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Biomarker for Hereditary Angioedema Disease Type 1 (BioHAE) (BioHAE)

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ClinicalTrials.gov Identifier: NCT03029728
Recruitment Status : Recruiting
First Posted : January 24, 2017
Last Update Posted : September 17, 2019
Sponsor:
Information provided by (Responsible Party):
Centogene AG Rostock

Tracking Information
First Submitted Date January 18, 2017
First Posted Date January 24, 2017
Last Update Posted Date September 17, 2019
Actual Study Start Date August 20, 2018
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: January 22, 2019)
Sequencing of the Hereditary Angioedema Disease Type 1 related gene [ Time Frame: 4 weeks ]
Next-Generation Sequencing (NGS) of the SERPING1 gene will be performed. The mutation will be confirmed by Sanger sequencing.
Original Primary Outcome Measures
 (submitted: January 23, 2017)
The diagnosis of hereditary angioedema disease type 1 measured by sequencing of hereditary angioedema disease type 1 [ Time Frame: 36 months ]
Change History Complete list of historical versions of study NCT03029728 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: January 22, 2019)
The hereditary angioedema disease type 1 specific biomarker candidates finding [ Time Frame: 24 months ]
The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.
Original Secondary Outcome Measures
 (submitted: January 23, 2017)
Number of correct identified patients with hereditary angioedema disease type 1 disease [ Time Frame: 36 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Biomarker for Hereditary Angioedema Disease Type 1 (BioHAE)
Official Title Biomarker for Hereditary Angioedema Disease Type 1 - An International, Multicenter, Epidemiological Protocol
Brief Summary Development of a new MS-based biomarker for the early and sensitive diagnosis of hereditary angioedema disease type 1 from the blood
Detailed Description

Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries).

In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals. The most common form of the disorder is hereditary angioedema type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions.

The characteristic symptom of hereditary angioedema is recurrent episodes of swelling of affected areas due to the accumulation of excessive body fluid. The areas of the body most commonly affected include the hands, feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts, which is more common in people with hereditary angioedema than in those who have other forms of angioedema (i.e., acquired or traumatic). People with this disorder typically have areas of swelling that are hard and painful, not red and itchy (pruritic). A skin rash (urticaria) rarely is present.

The symptoms of hereditary angioedema may recur and can become more severe. Injury, severe pain, surgery, dental procedures, viral illness, and/or stress can trigger or worsen the recurring symptoms.

Symptoms associated with swelling in the digestive system (gastrointestinal tract) include nausea, vomiting, acute abdominal pain, and/or other signs of obstruction. Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation.

Hereditary angioedema is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a spontaneous new mutation (gene change) in the affected individual.

The symptoms of hereditary angioedema type I develop due to a deficiency of a protein known as complement component C1 esterase inhibitor.

The gene that causes hereditary angioedema is located on the long arm of chromosome 11 (11q12-q13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual.

Hereditary angioedema is a rare disorder that affects males and females in equal numbers. Symptoms typically begin in early childhood. An estimated one in 50,000 to 150,000 individuals is affected by this disorder worldwide.

Symptoms of the following disorders can be similar to those of hereditary angioedema. Comparisons may be useful for a differential diagnosis:

Acute nonhereditary angioedema affects the skin and mucous membranes. It commonly clears up on its own after 1 or 2 days. Any number of allergens may be responsible including drugs, insect stings, bites, and certain foods (e.g., eggs, shellfish, nuts, and fruits). Some people can have very severe allergic reactions (anaphylaxis) that may result in respiratory angioedema. Acquired angioedema can also occur because of immune disorders (e.g., B-cell lymphoprolif-erative disease), chronic lymphocytic leukemia, multiple myeloma, lupus (SLE), chronic sinusi-tis, dental infection, or certain blood disorders (essential cryoglobulinemias). Other acquired edemas may occur because of surgery (i.e., mastectomy), malignancy, and/or autoimmune diseases. Acquired angioedema may occur at any age. (For more information on these disor-ders, choose "Anaphylaxis," "Leukemia," "Myeloma," "Lupus," and "Cryoglobulinemia" as your search term in the Rare Disease Database.)

