Trimodulin for Severe Community-acquired Pneumonia (ESsCAPE Trial)
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Biotest
Stay on your current meds
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests if trimodulin, added to usual care, helps adults with severe lung infections who need breathing machines recover faster by boosting their immune system.
Is Trimodulin a promising treatment for severe community-acquired pneumonia?Trimodulin is a promising treatment because it can help the immune system fight infections better, potentially improving recovery from severe pneumonia.12458
What safety data is available for Trimodulin in treating severe pneumonia?The research provided does not directly mention Trimodulin or its alternative names such as BT 588, BT086, or IgM concentrate - Biotest. However, it includes studies on similar treatments like gamma-globulin preparations and intravenous immune globulins, which are generally well-tolerated with minimal adverse reactions. For example, the study on SM-4300 reported no remarkable adverse reactions, and the study on a 10% liquid intravenous immune globulin noted headache as the most common adverse experience, occurring in 6.9% of infusions. These findings suggest that similar treatments have a good safety profile, but specific safety data for Trimodulin itself is not provided in the research.3671011
What data supports the idea that Trimodulin for Severe Community-acquired Pneumonia is an effective treatment?The available research shows that Trimodulin, a treatment for severe community-acquired pneumonia, was associated with lower death rates in patients who had high levels of a specific protein in their blood, called C-reactive protein, or low levels of a type of antibody called IgM. This suggests that Trimodulin can be effective in reducing mortality in these patients. Additionally, Trimodulin was shown to have a balancing effect on the immune system, which can help manage severe infections by enhancing the body's ability to fight off pathogens while preventing excessive inflammation.912131415
Do I have to stop taking my current medications for this trial?The trial protocol does not specify if you must stop all current medications. However, you cannot participate if you've been treated with certain medications in the last 5 days or with polyvalent immunoglobulin, plasma, or albumin preparations in the last 21 days. Ongoing treatment with immunosuppressants not recommended for pneumonia is also not allowed.
Eligibility Criteria
Adults hospitalized with severe community-acquired pneumonia who need mechanical ventilation can join this trial. They must not have COVID-19, should show signs of inflammation, and agree to use contraception. Excluded are those with severe kidney or liver issues, certain blood disorders, obesity or malnutrition extremes, other serious lung diseases or heart failure, recent cancer treatments outside the lungs/head/neck area, and those on specific medications.Inclusion Criteria
I have been diagnosed with active pneumonia.
I need a machine to help me breathe due to severe lung problems.
I am an adult currently in the hospital.
Exclusion Criteria
I am not on immunosuppressants, except for those prescribed for pneumonia.
I haven't had treatments for cancers in the chest, head, neck, or blood in the last year.
I do not have severe lung diseases that would affect my treatment.
I am on dialysis or have severe kidney problems.
I have a condition that breaks down my red blood cells.
My BMI is either above 40 or below 16.
I am suspected to have pneumonia acquired from a hospital stay.
I have end-stage kidney disease or a specific kidney condition called FSGS.
I have been diagnosed with severe heart failure.
I have not taken certain medications in the last 5 days.
I have severe liver problems or liver cancer.
I have a history of blood clots or am at high risk for them.
I have not received immunoglobulin, plasma, or albumin treatments in the last 21 days.
Treatment Details
The trial is testing Trimodulin as an extra treatment alongside standard care for adults with severe pneumonia requiring breathing support compared to a placebo plus standard care. It also looks at how the body processes Trimodulin and its effects on the disease.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: TrimodulinExperimental Treatment1 Intervention
Trimodulin (human IgM, IgA, IgG solution) for intravenous (IV) administration.
Group II: PlaceboPlacebo Group1 Intervention
Human albumin 1%
Find a clinic near you
Research locations nearbySelect from list below to view details:
Hannibal ClinicHannibal, MO
Medical City Fort WorthFort Worth, TX
Investigational site # 1010Lansing, MI
Buffalo VA Medical CenterBuffalo, NY
More Trial Locations
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Who is running the clinical trial?
