Pyruvate Kinase Deficiency Epidemiological Study (PIECE) (PIECE)

Pyruvate Kinase Deficiency Epidemiological Study. An International, Multicentre, Epidemiological Observational Study

Pyruvate kinase deficiency (PKD) is the most common red cell glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia, caused by mutations in the PKLR gene. The main goal of this study is the diagnosis of pyruvate kinase deficiency in patients who exhibit chronic anaemia and/or splenomegaly and/or judiance and/or hyperbilirubinemia and/or history of prolonged neonatal jaundice and/ or cholelithiasis of undetermined aetiology.

Study Overview

• Status: Completed
• Conditions: Pyruvate Kinase Deficiency

Detailed Description

Pyruvate kinase deficiency is the most common red cell glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia, caused by mutations in the PKLR gene. PKLR encodes a pyruvate kinase that catalyzes the transphosphorylation of phosphoenolpyruvate into pyruvate and ATP. The current treatment options are red cell transfusions, chelation and splenectomy.

This is an international, multicentre, epidemiological and observational study.

The patients fulfilling the inclusion criteria will be enrolled into the Study and genetically tested for PKLR mutations via Next generation sequencing (NGS). Any mutation being detected by NGS, will be confirmed by Sanger sequencing.

PKLR-positive samples (homozygous or compound heterozygous for pathogenic variants) will be analysed for the identification of potential biomarkers via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared to a merged control samples in order establish a PKD specific biomarker.

• Study Type: Observational
• Enrollment (Actual): 75

Contacts and Locations

Study Locations

• United States
  • Florida
    • Pembroke Pines, Florida, United States, 33024
      • Intervent Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 30 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients older than 5 years and younger than 30 years old, with high suspicion of PK deficiency, due to chronic anaemia or cholelithiasis or cholecystitis of undetermined aetiology

Description

INCLUSION CRITERIA:

• Informed consent is obtained from the participant or legal representative
• The participant is equal or older than 5 years or equal or younger than 30 years old
• The participant exhibits the following symptoms of no obvious etiology:
• chronic anaemia and/or
• splenomegaly and/or
• jaundice and/or
• cholelithiasis and/or
• cholecystitis and/or
• hyperbilirubinemia and/or
• history of prolonged neonatal jaundice
• The participant is clinically diagnosed with PK deficiency

EXCLUSION CRITERIA:

• Inability to provide informed consent
• The participant does not suffer from chronic anaemia and splenomegaly and jaundice and cholelithiasis and cholecystitis and hyperbilirubinemia and history of prolonged neonatal jaundice
• The etiology of chronic anaemia or splenomegaly or jaundice or cholelithiasis or cholecystitis or kernicterus is clearly determined and is not due to PK deficiency
• The participant is younger than 5 years or older than 30 years old
• Previously enrolled in the PIECE Study
• Participant in custody

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients being at risk for Pyruvate Kinase Deficiency; Patients, older than 5 years and younger than 30 years old, being at risk for Pyruvate Kinase Deficiency, due to chronic anaemia or cholelithiasis or cholecystitis of undetermined aetiology

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of 100 PKLR positive participants out of a cohort of 16,000 PK deficiency-suspected cases	Number of identified pyruvate kinase deficiency patients, which showing a mutation/pathogenic variant in their PKLR gene, within a cohort of 16.000 suspected cases via using respective patients' dry blood sample for confirmatory testing (next generation sequencing of PKLR gene)	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker/s establishment in PKLR-positive cohort	The quantitative determination of small molecules within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry, and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.	24 months

Collaborators and Investigators

• Sponsor: CENTOGENE GmbH Rostock
• Investigators: Study Chair: Peter Bauer, M.D., CENTOGENE GmbH

Publications and helpful links

General Publications

• Grace RF, Bianchi P, van Beers EJ, Eber SW, Glader B, Yaish HM, Despotovic JM, Rothman JA, Sharma M, McNaull MM, Fermo E, Lezon-Geyda K, Morton DH, Neufeld EJ, Chonat S, Kollmar N, Knoll CM, Kuo K, Kwiatkowski JL, Pospisilova D, Pastore YD, Thompson AA, Newburger PE, Ravindranath Y, Wang WC, Wlodarski MW, Wang H, Holzhauer S, Breakey VR, Kunz J, Sheth S, Rose MJ, Bradeen HA, Neu N, Guo D, Al-Sayegh H, London WB, Gallagher PG, Zanella A, Barcellini W. Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. Blood. 2018 May 17;131(20):2183-2192. doi: 10.1182/blood-2017-10-810796. Epub 2018 Mar 16.
• Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood. 2000 Jun 1;95(11):3585-8.
• Carey PJ, Chandler J, Hendrick A, Reid MM, Saunders PW, Tinegate H, Taylor PR, West N. Prevalence of pyruvate kinase deficiency in northern European population in the north of England. Northern Region Haematologists Group. Blood. 2000 Dec 1;96(12):4005-6. No abstract available.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 13, 2020
• Primary Completion (ACTUAL): May 31, 2021
• Study Completion (ACTUAL): May 31, 2021

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 6, 2019
• First Posted (ACTUAL): March 7, 2019

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 8, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Biomarker; Pyruvate Kinase Deficiency; Chronic anaemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia, Hemolytic, Congenital Nonspherocytic; Pyruvate Metabolism, Inborn Errors
• Other Study ID Numbers: PIECE 01-2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The plan will be defined at a later stages

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No