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Clinical Trial Results:
Pre-emptive therapy of acute graft versus host disease according to specific proteomic patterns after allogeneic hematopoietic stem cell transplantation.

Summary
EudraCT number	2008-005862-30
Trial protocol	DE
Global end of trial date	07 Dec 2015

Results information
Results version number	v1(current)
This version publication date	19 Jan 2024
First version publication date	19 Jan 2024
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

MHH-Pre-GvHD-001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Hannover Medical School

Sponsor organisation address

Carl-Neuberg-Str. 1, Hannover, Germany, 30625

Public contact

Stabsstelle Zentrum für Klinische Forschung, Hannover Medical School, EudraCT@mh-hannover.de

Scientific contact

Stabsstelle Zentrum für Klinische Forschung, Hannover Medical School, EudraCT@mh-hannover.de

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

06 Oct 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Dec 2015

Global end of trial reached?

Yes

Global end of trial date

07 Dec 2015

Was the trial ended prematurely?

Main objective of the trial

To test the efficacy of pre-emptive immunosuppressive treatment (2-2.5mg prednisolone/kg BW/day) versus placebo immediately when a positive acute Graft-versus-Host disease (aGvHD,grade II-IV) and a specific proteomic pattern is observed.

Protection of trial subjects

The clinical trial was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with the standards of International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). A continuous risk assessment was performed during the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Dec 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 259

Worldwide total number of subjects

259

EEA total number of subjects

259

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)

233

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

260 patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies or dysfunction syndromes were to be included in the clinical trial.

Screening details

Eligibility will be determined based upon the inclusion and exclusion criteria

Period 1 title

Study period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

observational

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo arm

Arm description

Arm type

Placebo

Investigational medicinal product name

physiological sodium chloride solution

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection in pre-filled syringe, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Treatment: 2 - 2.5 mg prednisolone/ kg BW/day or placebo (for 5 days or until clinical manifestation of aGvHD, if prior to day +5). Taper:1.5 mg/kg BW/ day 6-10, 1 mg/kg BW/day 11-14, 0.5 mg/kg/day 15-19 after administration

Prednisolone

Arm description

Arm type

Experimental

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Suspension for injection in pre-filled syringe

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Treatment: 2 - 2.5 mg prednisolone/ kg BW/day or placebo (for 5 days or until clinical manifestation of aGvHD, if prior to day +5). Taper: 1.5 mg/kg BW/ day 6-10, 1 mg/kg BW/day 11-14, 0.5 mg/kg/day 15-19 after administration

Number of subjects in period 1	observational	Placebo arm	Prednisolone
Started	167	48	44
Completed	130	30	26
Not completed	37	18	18
Consent withdrawn by subject	3	1	1
no information	-	1	-
death	34	15	16
Lost to follow-up	-	-	1
Protocol deviation	-	1	-

Baseline characteristics

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Reporting group title

observational

Reporting group description

Reporting group title

Placebo arm

Reporting group description

Reporting group title

Prednisolone

Reporting group description

Reporting group values	observational	Placebo arm	Prednisolone	Total
Number of subjects	167	48	44	259
Age categorical
Units: Subjects
Adults (18-64 years)				0
From 65-84 years				0
Age continuous
Units: years
arithmetic mean (standard deviation)	49.4 ± 14.12	52.9 ± 12.64	53.0 ± 11.62	-
Gender categorical
Units: Subjects
Female	59	21	15	95
Male	108	27	29	164

End points

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Reporting group title

observational

Reporting group description

Reporting group title

Placebo arm

Reporting group description

Reporting group title

Prednisolone

Reporting group description

Subject analysis set title

Intention to treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

all patients randomized

Subject analysis set title

Per Protocol

Subject analysis set type

Per protocol

Subject analysis set description

all randomized patients, who fulfilled the key inclusion criteria and received double-blind treatment for at least 3 days (pre-emptive dose of ≥ 2 mg/kg). Patients in the per-protocol population were analyzed as treated

Subject analysis set title

Safety

Subject analysis set type

Safety analysis

Subject analysis set description

patients were excluded from the safety analysis, because they didn’t take any study medication

Primary: occurence of aGvHD ≥grade 2

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End point title

occurence of aGvHD ≥grade 2 ^[1]

End point description

The primary endpoint was defined as the occurrence of aGvHD ≥grade II between time of randomization and 100 days after HSCT. If a death occurs between randomization and 100 days after HSCT in a patient without aGvHD (≥ grade II), then this was also considered as treatment failure, equivalent to an aGvHD (≥ grade II).

