Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04182737 |
| Other study ID # |
IgM-FAT-3.0-22-12-2018 |
| Secondary ID |
2018-001613-33 |
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2020 |
| Est. completion date |
March 31, 2022 |
Study information
| Verified date |
May 2021 |
| Source |
University of Modena and Reggio Emilia |
| Contact |
Massimo Girardis, PD |
| Phone |
0594225878 |
| Email |
massimo.girardis[@]unimore.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In patients with septic shock, low levels of circulating immunoglobulins are common and they
are kinetic, particularly of immunoglobulin M (IgM), seems to be related with clinical
outcome. These observations, combined with the pivotal role of immunoglobulins on host immune
response to infections, led to consider therapy with polyclonal intravenous immunoglobulins a
promising option in patients with septic shock.
IgM-enriched preparations have been used since now most of all at a standard dose recommended
by the producer although a more tailored approach may improve patients' outcomes.
This study hypothesizes that in patients with septic shock and low IgM immunoglobulins titers
at shock onset, adjunctive treatment with a personalized dose of IgM-enriched immunoglobulins
based on IgM serum titers of the patient may reduce mortality compared to a standard dose of
IgM-enriched immunoglobulins. The study is designed as a multicentre, national,
interventional, randomized, single-blinded, prospective, investigator-sponsored, two arms
study. Patients will be randomly assigned to IgM titer-based treatment or flat treatment
group in a 1:1 ratio. One group of patients will receive IgM-enriched immunoglobulins
adjunctive treatment in a standard dose of 250mg/kg for 3 days. The other group will receive
IgM-enriched immunoglobulins adjunctive treatment in a variable dose calculated taking note
of the extent of IgM deficit, in order to achieve an IgM threshold value of 100 mg/dL or
above. IgM preparation will be administered in this group up to the withdrawal of vasoactive
drugs with a maximum allowed of 7 days. The confirmation of the efficacy of a tailored
strategy for IgM-enriched immunoglobulin administration in reducing the mortality rate among
patients with septic shock and low IgM titers will lead to a revision of the current clinical
practice in the use of this adjunctive treatment.
Description:
Rationale:
Several clinical studies have reported that serum immunoglobulins concentrations are
generally low in patients with sepsis and that the level and kinetics of serum
immunoglobulins, particularly immunoglobulin M (IgM), seem to be somehow related to patient
outcome. Intravenous administration of immunoglobulin preparations seems to be a promising
treatment option due to their pleiotropic effects on bacteria and the host response to
infections.
In previous clinical experiences, IgM preparation has been mainly administered at the dosage
recommended by Summary of Product Characteristics (250 mg/Kg/day for three consecutive days)
regardless of the patient severity and without any adjustment based on immunoglobulins plasma
concentration or other biomarkers. The recent understanding of the high heterogeneity in
pathobiology led to recommend a more tailored approach in patients with sepsis by modulating
therapies on the basis of specific clinical and biological markers. Therefore, nowadays the
strategy of a fixed-dose should be revised.
Our study hypothesis is that a personalized administration of IgM-enriched immunoglobulin,
calculated based on serum IgM-titers of the patient, will decrease mortality compared to
standard IgM-enriched immunoglobulin treatment (fixed or flat dose).
Study objective:
The primary objective is to verify the hypothesis that adjunctive therapy with IgM-enriched
immunoglobulin with a personalized dose based on serum IgM-titers is more effective in
reducing any-cause mortality in patients with septic shock compared to a flat dose therapy.
Mortality will be measured at 28 days.
The confirmation of the efficacy of an IgM-titre based dose of IgM preparation reducing the
mortality rate among patients with septic shock will lead to a revision of the current
clinical practice in the use of this adjunctive therapy.
Study setting:
The study will involve 12 Italian Intensive Care Units (ICUs). The recruitment of 356
participants will be completed in around 24 months.
Interventions:
Patients who satisfy all inclusion criteria and no exclusion criteria will be randomly
assigned to an IgM titer-based treatment group (Group 1) or an IgM Flat treatment group
(group 2) in a ratio1:1.
The treatment given to patients of both groups during this independent study will be the
IgM-enriched immunoglobulin preparation (IgM preparation) (Pentaglobin®, Biotest, Germany)
commercially available. The IgM preparation contains high titers of antibodies against
lipopolysaccharides and outer membrane proteins of many Gram-negative bacteria. Composition
active ingredients: 1 ml solution contains Human plasma protein 50 mg of which immunoglobulin
at least 95 %, IgM 6 mg, immunoglobulin A (IgA) 6 mg, immunoglobulin G (IgG) 38 mg. Other
constituents: Glucose monohydrate (27.5 mg/ml), sodium chloride (78 μmol/ml), water for
injections (ad 1 ml).
