Download PDF

Clinical Trial Results:
Randomised controlled trial of 6-Mercaptopurine versus placebo to prevent recurrence of Crohn's disease following surgical resection (TOPPIC)

Summary
EudraCT number	2006-005800-15
Trial protocol	GB
Global end of trial date	30 Sep 2015

Results information
Results version number	v1(current)
This version publication date	08 Sep 2017
First version publication date	08 Sep 2017
Other versions
Summary report(s)	TOPPIC Report

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

MRCG060329

ISRCTN number

ISRCTN89489788

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University of Edinburgh

Sponsor organisation address

Old College, South Bridge, Edinburgh , United Kingdom, EH8 9YL

Public contact

Marise Bucukoglu (ACCORD Office), University of Edinburgh, 00 44 01312429262, Marise.Bucukoglu@ed.ac.uk

Scientific contact

Marise Bucukoglu (ACCORD Office), University of Edinburgh, 00 44 01312429262, Marise.Bucukoglu@ed.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

15 Jun 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 May 2015

Global end of trial reached?

Yes

Global end of trial date

30 Sep 2015

Was the trial ended prematurely?

Main objective of the trial

To assess whether Mercaptopurine can prevent or delay post-operative recurrence of Crohn’s disease

Protection of trial subjects

This multicentre clinical trial was carried out with the approval of the national research ethics committee (ref: 07/MRE00/74), in accordance with the Declaration of Helsinki (2000), under a Clinical Trial Authorization (01384/0206/001-0002) from the Medicine and Healthcare Products Regulatory Authority (MHRA, United Kingdom), and the written informed consent of all participants.

Background therapy

N/A. All eligible patients were required to be free of medication for Crohn’s disease and to have been off antibiotics for the two weeks prior to randomization.

Evidence for comparator

N/A.

Actual start date of recruitment

01 May 2008

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: 240

Worldwide total number of subjects

240

EEA total number of subjects

240

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)

232

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Patients with a histologically confirmed diagnosis of Crohn's disease undergoing ileocolonic or small bowel resection were recruited from 29 UK hospitals. Patients were ≥ 16 years in Scotland and ≥18 years in England and Wales. Prior to randomisation any post-operative infections were fully treated and existing treatments for Crohn's stopped.

Screening details

A total of 329 patients were screened for recruitment of whom 89 were excluded as ineligible or who declined to participate, leaving 240 patients to undergo randomisation.

Period 1 title

Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Assessor

Blinding implementation details

Treatment was blinded to both the research team and the subject, as well as to the central trials team. Study drugs were prepared by pharmacy staff independent of the study investigators or clinical team responsible for patient care. Safety blood test results were sent to the central trials team by independent members of staff and assessed by a blinded, independent panel of clinicians. Data Monitoring Reports were prepared by an unblinded statistician.

Are arms mutually exclusive

Yes

Active Arm

Arm description

Mercaptopurine tablets containing 50mg of the active substance 6-Mercaptopurine prepared by Glaxo Wellcome GmbH (batch 1) & Co or Aspen Pharma Trading Limited (batch 2) and packaged by Catalent (later Aptuit).

Arm type

Active comparator

Investigational medicinal product name

Mercaptopurine

Investigational medicinal product code

ATC Code: L01BB02

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50mg tablet taken once a day

Placebo

Arm description

Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50mg oral tablet

Number of subjects in period 1	Active Arm	Placebo
Started	128	112
Completed	62	42
Not completed	66	70
Adverse event, serious fatal	-	1
Withdrawn	8	13
Adverse event, non-fatal	39	41
Abnormal safety blood test	12	6
Lost to follow-up	7	9

Baseline characteristics

Top of page

Reporting group title

Active Arm

Reporting group description

Reporting group title

Placebo

Reporting group description

Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

Reporting group values	Active Arm	Placebo	Total
Number of subjects	128	112	240
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	1	2	3
Adults (18-64 years)	126	106	232
From 65-84 years	1	4	5
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	79	67	146
Male	49	45	94
Previous treatment with Mercaptopurine
Units: Subjects
Yes	14	5	19
No	114	107	221
Previous treatment with Azathioprine
Units: Subjects
Yes	80	48	128
No	48	64	112
Missing	0	0	0
Previous treatment with Infliximab
Units: Subjects
Yes	21	15	36
No	104	96	200
Missing	3	1	4
Previous treatment with Methotrexate
Units: Subjects
Yes	8	7	15
No	120	104	224
Missing	0	1	1
Previous surgery
Units: Subjects
Yes	46	28	74
No	82	83	165
Missing	0	1	1
Smoking status
Units: Subjects
Yes	29	26	55
No	99	86	185
Missing	0	0	0
Duration of disease
Units: Subjects
40 years or less	37	41	78
> 40 years	91	69	160
Unknown	0	2	2
Age at diagnosis
Units: Subjects
40 years or less	103	87	190
> 40 years	25	23	48
Unknown	0	2	2
CDAI Score
Crohn's Disease Activity Index Score
Units: Points
arithmetic mean (standard deviation)	130 ± 86	121 ± 72	-
Weight
Units: kg
arithmetic mean (standard deviation)	70.7 ± 14.4	70.7 ± 13.7	-