BiotestLead Sponsor
References
Localization of inhaled trimellitic anhydride to lung with a respiratory lymph node antibody secreting cell response. [2019]Male Sprague-Dawley rats were exposed to trimellitic anhydride (TMA) by inhalation (500 micrograms/m3), 4 hours a day, for 1 to 10 days. TMA was localized to lung cells by immunoelectron microscopy. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were used in an attempt to localize TMA to lung lavage proteins. The lung-associated lymph node (LALN) B-lymphocyte response was measured by quantitation of immunoglobulin (Ig)G, IgA, and IgM antibody secreting cells specific for TMA rat serum albumin (TM-RSA) by use of the enzyme-linked immunospot assay (ELISPOT) method. The IgG, IgM, and IgA antibody response to TM-RSA in serum and lavage fluid was quantitated by ELISA. Lung injury was assessed by the number of external lung hemorrhagic foci and lung weight. Immunoelectron microscopy localized TMA to alveolar and bronchial cells on all exposure days. ELISA detected trace amounts of TMA haptenized lavage proteins that could not be detected by Western blot analysis. A marked increase occurred in lung injury from day 7 to 10. The LALN IgG, IgA, and IgM antibody secreting cell response to TM-RSA paralleled measures of lung injury. IgG, IgM, and IgA serum and lavage antibody to TM-RSA were correlated with lung injury measures. Lavage and serum IgG antibody levels had the highest correlation with lung injury.
Specific immunological and bronchopulmonary responses following intradermal sensitization to free trimellitic anhydride in guinea pigs. [2019]We have developed a guinea pig model of trimellitic anhydride-induced airway hypersensitivity responses. In one group of guinea pigs, injected intradermally with 0.1 ml 30% trimellitic anhydride (TMA), we examined the specificity of the bronchopulmonary response to TMA comparing the effect of intravenous TMA conjugated to guinea pig serum albumin (GPSA) with a control hapten (procion dye) protein conjugate (PD-GPSA). A significant increase in pulmonary inflation pressure (PIP) was provoked in sensitized animals following intravenous injection with TMA-GPSA (20%; 0-400, median; range) as compared to intravenous injection of PD-GPSA. In the second group we compared three different methods of sensitization: single injection of 0.1 ml of 0.3% TMA; four injections of 0.1 ml of 0.1% TMA; and a single high dose injection of 30% TMA. Following intravenous TMA-GPSA guinea pigs sensitized with a single injection 0.3% TMA had an increase in PIP of 395%; 220-600, while those given four repeat injections of 0.1% TMA had an increase in PIP of 343%; 315-490. These results were significantly higher than the increase in PIP (160%; 0-220) which occurred in guinea pigs sensitized with a single dose of 30% TMA. Four of 11 guinea pigs given low dose injections of TMA had bronchopulmonary responses to inhaled TMA-GPSA. All sensitized guinea pigs had specific IgG1 antibodies demonstrated by enzyme linked immunosorbent assay (ELISA) and confirmed by ELISA inhibition. Four guinea pigs sensitized by low dose injections of TMA had IgE antibodies demonstrated by passive cutaneous anaphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)
[The concomitant effect of a newly developed gamma-globulin preparation (SM-4300) with some antibiotics on severe bacterial infections]. [2016]Twenty-six patients with bacterial infections, mainly respiratory infections, were treated with newly developed gamma-globulin preparation (SM-4300), as a combination therapy with some antibiotics. The result was as follows. Clinical effects of 18 cases evaluated were excellent in 1 case (5.6%), good in 10 (55.6%), fair in 4 (22.2%) and poor in 3 (16.7%). No remarkable adverse reactions and abnormal value in laboratory data due to administration of SM-4300 were observed. Significant changes of complement system before and after administration of SM-4300 were not observed. It was considered that SM-4300 was effective as a combination therapy with some antibiotics for the treatment of severe or refractory bacterial infections.
Induction of immunologic tolerance to the trimellitate haptenic group in mice: model for a therapeutic approach to trimellitic anhydride-induced hypersensitivity syndromes in humans? [2019]IgE and IgG antibody responses to the trimellitate (TM) hapten group were elicited in mice by the intraperitoneal injection of the hapten coupled with keyhole limpet hemocyanin (KLH). Treatment of such previously sensitized mice with the same hapten coupled to synthetic copolymer of D-glutamic acid and D-lysine (D-GL) after primary immunization resulted in significant and specific suppression of anti-TM antibody responses in both IgE and IgG classes. These results provide direct evidence for the potential clinical usefulness of the D-GL immunotherapeutic approach to TMA sensitivity in humans.