Cutis laxa is a rare congenital or acquired connective tissue disorder characterized by limp or slack skin. The affected areas of the skin may be thickened and dark. This disorder is usually diagnosed at birth or early in infancy. The initial symptom is usually an episode of swelling on the face and may be confused with hereditary angioedema. Cutis laxa progresses causing skin changes and damage to blood vessels. (For more information on this disorder, choose "Cutis Laxa" as your search term in the Rare Disease Database.) Diagnosis

The diagnosis of hereditary angioedema is made by a thorough clinical evaluation, a detailed patient history, and blood tests that detect decreased levels of complement proteins. In in-stances of high clinical suspicion and recurrent episodic angioedema of uncertain etiology, genetic testing is indicated.

The diagnosis is complicated because HAE is extremely rare and most physicians may never see a patient with the disorder. In addition, most cases of angioedema are caused by an allergic reaction. Abdominal attacks may be mistaken for conditions such as appendicitis and often results in unnecessary exploratory surgery. Often, patients are misdiagnosed as having psychosomatic symptoms and are inappropriately referred for psychiatric evaluation.

New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.

Therefore it is the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and there-by with an earlier treatment.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:

Laboratory Blood Test

For the development of the new biomarkers using the technique of Mass-spectrometry, a blood sample will be taken via using a dry blood spot filter card. To proof the correct di-agnosis in those patients where up to the enrollment in the study no genetic testing has been done, sequencing of hereditary angioedema disease type 1 will be done.

The analyses will be done at:

Centogene AG Am Strande 7 18055 Rostock Germany

Sampling Method Probability Sample
Study Population Patients with hereditary angioedema disease type 1 or high-grade suspicion for hereditary angioedema disease type 1
Condition
  • C1 Esterase Inhibitor Deficiency
  • Angio-Oedema of Lips
  • Angio-Oedema of Tongue
  • Abdominal Pain
  • Laryngeal Edema
Intervention Not Provided
Study Groups/Cohorts Observation
Patients with hereditary angioedema disease type 1 or high-grade suspicion for hereditary angioedema disease type 1
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: January 22, 2019)
1000
Original Estimated Enrollment
 (submitted: January 23, 2017)
50
Estimated Study Completion Date June 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

INCLUSION CRITERIA

  • Informed consent will be obtained from the patient or the parents before any study related procedures.
  • Patients of both genders older than 2 months
  • The patient has a diagnosis of hereditary angioedema disease type 1 or a high-grade suspicion for hereditary angioedema disease type 1
  • High-grade suspicion present, if one or more inclusion criteria are valid:

Positive family anamnesis for hereditary angioedema disease type 1

Swelling of the skin (most common symptom)

Swelling of the hands and feet

Abdominal pain (sometimes severe)

Laryngeal edema (medical emergency)

EXCLUSION CRITERIA

  • No Informed consent from the patient or the parents before any study related procedures.
  • Patients of both gender younger than 2 months
  • No diagnosis of hereditary angioedema disease type 1 or no valid criteria for profound suspicion of hereditary angioedema disease type 1
Sex/Gender
Sexes Eligible for Study: All
Ages 2 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Volha Skrahina, Dr +4938180113594 ext 594 volha.skrahina@centogene.com
Listed Location Countries Egypt,   Georgia,   Germany,   India
Removed Location Countries  
 
Administrative Information
NCT Number NCT03029728
Other Study ID Numbers BHAE 06-2018
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Centogene AG Rostock
Study Sponsor Centogene AG Rostock
Collaborators Not Provided
Investigators
Principal Investigator: Arndt Rolfs, MD Centogene AG Rostock
PRS Account Centogene AG Rostock
Verification Date March 2019