Clinical Trial Results:
Tratamiento con inmunoglobulinas y rituximab en el rechazo crónico humoral en el trasplante renal: estudio multicéntrico, prospectivo, randomizado y controlado con placebo. Treatment with intravenous immunoglobulins and rituximab in renal transplant recipients with chronic humoral rejection: a multicentre, prospective, randomized, placebo-controlled study.

Trial information Top of page
Trial identification
Sponsor protocol code	TRITON
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	VHIR
Sponsor organisation address	Passeig Vall Hebron 119-129, Barcelona, Spain, 08035
Public contact	Joaquin Lopez-Soriano, VHIR, joaquin.lopez.soriano@vhir.org
Scientific contact	Francesc Moreso, VHIR, fjmoreso@vhebron.net
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	13 Mar 2017
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	30 Dec 2016
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX)
Protection of trial subjects	The study was conducted in accordance with the Declaration of Helsinki and is consistent with the Principles of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism. Patients with proteinuria >0.5 g/day received an angiotensin converting enzyme inhibitor/angiotensin II receptor blocker.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	01 Aug 2012
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 25
Worldwide total number of subjects	25
EEA total number of subjects	25
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	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)	25
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	Patients eligible for the study were renal transplants with biopsy-proven chronic ABMR diagnosed less than 6 months before randomization. Other inclusion criteria were age ≥18 years, stability of renal function defined as a decrease of eGFR <15% between the time of the diagnostic biopsy and the inclusion. 1 patient withdrawed each group
Period 1
Period 1 title	Overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator
Blinding implementation details	A central blocked computerized random-generator was utilized to allocate patients to each group. Study drugs and placebo were wrapped to assure the double-blind procedure
Arms
Are arms mutually exclusive	Yes
Arm title	IG + RTX
Arm description	In the treatment group patients received four consecutive doses of intravenous immunoglobulins (IVIG) every 3 weeks and one single dose of Rituximab (RTX) 1 week after the last IVIG dose.
Arm type	Experimental
Investigational medicinal product name	Rituximab
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	375 mg/m2 1 dose, 1 week after IG treatment
Investigational medicinal product name	Immunoglobulin
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	0.5 g/kg intravenous, four consecutive doses every 3 weeks
Arm title	Placebo
Arm description	-
Arm type	Placebo
Investigational medicinal product name	Saline 0.9%
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	The control group received an isovolumetric saline solution, following the same schedule
Number of subjects in period 1 IG + RTX Placebo Started 12 13 Completed 11 12 Not completed 1 1      Consent withdrawn by subject 1 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	IG + RTX
Reporting group description	In the treatment group patients received four consecutive doses of intravenous immunoglobulins (IVIG) every 3 weeks and one single dose of Rituximab (RTX) 1 week after the last IVIG dose.
Reporting group title	Placebo
Reporting group description	-
Reporting group values IG + RTX Placebo Total Number of subjects 12 13 25 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 Units: years     median (standard deviation) 47 ( 13 ) 49 ( 15 ) - Gender categorical Units: Subjects     Female 4 6 10     Male 8 7 15

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	IG + RTX
Reporting group description	In the treatment group patients received four consecutive doses of intravenous immunoglobulins (IVIG) every 3 weeks and one single dose of Rituximab (RTX) 1 week after the last IVIG dose.
Reporting group title	Placebo
Reporting group description	-

End points Top of page

Primary: Decline of eGFR Top of page
End point title	Decline of eGFR
End point description
End point type	Primary
End point timeframe	One year
End point values IG + RTX Placebo Number of subjects analysed 12 13 Units: ml/min     median (standard deviation) -4.2 ( 14.4 ) -6.6 ( 12.0 )
Statistical analysis title	EGFR decline
Comparison groups	IG + RTX v Placebo
Number of subjects included in analysis	25
Analysis specification	Pre-specified
Analysis type	non-inferiority
P-value	= 0.475
Method	t-test, 2-sided
Confidence interval