End points

Top of page

Reporting group title

Active Arm

Reporting group description

Reporting group title

Placebo

Reporting group description

Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

Primary: Primary outcome - postoperative clinical recurrence of Crohn's disease

Top of page

End point title

Primary outcome - postoperative clinical recurrence of Crohn's disease

End point description

Crohn’s Disease Activity Index (CDAI) >150 with an increase from baseline of 100 points, together with the need for anti-inflammatory rescue therapy or primary surgical intervention.

End point type

Primary

End point timeframe

Up to the end of the trial (3 years).

End point values	Active Arm	Placebo
Number of subjects analysed	128	112
Units: Number of patients with recurrence
Yes	16	26
No	112	86

Statistical analysis of primary outcome

Statistical analysis description

Cox's proportional hazards model

Comparison groups

Active Arm v Placebo

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.073 ^[1]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.535

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.96

Variability estimate

Standard error of the mean

Dispersion value

0.349

Notes
[1] - Adjusted for randomisation stratification variables (centre and smoking status), also adjusted for previous treatment with 6MP or Azathioprine.

Secondary: Secondary outcome - postoperative clinical recurrence of Crohn's disease

Top of page

End point title

Secondary outcome - postoperative clinical recurrence of Crohn's disease

End point description

Crohn’s Disease Activity Index (CDAI) >150 with an increase from baseline of 100 points OR the need for anti-inflammatory rescue therapy OR primary surgical intervention.

End point type

Secondary

End point timeframe

Up to the end of the trial (3 years)

End point values	Active Arm	Placebo
Number of subjects analysed	128	112
Units: Number of patients
Yes	34	40
No	94	72

Statistical analysis of secondary outcome

Statistical analysis description

Cox’s proportional hazards model

Comparison groups

Active Arm v Placebo

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.243 ^[2]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.737

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.23

Variability estimate

Standard error of the mean

Dispersion value

0.262

Notes
[2] - Adjusted for randomisation stratification variables (centre and smoking status), also adjusted for previous treatment with 6MP or Azathioprine.

Adverse events

Top of page

Timeframe for reporting adverse events

All adverse events (AEs) that occurred after signing consent for the trial must be reported within the case report form (CRF) and all reported AEs were followed up before the end of the trial.

Adverse event reporting additional description

As above.

Assessment type

Non-systematic

Dictionary name

Coded by trial team

Dictionary version

N/A

Reporting group title

Active Arm

Reporting group description

Reporting group title

Placebo

Reporting group description

Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

Serious adverse events	Active Arm	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	51 / 128 (39.84%)	49 / 112 (43.75%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignnant and unspecified
subjects affected / exposed	1 / 128 (0.78%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Vascular disorders
subjects affected / exposed	1 / 128 (0.78%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Surgical and medical procedures
subjects affected / exposed	9 / 128 (7.03%)	5 / 112 (4.46%)
occurrences causally related to treatment / all	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General disorders
subjects affected / exposed	1 / 128 (0.78%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Reproductive system and breast disorders
subjects affected / exposed	2 / 128 (1.56%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Injury
subjects affected / exposed	1 / 128 (0.78%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
subjects affected / exposed	0 / 128 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac disorders
subjects affected / exposed	3 / 128 (2.34%)	2 / 112 (1.79%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Nervous system disorders
Nervous system disorders
subjects affected / exposed	0 / 128 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Ear and labyrinth disorders
subjects affected / exposed	0 / 128 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal disorders
subjects affected / exposed	23 / 128 (17.97%)	29 / 112 (25.89%)
occurrences causally related to treatment / all	2 / 26	4 / 33
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatobiliary disorders
subjects affected / exposed	1 / 128 (0.78%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
subjects affected / exposed	1 / 128 (0.78%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal and urinary disorders
subjects affected / exposed	4 / 128 (3.13%)	2 / 112 (1.79%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infections and infestations
subjects affected / exposed	4 / 128 (3.13%)	3 / 112 (2.68%)
occurrences causally related to treatment / all	0 / 7	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Active Arm	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	121 / 128 (94.53%)	105 / 112 (93.75%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancers
subjects affected / exposed	2 / 128 (1.56%)	1 / 112 (0.89%)
occurrences all number	3	1
Nervous system disorders
Pain
subjects affected / exposed	18 / 128 (14.06%)	17 / 112 (15.18%)
occurrences all number	30	19
Headache
subjects affected / exposed	26 / 128 (20.31%)	20 / 112 (17.86%)
occurrences all number	61	38
General disorders and administration site conditions
Other
subjects affected / exposed	85 / 128 (66.41%)	62 / 112 (55.36%)
occurrences all number	212	153
Pancreatitis
subjects affected / exposed	1 / 128 (0.78%)	1 / 112 (0.89%)
occurrences all number	1	1
Gastrointestinal disorders
GI Symptoms Other
subjects affected / exposed	34 / 128 (26.56%)	28 / 112 (25.00%)
occurrences all number	53	40
Nausea
subjects affected / exposed	45 / 128 (35.16%)	30 / 112 (26.79%)
occurrences all number	78	41
Abdominal pain
subjects affected / exposed	66 / 128 (51.56%)	67 / 112 (59.82%)
occurrences all number	132	141
Constipation
subjects affected / exposed	37 / 128 (28.91%)	37 / 112 (33.04%)
occurrences all number	54	56
Worsening Crohn's
subjects affected / exposed	24 / 128 (18.75%)	29 / 112 (25.89%)
occurrences all number	41	37
Hepatobiliary disorders
Deranged LFTs
subjects affected / exposed	4 / 128 (3.13%)	5 / 112 (4.46%)
occurrences all number	4	5
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	24 / 128 (18.75%)	14 / 112 (12.50%)
occurrences all number	35	17
Musculoskeletal and connective tissue disorders
Joint pain
subjects affected / exposed	40 / 128 (31.25%)	36 / 112 (32.14%)
occurrences all number	72	65
Infections and infestations
Infections
subjects affected / exposed	81 / 128 (63.28%)	68 / 112 (60.71%)
occurrences all number	171	184