Group 1 (IgM titer-based treatment): The treatment with IgM preparation will be initiated as
soon as possible after randomization (maximum allowed starting time 12h after randomization).
The calculation of the dose is based on IgM single compartment distribution. The first dose
of IgM preparation will be calculated on IgM serum concentration obtained within 24 hours
after shock appearance to achieve serum titers above 100mg/dl. In the next days, the daily
IgM preparation dose will be assessed individually on the basis of IgM serum titers morning
assessment, with the purpose of maintaining IgM serum titers above 100mg/dl, up to
discontinuation of vasoactive drugs or day 7 after enrolment. If the serum titer is above 100
mg/dl, the daily dose of IgM-preparation will be zero, up to the daily serum titer decreases
below 100 mg/dl. In this case, the patient will remain in the study despite he will not
receive the daily dose of IgM preparation. If for whatever reason, IgM serum titers result is
not available, the daily dose will be calculated using the last IgM result obtained within 48
hours. The threshold of 100 mg/dl of IgM serum titers is based on internal preliminary
unpublished data from the University Hospital of Modena showing protective effects compared
to lower levels of IgM. Daily, the calculated dose will be administered in 24 hours in
continuous infusion with a maximum infusion rate of 0,4 ml/kg per hour (20mg/kg per hour)
until reaching the calculated daily dose.
IgM preparation will be administered up to the withdrawal of vasoactive drugs with a maximum
allowed of 7 days of therapy and a maximum dose of 350mg/Kg/day, as reported from previous
experiences.
Group 2 (IgM Flat treatment): The IgM treatment will be initiated as soon as possible after
randomization (maximum allowed starting time 12h after randomization). The dose of IgM
preparation will be 250mg/kg for 3 days, the dose will be administered in 24 hours in
continuous infusion with a maximum infusion rate of 0,4 ml/kg (20mg/kg per hour) until
reaching 250mg/kg.
In both groups, before enrolment in the study, it will be allowed the administration of
intravenous immunoglobulins (either Immunoglobulin G or IgM-enriched preparation) at standard
dosages for a maximum of 6 hours.
Concomitant medications:
Depending on their clinical status, patients will be treated according to the principles of
the Good Clinical Practice, Survival Sepsis guidelines 2016 and clinical judgement of the
attending physician. No other pharmacological therapy or treatment will be influenced by the
study protocol. There are no restrictions to concomitant treatments provided to patients in
this study. All relevant concomitant medications and treatments took or administered in the
24 hours before the screening and during the study period will be recorded.
Criteria for discontinuing or modifying allocated interventions:
The duration of study therapy will be until the withdrawal of vasoactive drugs with a maximum
allowed of 7 days of therapy in the IgM titer based group and 3 days in the Flat treatment
group.
Patients may be prematurely discontinued from study protocol at the discretion of the
Investigator, should any untoward effect occur (including an adverse event (AE) or clinically
significant laboratory abnormality that, in the opinion of the Investigator, warrants the
subject's permanent discontinuation of study protocol-directed care).
Data collection and management:
Every patient who meets the inclusion criteria will be included and randomised in the two
groups. The study data will be collected along the entire study period in a dedicated
electronic Case Report Form (eCRF). The eCRF will be provided by the steering committee with
proper options to minimize data entry errors: the data will incorporate un-amendable fixed
intervals of values (for continuous variables) and pre-defined coding system (for binary or
categorical variables). Data entry will be performed and double-checked from a dedicated
researcher in each centre; in order to limit collection errors, records will be randomly
re-checked from the PI. The data collection will be also checked by a Clinical Monitor,
assigned by the contract research organization (CRO), by phone calls and visits at the study
sites as agreed with the investigators. The study Monitor will be responsible for performing
the monitoring in accordance with good clinical practice (GCP) guidelines. The investigators
and the CRO will agree on monitoring visits to assess the progress of the study, verify
adherence to the protocol, check the eligibility of patients, the accuracy and completeness
of the eCRF, check the correlation between the data reported into eCRF and those recorded in
the hospital documents (medical records, patient registries, etc.), check for the correct
reporting of adverse events, verify that evaluations planned and documentation of the study
are properly stored and handled.