The role of IgG1 and IgG2 in trimellitic anhydride-induced allergic response in the guinea pig lung. [2012]Trimellitic anhydride (TMA) is a small molecular weight chemical used in the paint and plastics industry that can cause asthma-like symptoms in humans. Guinea pigs sensitized intradermally with TMA will respond to antigen challenge with asthma-like symptoms, including an immediate bronchoconstriction and a delayed cellular infiltration into the lung, particularly eosinophil infiltration. Sensitized guinea pigs produce TMA-specific IgG1, which is thought to be important in asthmatic reactions in this animal model; however, they also produce TMA-specific IgG2 antibody. The purpose of the present study was to determine the role of IgG1 and IgG2 in the TMA-induced immediate bronchoconstriction and delayed cellular infiltration in the guinea pig. Guinea pigs were passively sensitized by intratracheal instillation of TMA-specific IgG2, an antibody preparation enriched with TMA-specific IgG1, or a combination of the two. The allergic response was induced by intratracheal instillation of TMA conjugated to guinea pig serum albumin (TMA-GPSA). A significantly greater bronchoconstrictor response was observed in animals sensitized with a combination of the IgG2 and IgG1 preparation compared to those sensitized with IgG2 or the IgG1 preparation alone. Cellular infiltration was quantified 24 h after antigen challenge by differential cell counts of bronchoalveolar lavage (BAL) cells as well as by using eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activity as a measure of the numbers of eosinophils and neutrophils, respectively. In the BAL, passively sensitizing with IgG2 alone resulted in an increase in both TMA-induced MPO and EPO activity. In contrast, in the lung, passively sensitizing with a partially purified preparation of TMA-specific IgG1 alone resulted in a significant increase in TMA-induced EPO activity. Passively sensitizing with IgG2 in conjunction with the IgG1 preparation resulted in an enhanced cellular infiltration and lung injury over that seen with either antibody preparation alone. These data demonstrate an augmentation of IgG1-mediated responses by the addition of IgG2 and suggest a significant role for both subclasses of IgG antibodies in this guinea pig model of TMA-induced occupational asthma.
Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [IGIV 10%] in patients with primary immunodeficiency. [2018]The present clinical study was designed to evaluate the efficacy, pharmacokinetics and safety of a new 10% liquid intravenous immune globulin in patients with primary immunodeficiency diseases. Sixty-one adults and children with primary immuno-deficiency diseases received doses of 300-600 mg/kg body weight every 21-28 days for 12 months. No validated acute serious bacterial infections were reported. The 95% confidence interval for the annualized rate of acute serious bacterial infections (primary endpoint) was 0-0.060. A total of four predefined validated other bacterial infections commonly occurring in primary immunodeficiency disease subjects were observed; none were serious, severe or resulted in hospitalization. The median elimination half-life of IgG was 35 days. Median total IgG trough levels varied from 9.6 to 11.2 g/L. Temporally associated adverse experiences were determined for 72 h after each infusion and the most common adverse experience was headache, which was associated with 6.9% of infusions. The study met the primary endpoint for efficacy and demonstrated excellent tolerability of the new 10% liquid intravenous imunoglobulin preparation.
Use of immunoglobulins in adults in a university hospital: a retrospective study. [2016]New applications are always being developed for immunoglobulins; new recommendations are regularly published. We wished to know the indications used in a large hospital. A hundred and thirty-six adult patients were prescribed immunoglobulins from January to December 2008. Three preparations in intravenous immunoglobulins were available (one liquid, 2 freeze-dried). Fourteen charts were rejected for clerical errors. A hundred and twenty two charts were available for statistical study. Thirty-six patients were on immunoglobulins for antibody deficiency, 19 were followed in haematology for chronic lymphoid leukaemia or multiple myeloma, 19 were treated after lung transplantation, 17 had received a kidney transplant, 1 after heart transplantation: these indications were substitution. Twenty for Guillain Barré and chronic demyelinating polyneuropathy, 10 in immune thrombocytopenic purpura: this was for immunomodulation. Recommendations were followed by the prescribers; charts were reviewed in March and November 2009. Side-effects were rare. (0.6%) (1).
A novel mannoside-glycocluster adjuvant: Compared in vitro to CpG ODN and MPL and tested in vivo in mouse asthma model. [2016]Allergen-specific immunotherapy balances the Th2-biased immunity towards Th1 and Treg responses. Adjuvants are used in allergen preparations to intensify the immune responses. The increased prevalence of allergies in developed societies has been associated with decreased microbial load during childhood. This has initiated a search for microbial structures to be used as adjuvants. Our study has shown that a synthetic triacedimannose (TADM) may suppress the Th2-type allergic inflammatory response. The aim of this study was to compare the properties of TADM with capacities of other adjuvants, CpG ODN and MPL, to modulate cytokine production in PBMC and regulate sensitisation in an OVA-sensitised mouse asthma model.
Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). [2021]The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP).
Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. [2022]Endogenous antibodies (eAbs) against Clostridioides (Clostridium) difficile toxins may protect against recurrence of C. difficile infection (rCDI). This hypothesis was tested using placebo group data from MODIFY (Monoclonal Antibodies for C. difficile Therapy) I and II (NCT01241552 and NCT01513239, respectively), global, randomized phase 3 trials that assessed the efficacy and safety of the antitoxin monoclonal antibodies bezlotoxumab and actoxumab in participants receiving antibiotic therapy for CDI.
Efficacy and Safety of Monoclonal Antibodies Against Clostridioides difficile Toxins for Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis. [2023]Clostridioides difficile infection is one of the most common health care-associated infections. To reduce the recurrent Clostridioides difficile infection (rCDI), monoclonal antibodies against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab) were developed. In the present study, we performed a systematic review and meta-analysis to assess their efficacy and safety.
Immunomodulation: Immunoglobulin Preparations Suppress Hyperinflammation in a COVID-19 Model via FcγRIIA and FcαRI. [2022]The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and "cytokine storm". The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.
The Dual Role of a Polyvalent IgM/IgA-Enriched Immunoglobulin Preparation in Activating and Inhibiting the Complement System. [2023]Activation of the complement system is important for efficient clearance of a wide variety of pathogens via opsonophagocytosis, or by direct lysis via complement-dependent cytotoxicity (CDC). However, in severe infections dysregulation of the complement system contributes to hyperinflammation. The influence of the novel IgM/IgA-enriched immunoglobulin preparation trimodulin on the complement pathway was investigated in in vitro opsonophagocytosis, binding and CDC assays. Immunoglobulin levels before and after trimodulin treatment were placed in relation to complement assessments in humans. In vitro, trimodulin activates complement and induces opsonophagocytosis, but also interacts with opsonins C3b, C4b and anaphylatoxin C5a in a concentration-dependent manner. This was not observed for standard intravenous IgG preparation (IVIg). Accordingly, trimodulin, but not IVIg, inhibited the downstream CDC pathway and target cell lysis. If applied at a similar concentration range in healthy subjects, trimodulin treatment resulted in C3 and C4 consumption in a concentration-dependent manner, which was extended in patients with severe community-acquired pneumonia. Complement consumption is found to be dependent on underlying immunoglobulin levels, particularly IgM, pinpointing their regulative function in humans. IgM/IgA provide a balancing effect on the complement system. Trimodulin may enhance phagocytosis and opsonophagocytosis in patients with severe infections and prevent excessive pathogen lysis and release of harmful anaphylatoxins.
The Functional Role of IgA in the IgM/IgA-Enriched Immunoglobulin Preparation Trimodulin. [2023]In comparison to human immunoglobulin (Ig) G, antibodies of IgA class are not well investigated. In line with this, the functional role of the IgA component in IgM/IgA-enriched immunoglobulin preparations is also largely unknown. In recent years, powerful anti-pathogenic and immunomodulatory properties of human serum IgA especially on neutrophil function were unraveled. Therefore, the aim of our work is to investigate functional aspects of the trimodulin IgA component, a new plasma-derived polyvalent immunoglobulin preparation containing ~56% IgG, ~23% IgM and ~21% IgA. The functional role of IgA was investigated by analyzing the interaction of IgA with FcαRI, comparing trimodulin with standard intravenous IgG (IVIG) preparation and investigating Fc receptor (FcR)-dependent functions by excluding IgM-mediated effects. Trimodulin demonstrated potent immunomodulatory, as well as anti-pathogenic effects in our neutrophil model (neutrophil-like HL-60 cells). The IgA component of trimodulin was shown to induce a strong FcαRI-dependent inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) signaling, counteract lipopolysaccharide-induced inflammation and mediate phagocytosis of Staphylococcus aureus. The fine-tuned balance between immunomodulatory and anti-pathogenic effects of trimodulin were shown to be dose-dependent. Summarized, our data demonstrate the functional role of IgA in trimodulin, highlighting the importance of this immunoglobulin class in immunoglobulin therapy.
The immunomodulating activity of trimodulin (polyvalent IgM, IgA, IgG solution): a post hoc analysis of the phase II CIGMA trial. [2023]The phase II CIGMA trial performed in 160 patients with severe community-acquired pneumonia (sCAP) found treatment with trimodulin (human polyvalent immunoglobulin [Ig]: ~ 23% IgM, ~ 21% IgA, ~ 56% IgG) was associated with a lower mortality in those patients with elevated baseline serum levels of C-reactive protein (CRP) and/or subnormal IgM.