Personalised Medicine With IgGAM Compared With Standard of Care for Treatment of Peritonitis After Infectious Source Control (the PEPPER Trial)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test the adjuvant Immuneglobulins G, A and M (IgGAM) treatment for: An improvement of the outcome for the patient's peritonitis. This will be investigated by using scores such as the multiple organ failure (MOF) and Sequential Organ Failure Assessment (SOFA) scores as well as survival data. Identification of biomarkers [Ig level, procalcitonin (PCT), interleukin-6 (IL 6), Human Leukocyte Antigen - antigen D Related (HLA DR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF kB1), adrenomedullin (ADM), pathogen spectrum], to identify patient subpopulations that profit most from treatment with IgGAM. Such patients will comprise the basis for a further study, which will be a randomised, controlled, double-blind trial (RCT) to demonstrate the value of this treatment. Furthermore, these biomarkers are expected to help with developing a personalised adjuvant therapy with IgGAM in the indication of peritonitis.

Detailed Description
-----------------
The purpose of this study is to test the adjuvant IgGAM treatment for: An improvement of the outcome for the patient's peritonitis. This will be investigated by using scores such as the multiple organ failure and SOFA scores as well as survival data. Identification of biomarkers (Ig level, PCT, IL 6, HLA DR, Nf kB1, ADM, pathogen spectrum), to identify patient subpopulations that profit most from treatment with IgGAM. Such patients will comprise the basis for a further study, which will be a randomised, controlled, double-blind trial (RCT) to demonstrate the value of this treatment. Furthermore, these biomarkers are expected to help with developing a personalised adjuvant therapy with IgGAM in the indication of peritonitis. The control group will receive standard-of-care treatment, i.e., the IgGAM is an add-on treatment in this study. The active study treatment is IgGAM (Pentaglobin®). IgGAM is administered by continuous infusion over 5 days at a dose level of 0.4 ml per kg body weight per hour, until a total dose of 7 ml/kg on that day has been reached; administration will then be stopped and recommenced on the following day, until administration has been completed for 5 consecutive days. Primary target variable The relative number of patients whose MOF score improves by 0.8 points on Day 7 (i.e., percentage of 'responders'). The primary analysis will be performed with the per protocol population (see below). The MOF score is determined in the morning, with the following scoring for each organ (lungs, heart, kidneys, liver, blood): normal function, 0; dysfunction, 1; individual organ failure, 2. An aggregate score greater than 4 implies multi-organ failure. Patients who die will be assigned the maximum score of 10 and will be included in the population assessment. Secondary target variables Overall 28-day survival, Overall 90-day survival, MOF score on Day 5, Relative number of patients with MOF (i.e., > 4 MOF points) on Day 7. Additional study variables Time course of the biomarkers (PCT, IL 6, HLA DR, ADM, Immuneglobulins M, G, A), the SOFA score, the Mannheim Peritonitis Index, the surrogate variables for organ dysfunction and survival according to Heyland et al. 2011 and vital signs. Influence of the biomarkers NF kB1, ADM and pathogen spectrum upon the outcome for the patient. Comparison of the MOF score with other scores, such as the SOFA score, for assessment of organ dysfunction.

Official Title
-----------------
Personalised Medicine With IgGAM Compared With Standard of Care for Treatment of Peritonitis After Infectious Source Control (the PEPPER Trial): a Randomised, Controlled Trial

Conditions
-----------------
Peritonitis, Sepsis

Intervention / Treatment
-----------------
* Drug: Pentaglobin®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Peritonitis The time of the surgical infectious source control must have been within 6 h after the indication (defined as the time of the registration of the surgical procedure/ minimal invasive surgery) Sepsis and septic shock (according to the current Sepsis Guideline) SOFA Score ≥ 8 IL-6 ≥ 1000 pg / ml Start of therapy with antibiotics and IgGAM (Pentaglobin) within 12 hours after admission to the ICU Signed informed consent by the patient himself or by his legal representative, such as a court-appointed supervisor or by an authorized proxy authorized representative or by a consultant Exclusion criteria Patients with a life expectancy of less than 90 days due to medical conditions that are not associated with postoperative peritonitis or with sepsis / septic shock Pregnant, breastfeeding women Minors (< 18 years) Patients with a known dialysis-requiring chronic renal function (creatinine ≥ 3.4 mg / dl or creatinine clearance ≤ 30 mL / min / 1.73 m2) Patients with acute, primary non-infectious pancreatitis or mediastinitis BMI> 40 Patients with a contraindication to study medication Participate in another medication study within the last 30 days Persons who are in a relationship of dependency or employment relationship with the sponsor or auditor Persons who are placed in an institution on a judicial or administrative order

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The control group will receive standard-of-care treatment, i.e., the IgGAM is an add-on treatment in this study. The active study treatment is IgGAM (Pentaglobin®). The preparation to be provided contains (per ml solution) 50 mg human plasma proteins, of which >95% are immunoglobulins: IgM 6 mg, IgA 6 mg and IgG 38 mg. The IgG subclass distribution is IgG1  63%, IgG2  26%, IgG3  4%, IgG4  7%. IgGAM is administered by continuous infusion over 5 days at a dose level of 0.4 ml per kg body weight per hour, until a total dose of 7 ml/kg on that day has been reached; administration will then be stopped and recommenced on the following day, until administration has been completed for 5 consecutive days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: A: Control group<br>Standard of Care | |
| Active Comparator: B: Pentaglobin®<br>Standard of Care + Pentaglobin® | Drug: Pentaglobin®<br>* Standard of Care + Pentaglobin®<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative number of patients whose MOF score improves by 0.8 points on Day 7 (i.e., percentage of 'responders') [%] | The relative number of patients whose MOF score improves by 0.8 points on Day 7 (i.e., percentage of 'responders'). The MOF score is determined in the morning, with the following scoring for each organ (lungs, heart, kidneys, liver, blood): normal function, 0; dysfunction, 1; individual organ failure, 2. An aggregate score greater than 4 implies multi-organ failure. Patients who die will be assigned the maximum score of 10 and will be included in the population assessment. Day 7 | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of survivers on day 28 [-] | Evaluation of the Overall 28-day survival. Day 28 | 28 days | 
| Number of survivers on day 90 [-] | Evaluation of the Overall 90-day survival. Day 90 | 90 days | 
| MOF Score on day 5 [-] | MOF Score on day 5 Day 5 | 5 days | 
| Relative number of patients with MOF (i.e., > 4 MOF points) on Day 7 [%] | Relative number of patients with MOF (i.e., > 4 MOF points) on Day 7 [%] Day 7 | 7 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pentaglobin®, Personalised Medicine