All the data about the included patients will be extrapolated from the clinical documentation
and recorded in an eCRF from the adequately trained researcher. Demographic information
(gender, age), co-morbidities, reason of ICU admission, type of ICU admission (medical,
elective surgery, emergency surgery) will be registered at the inclusion, severity of
critical illness quantified by the Simplified Acute Physiology Score II (SAPS II) will be
calculated by the data from the first 24 h of ICU stay. During the study duration clinical
and laboratory parameters will be evaluated and recorded following the scheduled times: IgM
titers, simplified organ failure assessment (SOFA) score and its components, Multiple Organ
Failure score (MOF score) and its components, vital signs such as mean arterial pressure,
heart rate, respiratory rate, systemic temperature, diuresis, fluid balance, data from
routine laboratory test such as haemoglobin, platelets count, white blood cells count,
troponin, coagulative parameters, parameters for liver and renal function, oxygen inspired
fraction, blood gas analysis results, ventilation mode, need of renal replacement therapy,
blood cells count, C-reactive protein, procalcitonin, occurrence of ICU-acquired blood,
respiratory and urinary-tract infection and the implicated microorganisms, reactivation of
viral infections and MRC scale.
Other recorded parameters will include the duration of ventilatory support in days, duration
and type of antibiotic and antifungal therapy in days, need and the dose of vasoactive drugs.
The application of evidence-based treatments recommended by the guidelines (i.e. blood
collection for microbiological culture, antibiotic and fluid therapies, and the eventual use
of specific adjunctive therapies as for instance steroids and blood purification) will be
recorded.
As a blood-bank for possible further biochemical investigations (e.g. cytokines titers,
different biomarkers), for each patient who will be included in the study a blood sample of
about 6 ml will be collected at baseline, day 7 and 28 or ICU discharge and stored, after
centrifugation, at -70°C in the local laboratory of each site.
Methods for statistical analysis The intention to treat population will be considered for the
primary analysis. A descriptive statistical analysis will be performed to describe every
relevant variable. Kolmogorov-Smirnov normality test will be performed in order to verify the
distribution of the variables. Baseline variables will be compared between the two groups
using the Mann-Whitney U test or t-test as appropriate. Categorical variables will be
compared using Fisher's Exact test. The primary outcome will be assessed by comparison of
proportions of patients alive in both groups at day 28 by using Fisher's exact test. To
compare the treatment effect on the secondary outcomes will be assessed as follow: all-cause
of mortality at ICU discharge, at hospital discharge and at day 90 by Fisher's exact test;
occurrence of new organ dysfunctions and grade or dysfunctions in all the study period by
Fisher's exact test and distribution-free test such as median test respectively; intensive
care unit free hours (IFHs) at 28-day, hospital free days (HFDs) at day 90, ventilator-free
days (VFDs) at 28-day, vasopressors free days (VasoFDs) at 28-day, antibiotic-free days
(AFDs) at 28-day by distribution-free test such as median; ICU acquired weakness assessed
with Medical Research Council (MRC) Scale for Muscle Strength by analysis of variance
including terms for treatment, time and centre.
Every test will be performed considering a two-sided p-value < 0,05 for statistical
significance. In general, categorical data will be presented using counts and percentages,
whilst continuous variables will be presented using the number of patients, mean, standard
deviation, median, minimum, and maximum. 95% confidence interval will be calculated for the
primary variable and the relevant secondary variables.
Subgroup analysis: The primary and secondary outcomes will be evaluated in pre-defined
subgroups: distribution of SAPS II and SOFA score (total and for single organ) at admission,
surgical admissions compared to non-surgical admissions, type of pathogen cause of septic
shock, site and type of infection, distribution of IgM and IgG plasma concentration at
baseline and at day 3, biomarkers reactive protein C (CRP) and procalcitonin (PCT)
distribution at baseline and at day 3, patients with end-stage liver disease compared to
patients without and patients with malignancies compared to patients without.
Data monitoring An independent Data Safety Monitoring Board (DSMB), consisting of 2 experts
in clinical research in intensive care and 1bio-statistic will be established before patient
enrolment. The DSMB Charter will be prepared by the steering committee and signed by the
members of the DSMB before the trial commences. The DSMB will have access to all results and
make the appropriate considerations about the appropriateness of the sample size, the
efficiency and quality of data collection system, eventual occurrence of a suspected
protocol-related adverse event. The DSMB has the right to stop the trial for safety reasons.
Analyses ad interim Considering a statistical approach based on two phases, an interim
analysis is planned after the randomization of 178 patients (50% of sample size) for the
double objective of monitoring safety and verifying the accuracy of the assumptions made for
sample size estimation regarding the primary end-point event rate in relation to the
anticipated survival benefit. With the interim analysis, we will be able to evaluate whether
there is a substantial superiority of one treatment. The obtained results will be evaluated
by the DSMB and by the steering committee and, in case of significant differences in survival
among the two groups, all patients will be switched to the most promising treatment.
