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Transcriptome and Metabolic Analyses of CHAPLE Disease (CHAPLEOMIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03950804
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : August 14, 2019
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Ahmet Ozen, Marmara University

Brief Summary:
CHAPLE syndrome (complement hyperactivation, angiopathic thrombosis, protein losing enteropathy) is a newly discovered genetic disorder, which is caused by deleterious mutations in the CD55 gene. Patients often suffer from chronic manifestations that may lead to life-threatening complications despite conventional treatment options.The cause of gastrointestinal protein loss is distorted lacteals in the gut, referred to as primary intestinal lymphangiectasia (PIL). There is a second group of patients with PIL with intact CD55, referred to here as "non-CHAPLE PIL". The current study aims to explore the signatures of CHAPLE and non-CHAPLE PILs, discover druggable molecular targets and identify biomarkers that can direct therapy. A subgroup of patients with CHAPLE syndrome receive treatment with a complement C5 blocker, eculizumab, on an off-label basis. This study involves serial transcriptome and metabolic profiling of biological samples under eculizumab therapy and correlates them with the clinical response. Overall, the aim of this research is to integrate clinical data and high-throughput metabolic profiling approaches to better characterize the etiology of PILs and develop novel therapeutic approaches.

Condition or disease Intervention/treatment
CD55 - Cluster of Differentiation Antigen 55 Deficiency Primary Intestinal Lymphangiectasis Protein-Losing Enteropathies Complement Regulatory Factor Defect Drug: Eculizumab Injection

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 60 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 24 Months
Official Title: Transcriptome and Metabolic Analyses of CHAPLE Disease Patients With or Without Eculizumab Treatment
Actual Study Start Date : June 15, 2018
Estimated Primary Completion Date : September 15, 2019
Estimated Study Completion Date : June 15, 2020

Group/Cohort Intervention/treatment
CHAPLE patients, without eculizumab treatment
Patients with suspected CHAPLE syndrome undergo flow-cytometry based CD55 surface staining of peripheral blood samples. Those patients with loss of CD55 protein expression are diagnosed with CHAPLE syndrome. A subgroup of the CHAPLE patients describe only mild symptoms and are not treated with eculizumab, but monitored closely for any disease progression.
Control subjects- no intervention
Healthy subjects with no history of any chronic disease. All investigational analyses are performed on both the case and the control subjects. Therefore, the same type of biological specimens collected from the case group are collected from the control group simultaneously.
PIL patients with intact CD55 on flow-cytometry assesment undergo genetic testing to exclude a potential missense mutation in the CD55 gene that impairs its function while retaining protein expression. Overall, patients and their parents undergo exome sequencing as trios, and examined for potential gene mutations underlying their disease. Non-CHAPLE PILs are also examined by high-throughput investigation similarly to CHAPLE patients.
CHAPLE patients on eculizumab
Among CHAPLE patients, there is a subgroup who receive eculizumab treatment. These patients are prospectively followed and biological samples collected at baseline as well as periodically under therapy. Eculizumab (Soliris) is being provided for CHAPLE patients on an off-label basis upon approval of the physician's request of the drug by Turkish Medicines and Medical Devices Agency (TMMDA) of Turkish Ministry of Health. The dosage and interval of the drug is determined according to manufacturer's recommendations based on the weight of the patients.
Drug: Eculizumab Injection
Patients receive eculizumab as deemed necessary by the primary physician
Other Name: Soliris

Primary Outcome Measures :
  1. Reversal of protein-losing enteropathy [ Time Frame: 3-6 months ]
    Serum levels of blood proteins should be normalized. At least 2 out of 3 parameters including albumin, total protein and immunoglobulin G should reach age-specific normal range.

  2. Reversal of patient-specific major symptoms [ Time Frame: 12-18 months ]
    The major symptoms are variable in CHAPLE patients. The symptoms present in a particular patient should be corrected under therapy.

Secondary Outcome Measures :
  1. Reversal of other systemic components of the disease. [ Time Frame: 12-18 months ]
    E.g., thrombosis, enterocolitis, micronutrient deficiency, etc.

  2. Correction of previous biochemical and radiological abnormalities [ Time Frame: 6-18 months ]
    E.g., micronutrient deficiency, thrombocytosis; bowell wall thickening, contrast enhancement, recanalization of a thrombotic vessel segment, etc.

  3. Cessation of previous medications [ Time Frame: 3-18 months ]
    Continueed need for previous medications to treat various manifestations of CHAPLE syndrome will be monitored

Biospecimen Retention:   Samples With DNA
Peripheral blood mononuclear cells (PBMC) Serum Plasma Stool

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
All PIL patients, including CHAPLE and non-CHAPLE PILs are to be included in the study.Among the CHAPLE patients who receive eculizumab therapy a prospective follow-up is made. Age matched healthy subjects form the control group.

Inclusion Criteria:

  1. Patients diagnosed with PIL form the study groups and deem eligible for the study unless there is a risk associated with blood draw.
  2. The patients with CHAPLE syndrome who receive eculizumab therapy and consent to participate in this study are followed prospectively and clinical data collected. Biological sample collection and molecular investigations are to be made only if the patient is willing to provide biological samples, including peripheral blood and stool.

Exclusion Criteria:

  1. Presence of a concomitant disease that leads to hypoproteinemia at the time of starting eculizumab such as a urinary protein loss or a hepatic disease that affects production of proteins by liver.
  2. A concomitant disease that leads to secondary intestinal lymphangiectasia such as a fontan procedure for congenital heart disease.
  3. Unstable clinical condition not allowing blood draw, such as severe anemia.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03950804

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Contact: Ahmet O Özen, M.D. 905357400857
Contact: Nurhan Kasap, M.D. 905357400857

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Marmara University Recruiting
Istanbul, Turkey
Contact: Ahmet O Özen, M.D.    905357400857   
Contact: Nurhan Kasap, M.D.    905357400857   
Sponsors and Collaborators
Marmara University
National Institute of Allergy and Infectious Diseases (NIAID)
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Study Director: Michael J Lenardo, M.D. National Institute of Allergy and Infectious Diseases (NIAID)

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Responsible Party: Ahmet Ozen, M.D., Prof. Of Pediatrics, Division of Allergy and Immunology, Marmara University Identifier: NCT03950804    
Other Study ID Numbers: 09.2018.242
ZIAAI000717-22 ( U.S. NIH Grant/Contract )
First Posted: May 15, 2019    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ahmet Ozen, Marmara University:
Complement hyperactivation
CD55 deficiency
Complement C5
Multi-OMICs Analyses
Protein losing enteropathy
Additional relevant MeSH terms:
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Intestinal Diseases
Protein-Losing Enteropathies
Lymphangiectasis, Intestinal
Gastrointestinal Diseases
Digestive System Diseases
Lymphatic Diseases
Lymphatic Abnormalities
Congenital Abnormalities