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Clinical Trial Results:
Reducing vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia (ALL): comparing one-hour infusions with bolus injections (the VINCA trial)

Summary
EudraCT number	2014-001561-27
Trial protocol	NL BE
Global end of trial date	01 Feb 2022

Results information
Results version number	v1(current)
This version publication date	23 Nov 2023
First version publication date	23 Nov 2023
Other versions
Summary report(s)	Van de Velde ME 2020 (2)

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

2000790

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Netherlands Trial Register: NTR4262, Dutch trial Register: NL4019

Sponsor organisation name

Amsterdam UMC

Sponsor organisation address

De Boelelaan 1117, Amsterdam, Netherlands, 1081 HV

Public contact

Department of Pediatric Oncology, VU university medical center, 0031 204444444, Mh.vandenberg@amsterdamumc.nl

Scientific contact

Department of Pediatric Oncology, VU university medical center, 0031 204444444, Mh.vandenberg@amsterdamumc.nl

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

01 Feb 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Feb 2022

Global end of trial reached?

Yes

Global end of trial date

01 Feb 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate whether the administration of vincristine (VCR) in children with acute lymphoblastic leukemia, nephroblastoma, medulloblastoma, low-grade glioma, Hodgkin lymphoma or rhabdomyosarcoma by one-hour infusions leads to less peripheral neuropathy (PNP) compared to the administration by short-term (1-5 minutes) infusions or injections.

Protection of trial subjects

Safety Committee

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Sep 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 57

Country: Number of subjects enrolled

Belgium: 33

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

Patients diagnosed with ALL

Screening details

Patients diagnosed with ALL, who received vincristine treatment. Baseline perpheral neuropathy scores were reported

Period 1 title

Baseline

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Recruitment period within one week

Are arms mutually exclusive

Yes

One-hour administration

Arm description

Vincristine administered via one hour infusion

Arm type

Active comparator

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Dosage according to individual treatment schedule 1.5-2mg/m2 with a maximum of 2 mg, IV infusion

Push Injection

Arm description

Vincristine administered via push injection

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous bolus use

Dosage and administration details

Dosage according to individual treatment schedule 1.5-2 mg/m2 with a maximum of 2 mg, IV infusion

Number of subjects in period 1	One-hour administration	Push Injection
Started	45	45
Completed	45	45

Period 2 title

Treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

One-hour administration

Arm description

Vincristine administered via one hour infusion

Arm type

Active comparator

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Dosage according to individual treatment schedule 1.5-2mg/m2 with a maximum of 2 mg, IV infusion

Push Injection

Arm description

Vincristine administered via push injection

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous bolus use

Dosage and administration details

Dosage according to individual treatment schedule 1.5-2 mg/m2 with a maximum of 2 mg, IV infusion

Number of subjects in period 2	One-hour administration	Push Injection
Started	45	45
Completed	44	38
Not completed	1	7
Physician decision	1	3
Consent withdrawn by subject	-	2
Adverse event, non-fatal	-	2

Baseline characteristics

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Reporting group title

Baseline

Reporting group description

entire cohort

Reporting group values	Baseline	Total
Number of subjects	90	90
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	57	57
Adolescents (12-17 years)	33	33
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Gender categorical
Units: Subjects
Female	40	40
Male	50	50

Subject analysis set title

Entire cohort

Subject analysis set type

Intention-to-treat

Subject analysis set description

all participants

Subject analysis set title

VCR push

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects receiving vincristine by a push

Subject analysis set title

VCR one-hour infusion

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject receiving vincristine during a one hour infusion

Subject analysis sets values	Entire cohort	VCR push	VCR one-hour infusion
Number of subjects	90	45	45
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)	57
Adolescents (12-17 years)	33
Adults (18-64 years)	0
From 65-84 years	0
85 years and over	0
Age continuous
Units:
	( )	( )	( )
Gender categorical
Units: Subjects
Female	40
Male	50

End points

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Reporting group title

One-hour administration

Reporting group description

Vincristine administered via one hour infusion

Reporting group title

Push Injection

Reporting group description

Vincristine administered via push injection

Reporting group title

One-hour administration

Reporting group description

Vincristine administered via one hour infusion

Reporting group title

Push Injection

Reporting group description

Vincristine administered via push injection

Subject analysis set title

Entire cohort

Subject analysis set type

Intention-to-treat

Subject analysis set description

all participants

Subject analysis set title

VCR push

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects receiving vincristine by a push

Subject analysis set title

VCR one-hour infusion

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject receiving vincristine during a one hour infusion

Primary: Vincristine induced peripheral neuropathy (VIPN)

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End point title

Vincristine induced peripheral neuropathy (VIPN)

End point description

End point type

Primary

End point timeframe

One year after treatment initiation or at the last vincristine administration (whichever came first)

End point values	One-hour administration	Push Injection
Number of subjects analysed	45	45
Units: number of patients	21	23

Mixed effect modelling

Comparison groups

One-hour administration v Push Injection

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≥ 0.34

Method

Mixed models analysis

Parameter type

Slope

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

0.31

Variability estimate

Standard deviation

Adverse events

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Timeframe for reporting adverse events

Duration of the trial

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

4.03

Reporting group title

One-hour infusion

Reporting group description

Reporting group title

push

Reporting group description

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Adverse events and Serious adverse events for this study were derived from the treatment protocols according to which these children were being treated. The adverse events were not collected seperately for this study

Serious adverse events	One-hour infusion	push
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 45 (20.00%)	3 / 45 (6.67%)
number of deaths (all causes)	2	2
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia recurrent
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Seizure
Additional description: Caused by CNS infection
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Allergic reaction to excipient
Additional description: Allergic reaction to IVIG
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic reaction
Additional description: Anaphylactic reaction to Asparaginase
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	3 / 45 (6.67%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucositis management
subjects affected / exposed	0 / 45 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
other
Additional description: cholestatic icterus
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
Additional description: sepsis and gastro-intestinal bleeding
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
Additional description: MTX intoxication and acute renal failure
subjects affected / exposed	0 / 45 (0.00%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteonecrosis
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Fungal infection
Additional description: Invasive aspergillosis
subjects affected / exposed	4 / 45 (8.89%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 45 (4.44%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
Additional description: Infection with febrile neutropenia
subjects affected / exposed	1 / 45 (2.22%)	0 / 45 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	One-hour infusion	push
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 45 (0.00%)	0 / 45 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2015

Inclusion of other diseases

21 Mar 2016

Addition of other sites

26 Jul 2017

Change of SAE reporting

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/33322788
http://www.ncbi.nlm.nih.gov/pubmed/36900422

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Clinical trials

Clinical Trial Results:
Reducing vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia (ALL): comparing one-hour infusions with bolus injections (the VINCA trial)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Vincristine induced peripheral neuropathy (VIPN)

Primary: Vincristine induced peripheral neuropathy (VIPN)

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: Reducing vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia (ALL): comparing one-hour infusions with bolus injections (the VINCA trial)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Vincristine induced peripheral neuropathy (VIPN)

Primary: Vincristine induced peripheral neuropathy (VIPN)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Reducing vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia (ALL): comparing one-hour infusions with bolus injections (the VINCA trial)