Clinical Trial Results:
The SYNBioSe Study
A proof-of-concept study involving synergetic B-cell imunnomodulation in patients with refractory systemic lupus erythematosus
Summary
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EudraCT number |
2014-000488-42 |
Trial protocol |
NL |
Global end of trial date |
31 Oct 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Nov 2021
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First version publication date |
29 Nov 2021
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Other versions |
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Summary report(s) |
Synbiose-1 publication |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
P14.065
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02284984 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Leiden University Medical Center
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Sponsor organisation address |
Albinusdreef 2, Leiden, Netherlands, 2333 ZA
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Public contact |
Teng, Leiden University Medical Center, 31 715268157, y.k.o.teng@lumc.nl
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Scientific contact |
Teng, Leiden University Medical Center, 31 715268157, y.k.o.teng@lumc.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Feb 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Oct 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Oct 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
In this proof-of-concept study the primary objective is to assess whether a combination treatment ofrituximab (anti-CD20) and belimumab (anti-BAFF) will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation, which portentially forms the basis of a new therapeutic approach in severe SLE.
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Protection of trial subjects |
Within the study safety and toxicity monitoring includes:
- the recording of adverse events according to WHO Toxicity criteria
- evaluation of the time to immune reconstitution of B-cells
- the recording of infectious events, with special interest for serious infections, including herpes zoster and opportunistic infections
- Serious hypersensitivity or infusion reactions
- Malignancy
- Suicidal thought, intent or behaviour
In accordance to Good Clinical Practice (GCP) guidelines, serious adverse events and SUSARs will be reported to the METC.
In order to guarantee the feasibility of the study, the principal investigators will meet every 3 months to evaluate all adverse events (AEs). For every AE the severity and relation to the study treatment will be recorded. An advice will be formulated when an AE or a series of AEs necessitates a protocol change or a consideration to terminate the study. The METC will advise to continue the study, to implement protocol changes or to terminate this study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 15
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Worldwide total number of subjects |
15
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EEA total number of subjects |
15
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
15
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
31 subjects were screened of which 16 patients were eligible for the study. 1 patient dropped out during screening while treated with intravenous methylprednisolone as remission induction treatment | ||||||
Pre-assignment
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Screening details |
the majority of SLE patients was female and had severe disease with major organ involvement. The median [range] SLEDAI was 18 [6-29] and 13 patients (81%) had active lupus nephritis (LN) with a median [range] proteinuria of 2.3 g/day [1e8.2]. One patient had transverse myelitis at inclusion and presented with paralysis of the lower extremities. | ||||||
Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
n.a.
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Arms
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Arm title
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overall trial | ||||||
Arm description |
- | ||||||
Arm type |
single arm | ||||||
Investigational medicinal product name |
rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients will be intravenously treated with Rituximab 1000mg on day 0 and day 14. Before every infusion of Rituximab patients will receive intravenous methylprednisolon 100mg together with oral acetaminophen 1000 mg and intravenous Tavegil 2 mg
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Investigational medicinal product name |
belimumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients will be intravenously treated with Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. No pre-medication is administered.
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
sixteen patients(88% female) were included, with median age of 31 years[19;51]. All patients had refractory disease, of which 12(80%) had active LN at baseline. One patient experienced severe hypogammaglobulinemia at week 8 after completion of methylprednisolone and RTX, therefore BLM treatment was not initiated. This patient was excluded from the long-term follow-up study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
All subjects
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
15 subjects who completed the study were included in the analysis
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End points reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||
Subject analysis set title |
All subjects
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
15 subjects who completed the study were included in the analysis
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End point title |
Reduction of pathogenic autoantibodies [1] | ||||||||
End point description |
Anti-dsDNA levels of 268AU/mL[50;827] at baseline decreased at week 24 to 29.6[0;104.5](p=0.02) equal to a median decrease of 87%[-100;+3].
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End point type |
Primary
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End point timeframe |
- Reduction of pathogenic autoantibodies, i.e.. a sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start.
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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: This is a single-arm study with immunological endpoint compared to each subject's baseline value. In accordance to mail correspondence: "Please note that inserting the statistical analysis related to an endpoint is not mandatory. You can delete the statistical analysis, however you need to provide a justification in the correct field" |
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Attachments |
Primary endpoint adsDNA |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Throughout the complete study from 0-104 weeks
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
WHO | ||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
All subjects
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
As defined by the study protocol, sujects that faile study treatment were withdrawn from the study and no further follow-up was available. In total 8/15 subjects completed 104 weeks. Hence, 7 subjects no complete follow-up of 104 weeks was recorded | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/29636274 |