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Complement Prospective Evaluation of Thrombotic Microangiopathy on Endothelium (COMPETE)

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ClinicalTrials.gov Identifier: NCT04745195
Recruitment Status : Recruiting
First Posted : February 9, 2021
Last Update Posted : August 23, 2021
Sponsor:
Information provided by (Responsible Party):
Maastricht University Medical Center

Study Description
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Brief Summary:

Thrombotic microangiopathy (TMA) is a severe and life-threatening condition, often affecting the kidneys and brain. It can occur on the background of various clinical conditions. Dysregulation of the alternative pathway of complement may be the etiological factor and this type of TMA is classified, according to the current nomenclature, as primary atypical hemolytic uremic syndrome (HUS). Half the patients with primary atypical HUS present with rare variants in complement genes, although coexisting conditions are often needed for the TMA to become manifest. In patients with secondary atypical HUS, certain coexisting conditions appear to drive the disease and treatment should target the underlying condition to remit the TMA.

Recently, the investigators demonstrated, by using a novel in-house developed functional endothelial cell-based test, that complement dysregulation and overactivation is the dominant cause of disease and its sequelae in a subset of patients with secondary atypical HUS, having impact on treatment and prognosis. The investigators did first prove this concept in patients presenting with TMA and hypertensive emergency. A prospective study is needed to further corroborate these findings along the spectrum of TMA. The investigators hypothesize that their functional endothelial cell-based test, the so-called "HMEC" test, can better categorizes the TMA into different groups with potential therapeutic and prognostic implications. Thus, paving the road to the ultimate goal of precision medicine.


Condition or disease
Thrombotic Microangiopathies Hemolytic Uremic Syndrome, Atypical Hemolytic-Uremic Syndrome

Study Design
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Study Type : Observational [Patient Registry]
Estimated Enrollment : 42 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 12 Months
Official Title: Diagnostic and Risk Criteria for Complement Defects in Thrombotic Microangiopathy and Amplifying Conditions, Such as Severe Hypertension: The COMPETE Study.
Actual Study Start Date : August 12, 2021
Estimated Primary Completion Date : August 31, 2023
Estimated Study Completion Date : August 31, 2024

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort
Complement-mediated thrombotic microangiopathy
Thrombotic microangiopathty with normal complement regulation


Outcome Measures
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Primary Outcome Measures :
  1. The prevalence of complement-mediated TMA along the spectrum of TMA [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. The diagnostic performance of the "HMEC" test for the diagnosis of complement-mediated TMA [ Time Frame: 1 year ]
  2. The dynamics of ex vivo C5b9 formation on the endothelium during the course of TMA [ Time Frame: every month for up to 1 year ]
  3. The dynamics of ex vivo C5b9 formation on the endothelium as compared to routine complement measures during the course of TMA [ Time Frame: every month for up to 1 year ]
  4. Composite kidney endpoint: 50% eGFR decline, chronic kidney disease stage G5, end-stage kidney disease [ Time Frame: 1 year ]
    The diagnostic and prognostic value of pathologic features and chronicity indices on kidney biopsy at the time of presentation

  5. composite TMA endopoint: TMA recurrence, end-stage kidney disease [ Time Frame: 1 year ]
    The prognostic value of genetic variants in complement genes


Biospecimen Retention:   Samples With DNA

The following samples will be obtained and stored at the time of presentation and during follow-up:

  • DNA
  • Kidney tissue sections (on indication)
  • Plasma
  • Serum
  • Urine

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients of at least 18 years of age presenting with TMA, either on peripheral blood or kidney biopsy, will be recruited at the emergency departments of (regional) hospitals affiliated to the Limburg Renal Registry, Maastricht University Medical Center, Maastricht, NLD. Patients who meet the eligibility criteria will be included.
Criteria

Inclusion Criteria:

  • Males or females at least 18 years of age;
  • Have acute kidney injury, defined as estimated GFR <45 mL/min/1.73m2;
  • Have documented TMA either on peripheral blood, defined as Coombs negative microangiopathic hemolytic anemia (hematocrit <30%, hemoglobin <6.5 mmol/L [<10 g/dL], lactate dehydrogenase >500 U/L, and either schistocytes on peripheral blood smear or undetectable haptoglobin), and platelets <150,000 per µL, or kidney biopsy;

  • Have primary atypical HUS or a coexisting condition linked to complement dysregulation:

    • Hypertensive emergency, defined as SBP/DBP of >180/120 mmHg and impending organ damage secondary to hypertension (at least one of the following: neurologic disease, hypertensive retinopathy grade III and/or IV, left ventricular hypertrophy); OR
    • Pregnancy, including 12 weeks postpartum; OR
    • Kidney donor recipient; OR
    • Systemic auto-immune disease associated with TMA, including systemic sclerosis, systemic lupus erythematosus, anti-phospholipid syndrome;
  • Have the ability to understand the requirements of the study, provide written informed consent, and comply with the study protocol procedures.

Exclusion Criteria:

  • Have secondary causes of hypertensive emergency, including renovascular hypertension, Cushing syndrome, aldosteronism, pheochromocytoma, thyroid disease;
  • Have a nephropathy not related to thrombosis on kidney biopsy;
  • Have ADAMTS13 deficiency, defined as ADAMTS13 activity <10%;
  • Have a positive stool culture for Shiga toxin producing bacteria;
  • Have positive serologic test for viral infections, including HIV and CMV;
  • Have a history of malignant disease, excluding non-melanoma skin cancer;
  • Have a history of bone marrow or solid organ transplantation, excluding kidney transplantation;
  • Received at least one of the following agents: chemotherapeutics, sirolimus, anti-VEGF agents;
  • Have a history of recent past exposure to illicit drug(s).
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT04745195


Contacts
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Contact: Pieter van Paassen, MD, PhD +31(0)433871198 p.vanpaassen@maastrichtuniversity.nl
Contact: Sjoerd Timmermans, MD +31(0)433871198 sjoerd.timmermans@mumc.nl

Locations
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Netherlands
Maastricht University Medical Center Recruiting
Maastricht, Limburg, Netherlands, 6229HX
Contact: Pieter van Paassen, MD, PhD    +31(0)433871198    p.vanpaassen@maastrichtuniversity.nl   
Contact: Sjoerd Timmermans, MD    +31(0)433871198    sjoerd.timmermans@mumc.nl   
Sponsors and Collaborators
Maastricht University Medical Center
More Information
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Responsible Party: Maastricht University Medical Center
ClinicalTrials.gov Identifier: NCT04745195    
Other Study ID Numbers: NL74928.068.20
First Posted: February 9, 2021    Key Record Dates
Last Update Posted: August 23, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Azotemia
Hemolytic-Uremic Syndrome
Atypical Hemolytic Uremic Syndrome
Vascular Diseases
Thrombotic Microangiopathies
Syndrome
Hemolysis
Disease
Pathologic Processes
 Uremia
Kidney Diseases
Urologic Diseases
Anemia, Hemolytic
Anemia
Hematologic Diseases
Thrombocytopenia
Blood Platelet Disorders
Cardiovascular Diseases