, and clarify that patients will be recruited from five participating hospital sites (two for the oncology setting in Wales and three for the haematology setting in England) 2. Remove reference to a Researcher at Birmingham University. 3. Reduce the current 16 RSIs to three, i.e. one per active ingredient. 4. Specify that one DSUR will be submitted for all three active ingredients. 5. Clarification of the conduct of the patient mapping component of the study. 6. Other minor typographical errors. Notification on to REC only of removal of the ALICAT Consultant Letter Version 1.0 160112. This document was no longer required as patients were no longer recruited from the primary care setting. Amendment to the ALICAT PIS and consent forms to address minor typographical errors, and reflect changes to the design of the focus group component of the study following implementation of the first three focus groups.

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.

Low recruitment and randomisation numbers suggest progression to a full RTC was not feasible. Reasons for non-consenting were due to fixed preference for continuing or discontinuing treatment after 6 months of LMWH.

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Clinical trials

Clinical Trial Results:
A feasibility study to inform the design of a randomised controlled trial to identify the most clinically and cost effective length of Anticoagulation with Low molecular weight heparin In the treatment of Cancer Associated Thrombosis (ALICAT).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: (i) Number of eligible patients

Primary: (i) Number of eligible patients

Primary: (ii) Number of recruited patients

Primary: (ii) Number of recruited patients

Primary: (iii) Proportion of randomised participants with recurrent VTEs during follow-up

Primary: (iii) Proportion of randomised participants with recurrent VTEs during follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A feasibility study to inform the design of a randomised controlled trial to identify the most clinically and cost effective length of Anticoagulation with Low molecular weight heparin In the treatment of Cancer Associated Thrombosis (ALICAT).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: (i) Number of eligible patients

Primary: (i) Number of eligible patients

Primary: (ii) Number of recruited patients

Primary: (ii) Number of recruited patients

Primary: (iii) Proportion of randomised participants with recurrent VTEs during follow-up

Primary: (iii) Proportion of randomised participants with recurrent VTEs during follow-up

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A feasibility study to inform the design of a randomised controlled trial to identify the most clinically and cost effective length of Anticoagulation with Low molecular weight heparin In the treatment of Cancer Associated Thrombosis (ALICAT).