Harms Previous studies did not identify specific risks correlated to intravenous
immunoglobulins preparations enriched with IgM. However, all the included patients will be
intensively monitored following the standard procedures of intensive care medicine and any
suspected protocol-related adverse event will be reported to the steering committee, the data
safety and monitoring board, other participating centres and the competent authorities. In
Beyond suspected protocol-related adverse event, the data safety and monitoring board will
have access to all results of the trial and make the appropriate considerations about the
appropriateness of the sample size, the efficiency and quality of data collection system and
has the right to stop the trial for safety reasons or futility.
Ethics and dissemination The study will be conducted in line with the protocol, the
Declaration of Helsinki (1964) and subsequent amendments and updates(Fortaleza, Brazil,
October 2013). Moreover, it is the responsibility of the investigator to ensure that the
study will be done in line with the requirements of Good Clinical Practice(GCP) and the
applicable regulatory requirements.
Research ethics approval The entire study protocol, including informative material for the
patients and modules for the informed consent, ill be evaluated by the Local Ethics Committee
(EC) from the coordinating centre and all the collaborating centres. The study will not start
before obtaining a favourable opinion from the EC, the Competent Authority Authorization and
any other authorization required by local regulation. Every intention to modify any element
of the original protocol after the first approval will be promptly notified to the Ethics
Committee and will be applied only after its written authorization.
Investigator/sponsor will be responsible to submit to the Ethics Committee any amendments to
the protocol.
Consent and confidentiality Before inclusion in the study, conscious patients must be
informed of the purpose and clinical procedures required by the protocol. The investigators
will explain the purpose, risks and benefits associated with study participation. Besides,
patients will be informed of his right to withdraw from the study at any time without
explanation and without losing the right to future medical care.
If the patient will be unable to comprehend or to give his consent (because of compromised
neurological status), the following consent options are acceptable: (i) A priori consent by a
legal representative (ii) delayed consent from a legal representative; (iii) Delayed consent
from the patient; (iv) waiver of consent; (v) consent provided by an ethics committee or
other legal authority. Which options are available at individual participating sites will be
determined by the relevant ethics committee and subject to applicable laws. All participants
who recover sufficiently will be allowed to provide informed consent for ongoing study
participation and the use of data collected for the study. Every patient is free to leave the
study protocol at any stage of the study and can request to retire his consent and,
consequently, to ask the elimination of all his data from the database.
In order to comply with legal requirements regarding privacy and the processing of sensitive
personal data, Legislative Decree 30/06/2003 n. 196 on the protection of personal data and
Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on
the protection of natural persons with regard to the processing of personal data and on the
free movement of such data, and repealing Directive 95/46/EC (General Data Protection
Regulation), each patient will be given an information sheet on the study they participate in
and will be asked for sign the consent to the processing of personal data.
Data about personal and private information, included sensible data, will be treated
following current legislation on data protection; patients will be identified with a coding
system and data registered in an anonymous form. Collected data will be processed by the
Investigator for the exclusive purposes of fulfilling to the present study requirements, and
in an anonymous form, aggregate in the study database with data obtained from the other
patients participating, solely on the basis of finalizing the study and achievement
objectives.
Obtained data will not be disclosed except in strictly anonymous and aggregated form. Direct
access to the original medical records may be requested only by commissioning DSMB of the
study and will be accessible by a representative of the CRO, its delegate to perform
monitoring on the conduct of the trial, the EC or by the Regulatory Authorities, such as
personnel of the Italian Ministry of Health and the Italian Medicines Agency (AIFA) to verify
that the information entered in the documents of the study is correct and methods that
guarantee the privacy and confidentiality of the data are respected.
Dissemination policy The Circ. Min. Health N° 6 of 09/02/2002 obliges each researcher who
gets any results of interest to public health, to publish the results within 12 months from
the end of the study. All the patients will freely agree or disagree to participate in the
study in the belief that the results will be useful to improve knowledge about their
pathologies, for health benefit from themselves or other patients. To respect their will and
in the maximum interest of honest clinical research, the investigators agree on the need to
ensure the wide publication and diffusion of their results in a consistent and responsible
way under their responsibility. The study coordinator is the official data owner. The
steering committee has the right to present methods and results of the study at public
symposia and conferences. The principal publications from the trial will be in the name of
Investigators with full credit assigned to all collaborating investigators and institutions.