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

16 Dec 2007

Substantial Amendment 1: Amendment to protocol concerning use of 6MP in pregnancy/subjects of childbearing age, switch to matching placebo (rather than over-encapsulation) supplied by GSK and amendment to safety blood procedures.

07 Jul 2008

Substantial Amendment 6: Decision to stop study drug if subjects prescribed Allopurinol.

18 Nov 2008

Substantial Amendment 3: Use of all Scottish district hospitals for referrals, repeat safety bloods not required at V2, clarifications to protocol: V2 ≤7 days of V1; point 3 of inclusion criteria added.

15 Jun 2009

Substantial Amendment 5: Reduce number of colonoscopies and clarification in PIL/Consent the types of sample and how they are handled and stored.

15 Dec 2009

Substantial Amendment 7: Amendment to safety assessments in protocol, prohibited medications added as appendix.

03 Mar 2010

Substantial Amendment 8: Isolated elevation of GGT do not represent exclusion to recruitment or withdrawal.

28 Sep 2010

Substantial Amendment 12: Extension to study, clarifications to protocol including amendment to exclusion criteria, retention of original signed consent forms in site files, updated policy on pharmacovigilance and protocol deviations.

10 Feb 2011

Substantial Amendment 13: Clarifications to the protocol

15 Mar 2012

Substantial Amendment 17: Protocol modified to add a secondary outcome, amend exclusion criteria error, MA holder and SmPC change, amendments to appendices 3,4,6,7.

03 Oct 2013

Substantial Amendment 20: Protocol modified: change of MA holder name and address, SmPc update of drug brand name, trial manager and trial statistician change, clarification of Appendix 8 on prohibited medications.

07 May 2015

Substantial Amendment 21: Protocol modified: health economics analysis plan revised, revisions to planned analysis section to bring in line with Statistical Analysis Plan, minor change to MA Holder and SmPC, removal of blank Annexes.

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/28404197

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
Randomised controlled trial of 6-Mercaptopurine versus placebo to prevent recurrence of Crohn's disease following surgical resection (TOPPIC)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary outcome - postoperative clinical recurrence of Crohn's disease

Primary: Primary outcome - postoperative clinical recurrence of Crohn's disease

Secondary: Secondary outcome - postoperative clinical recurrence of Crohn's disease

Secondary: Secondary outcome - postoperative clinical recurrence of Crohn's disease

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: Randomised controlled trial of 6-Mercaptopurine versus placebo to prevent recurrence of Crohn's disease following surgical resection (TOPPIC)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary outcome - postoperative clinical recurrence of Crohn's disease

Primary: Primary outcome - postoperative clinical recurrence of Crohn's disease

Secondary: Secondary outcome - postoperative clinical recurrence of Crohn's disease

Secondary: Secondary outcome - postoperative clinical recurrence of Crohn's disease

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Randomised controlled trial of 6-Mercaptopurine versus placebo to prevent recurrence of Crohn's disease following surgical resection (TOPPIC)