Transcriptome and Metabolic Analyses of CHAPLE Disease

NCT03950804 | Unknown

• 2 other identifiers: 09.2018.242ZIAAI000717-22
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

CD55 - Cluster of Differentiation Antigen 55 Deficiency; Primary Intestinal Lymphangiectasis; Protein-Losing Enteropathies; Complement Regulatory Factor Defect

Keywords

Complement hyperactivation; CD55 deficiency; Complement C5; Eculizumab; Multi-OMICs Analyses; Protein losing enteropathy

Outcome Measures

Primary Outcomes (2)

• Reversal of protein-losing enteropathy

  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.

  3-6 months

• Reversal of patient-specific major symptoms

  The major symptoms are variable in CHAPLE patients. The symptoms present in a particular patient should be corrected under therapy.

  12-18 months

Secondary Outcomes (3)

• Reversal of other systemic components of the disease.

  12-18 months

• Correction of previous biochemical and radiological abnormalities

  6-18 months

• Cessation of previous medications

  3-18 months

Study Arms (4)

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.

Non-CHAPLE PILs

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

Interventions

Eculizumab Injection DRUG

Patients receive eculizumab as deemed necessary by the primary physician

Also known as: Soliris

CHAPLE patients on eculizumab

Eligibility Criteria

• Age: Up to 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• Patients diagnosed with PIL form the study groups and deem eligible for the study unless there is a risk associated with blood draw.
• 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.

You may not qualify if:

• 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.
• A concomitant disease that leads to secondary intestinal lymphangiectasia such as a fontan procedure for congenital heart disease.
• Unstable clinical condition not allowing blood draw, such as severe anemia.

Sponsors & Collaborators

• Marmara University: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

Marmara University

Istanbul, Turkey (Türkiye)

RECRUITING

Related Publications (5)

• Ozen A. CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease. Immunol Rev. 2019 Jan;287(1):20-32. doi: 10.1111/imr.12715.

  PMID: 30565236 BACKGROUND

• Ozen A, Comrie WA, Lenardo MJ. CD55 Deficiency and Protein-Losing Enteropathy. N Engl J Med. 2017 Oct 12;377(15):1499-1500. doi: 10.1056/NEJMc1710011. No abstract available.

  PMID: 29020581 BACKGROUND

• Ozen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K, Lenardo MJ. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med. 2017 Jul 6;377(1):52-61. doi: 10.1056/NEJMoa1615887. Epub 2017 Jun 28.

  PMID: 28657829 BACKGROUND

• Kurolap A, Eshach Adiv O, Hershkovitz T, Tabib A, Karbian N, Paperna T, Mory A, Vachyan A, Slijper N, Steinberg R, Zohar Y, Mevorach D, Baris Feldman H. Eculizumab Is Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 Deficiency. J Pediatr Gastroenterol Nutr. 2019 Mar;68(3):325-333. doi: 10.1097/MPG.0000000000002198.

  PMID: 30418410 BACKGROUND

• Kurolap A, Eshach-Adiv O, Hershkovitz T, Paperna T, Mory A, Oz-Levi D, Zohar Y, Mandel H, Chezar J, Azoulay D, Peleg S, Half EE, Yahalom V, Finkel L, Weissbrod O, Geiger D, Tabib A, Shaoul R, Magen D, Bonstein L, Mevorach D, Baris HN. Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med. 2017 Jul 6;377(1):87-89. doi: 10.1056/NEJMc1707173. Epub 2017 Jun 28. No abstract available.

  PMID: 28657861 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Peripheral blood mononuclear cells (PBMC) Serum Plasma Stool

MeSH Terms

Conditions

Waldmann disease; Protein-Losing Enteropathies

Interventions

eculizumab

Condition Hierarchy (Ancestors)

Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Study Officials

• Michael J Lenardo, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  STUDY DIRECTOR

Central Study Contacts

Ahmet O Özen, M.D.

CONTACT

905357400857; ahmet.ozen@marmara.edu.tr

Nurhan Kasap, M.D.

CONTACT

905357400857; n_aruci@hotmail.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 24 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D., Prof. Of Pediatrics, Division of Allergy and Immunology

Study Record Dates

• First Submitted: May 12, 2019
• First Posted: May 15, 2019
• Study Start: June 15, 2018
• Primary Completion: September 15, 2019
• Study Completion: June 15, 2020
• Last Updated: August 14, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

TU (1)