End point type

Primary

End point timeframe

100 days after HSCT

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Patients who were not randomized were included into the observational study group, this group was not included in the analysis of the primary endpoint

End point values	Placebo arm	Prednisolone	Intention to treat
Number of subjects analysed	48	44	92
Units: patients with aGvHD ≥grade II	12	11	23

difference between treatment groups at 100 days

Comparison groups

Prednisolone v Placebo arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 1

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[2] - efficacy

Adverse events

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Timeframe for reporting adverse events

Documentation of (S)AEs was done only for the duration of IMP intake (e.g. prednisolon/placebo for 19 days).

Adverse event reporting additional description

Only number of affected subjects available, not number of events.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Prednisolone

Reporting group description

Prednisolone

Serious adverse events	Placebo	Prednisolone
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 45 (13.33%)	3 / 42 (7.14%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Graft versus host disease in skin
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Swallowing difficult
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary haemorrhage
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infections and infestations
Oral herpes
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Placebo	Prednisolone
Total subjects affected by non serious adverse events
subjects affected / exposed	29 / 45 (64.44%)	21 / 42 (50.00%)
Investigations
C-reactive protein increased
subjects affected / exposed	2 / 45 (4.44%)	1 / 42 (2.38%)
occurrences all number	2	1
Congenital, familial and genetic disorders
Aplasia
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences all number	2	0
Nervous system disorders
Headache
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences all number	2	0
General disorders and administration site conditions
Mucosal inflammation
subjects affected / exposed	0 / 45 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	2
Oedema peripheral
subjects affected / exposed	0 / 45 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	2
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	8 / 45 (17.78%)	4 / 42 (9.52%)
occurrences all number	8	4
Nausea
subjects affected / exposed	5 / 45 (11.11%)	2 / 42 (4.76%)
occurrences all number	5	2
Vomiting
subjects affected / exposed	2 / 45 (4.44%)	2 / 42 (4.76%)
occurrences all number	2	2
Abdominal pain upper
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences all number	1	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences all number	1	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 45 (6.67%)	1 / 42 (2.38%)
occurrences all number	3	1
Cystitis haemorrhagic
subjects affected / exposed	0 / 45 (0.00%)	3 / 42 (7.14%)
occurrences all number	0	3
Renal failure
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences all number	1	1
Infections and infestations
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences all number	1	1
Candida infection
subjects affected / exposed	0 / 45 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	2
Oral herpes
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences all number	1	1
Metabolism and nutrition disorders
Oedema
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences all number	2	0
Decreased appetite
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences all number	2	0
Hyperglycaemia
subjects affected / exposed	0 / 45 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	2

More information

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Were there any global substantial amendments to the protocol? Yes

29 Oct 2009

Protocol version 4

07 Jan 2010

Protocol version 5

04 Aug 2011

Protocol verison 6

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/33082512

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Clinical trials

Clinical Trial Results:
Pre-emptive therapy of acute graft versus host disease according to specific proteomic patterns after allogeneic hematopoietic stem cell transplantation.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: occurence of aGvHD ≥grade 2

Primary: occurence of aGvHD ≥grade 2

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: Pre-emptive therapy of acute graft versus host disease according to specific proteomic patterns after allogeneic hematopoietic stem cell transplantation.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: occurence of aGvHD ≥grade 2

Primary: occurence of aGvHD ≥grade 2

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Pre-emptive therapy of acute graft versus host disease according to specific proteomic patterns after allogeneic hematopoietic stem cell transplantation.