Efficacy and Safety of Therapy With IgM-enriched Immunoglobulin With a Personalized Dose vs Standard Dose in Patients With Septic Shock.

NCT04182737 | Unknown Phase 3 DMC

• 2 other identifiers: IgM-FAT-3.0-22-12-20182018-001613-33
• Study Type: interventional
• Target: 356
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Shock, Septic; Sepsis; Hypoglobulinemia

Keywords

immunoglobulins; septic shock; adjunctive treatment; critically ill patients

Outcome Measures

Primary Outcomes (1)

• All-cause mortality at day 28

  All-cause mortality at day 28, defined as the comparison of proportions of patients death for any cause at day 28 from randomization.

  Day 28 from randomization

Secondary Outcomes (13)

• All-cause mortality at ICU discharge

  ICU discharge, censored at day 28

• All-cause mortality at hospital discharge

  Hospital discharge, censored at day 90

• All-cause mortality at day 90

  Day 90 from randomization

• New organ dysfunction during ICU stay

  From randomization to ICU discharge, censored at day 28

• New organ dysfunction during ICU stay

  From randomization to ICU discharge, censored at day 28

Study Arms (2)

IgM titer-based treatment

EXPERIMENTAL

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 assessment performed in the morning with the purpose of maintaining IgM serum titers above 100 mg/dl, up to discontinuation of vasoactive drugs or day 7 after enrolment. 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). 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.

Drug: IgM-enriched polyclonal immunoglobulins titer-based treatment

IgM Flat treatment

ACTIVE COMPARATOR

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.

Drug: IgM-enriched polyclonal immunoglobulins Flat treatment

Interventions

IgM-enriched polyclonal immunoglobulins titer-based treatment DRUG

Immunoglobulins will be administered in a personalized dose based on serum IgM-titers

Also known as: Pentaglobin®, IgM-enriched polyclonal immunoglobulins

IgM titer-based treatment

IgM-enriched polyclonal immunoglobulins Flat treatment DRUG

Polyclonal endovenous immunoglobulins enriched in IgM administered in standard fixed dosages

Also known as: Pentaglobin®, IgM-enriched polyclonal immunoglobulins

IgM Flat treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years;
• Septic shock occurrence \< 24 hours; septic shock is identified according to Sepsis-3 definition by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (\>18 mg/dL) in the absence of hypovolemia in patients with sepsis2. Sepsis is defined as a life threatening organ dysfunction identified as an acute change in total SOFA score ≥2 points consequent to the infection;
• IgM-titers\< 60mg/dl (or \< 20% of the lower threshold value of local laboratory) within24hours from shock occurrence.

You may not qualify if:

• Shock of uncertain diagnosis;
• Hypersensitivity to IgM Preparation in use or its excipients;
• Patients receiving intravenous immunoglobulins (e.g. IgG or IgM enriched preparations) for \> 6 hours before enrolment;
• Selective absolute IgA deficiency with antibodies to IgA;
• Clinical decision to withhold life-sustaining treatment or "too sick to benefit";
• Neutrophil count \<1.000/mm3;
• Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition);
• Patients with a known, chronic kidney dysfunction needing dialysis (creatinine ≥ 3.4 mg/dl or creatinine clearance ≤ 30 ml/min/1.73m2);
• Body Mass Index (BMI) \>40;
• Participation in other clinical trials on adjunctive therapies for sepsis (during past 3 months);
• Lack of withdrawal of informed consent.

Sponsors & Collaborators

• Massimo Girardis: lead

Study Sites (1)

ICU- University Hospital Modena

Modena, 41124, Italy

RECRUITING

Related Publications (1)

• Biagioni E, Tosi M, Berlot G, Castiglione G, Corona A, De Cristofaro MG, Donati A, Feltracco P, Forfori F, Fragranza F, Murino P, Piazza O, Tullo L, Grasselli G, D'Amico R, Girardis M. Adjunctive IgM-enriched immunoglobulin therapy with a personalised dose based on serum IgM-titres versus standard dose in the treatment of septic shock: a randomised controlled trial (IgM-fat trial). BMJ Open. 2021 Feb 11;11(2):e036616. doi: 10.1136/bmjopen-2019-036616.

  PMID: 33574139 DERIVED

MeSH Terms

Conditions

Shock, Septic; Sepsis

Interventions

pentaglobulin

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Central Study Contacts

Massimo Girardis, PD

CONTACT

0594225878; massimo.girardis@unimore.it

Emanuela Biagioni, MD

CONTACT

0594224897; emanuela.biagioni@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: The study is conceived as single blinded: only the patients will be not aware of the group allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: The study is designed as a multicentre, national, interventional, randomized, single-blinded, prospective, investigator sponsored, two arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to IgM titer-based treatment or flat treatment group in a ratio 1:1. A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by centre. Central randomisation will be performed using a secure, web-based, randomisation system. The allocation sequence will be generated by the study statistician using computer generated random numbers.

Study Record Dates

• First Submitted: November 26, 2019
• First Posted: December 2, 2019
• Study Start: May 1, 2020
• Primary Completion: February 28, 2022
• Study Completion: March 31, 2022
• Last Updated: May 6, 2021

Record last verified: 2021-05

Locations

IT (1)