Primary: Decline of eGFR Top of page

Secondary: Proteinuria Increase Top of page
End point title	Proteinuria Increase
End point description
End point type	Secondary
End point timeframe	1 year
End point values IG + RTX Placebo Number of subjects analysed 12 13 Units: gram/day     arithmetic mean (standard error) 0.9 ( 2.1 ) 0.9 ( 2.1 )
Statistical analysis title	Proteinuria
Comparison groups	IG + RTX v Placebo
Number of subjects included in analysis	25
Analysis specification	Pre-specified
Analysis type	non-inferiority
P-value	= 0.378
Method	t-test, 2-sided
Confidence interval

Secondary: Proteinuria Increase Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	All the study
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	14.1
Reporting groups
Reporting group title	IG + RTX
Reporting group description	In the treatment group patients received four consecutive doses of intravenous immunoglobulins (IVIG) every 3 weeks and one single dose of Rituximab (RTX) 1 week after the last IVIG dose.
Reporting group title	Placebo
Reporting group description	-
Serious adverse events IG + RTX Placebo Total subjects affected by serious adverse events      subjects affected / exposed 5 / 12 (41.67%) 4 / 13 (30.77%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 General disorders and administration site conditions Fever      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Gastrointestinal disorders Diverticulitis      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Gastroenteritis Additional description: Acute gastroenteritis with acute renal failure      subjects affected / exposed 0 / 12 (0.00%) 2 / 13 (15.38%)      occurrences causally related to treatment / all 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Esophagus perforation      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      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 neoplasm      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Infection      subjects affected / exposed 2 / 12 (16.67%) 0 / 13 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Endocrine disorders Hyponatraemia      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (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 IG + RTX Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 8 / 12 (66.67%) 11 / 13 (84.62%) Nervous system disorders Memory impairment      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 1 / 12 (8.33%) 1 / 13 (7.69%)      occurrences all number 1 1 Venous thrombosis      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Thrombocytopenia      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Leukopenia      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Coagulation time abnormal      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 General disorders and administration site conditions Asthenia      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Discomfort      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Gastrointestinal disorders Diarrhoea      subjects affected / exposed 1 / 12 (8.33%) 1 / 13 (7.69%)      occurrences all number 1 1 Odynophagia      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Pancreatic pseudocyst      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Gastroenteritis      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Respiratory, thoracic and mediastinal disorders Mucus      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Cold burn      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Cough      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Pulmonar thromboembolism      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Skin and subcutaneous tissue disorders Eczema      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Oedema      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Rash      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Renal and urinary disorders Renal failure      subjects affected / exposed 1 / 12 (8.33%) 1 / 13 (7.69%)      occurrences all number 1 1 Graft complication      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Renal transplant      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Endocrine disorders Adenopathy submandibular      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Hyperparathyroidism      subjects affected / exposed 0 / 12 (0.00%) 2 / 13 (15.38%)      occurrences all number 0 2 Musculoskeletal and connective tissue disorders Pain in extremity      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Hip pain      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Lumbar pain      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Malleolar oedema      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Infections and infestations Upper respiratory tract infection      subjects affected / exposed 1 / 12 (8.33%) 0 / 13 (0.00%)      occurrences all number 1 0 Urinary tract infection      subjects affected / exposed 0 / 12 (0.00%) 2 / 13 (15.38%)      occurrences all number 0 2 Metabolism and nutrition disorders Hypercholesterolaemia      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Hypertriglyceridaemia      subjects affected / exposed 0 / 12 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Acidosis      subjects affected / exposed 0 / 12 (0.00%) 3 / 13 (23.08%)      occurrences all number 0 3

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
The absence of any effect on circulating donor specific antibodies uggests that this treatment may also be not efficient in patients with chronic ABMR diagnosed at earlier stages
Online references
http://www.ncbi.nlm.nih.gov/pubmed/28949089

More information Top of page