Developing a Management Approach for Patients With "Late-Onset" Pompe Disease

Pompe Disease Clinical Trial

Official title:

Developing a Management Approach for Patients With "Late-Onset" Pompe Disease GAA Variant Identified by Newborn Screening

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03694561
• Other study ID #: Pro00100223
• Status: Active, not recruiting
• Start date: March 25, 2019
• Est. completion date: August 31, 2024

Study information

• Verified date: September 2023
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is an observational study with no study related treatment of interventions. The purpose of the study is to investigate and document disease specific clinical symptoms in newborns, infants and children with Pompe disease without cardiomyopathy identified in newborn screening(NBS).

There will be baseline, months 6 and months 12 visits for infants and newborns (infants study). For children of ages 24 months to 54 months, there will be baseline, year 1 and year 2 visits (children study).

The study has four goals:

1. To study and record disease specific clinical symptoms in newborns, infants and children with Pompe disease without cardiomyopathy (disease of the heart muscle) in the first year of life identified through newborn screening (NBS)

2. To devise an approach to characterize early musculoskeletal (muscles and joints) involvement in subjects with the "late-onset" GAA variant identified by NBS including ability to collect research information via virtual health platforms.

3. To determine criteria to start preventative therapies including enzyme replacement therapy (ERT) in patients with clinical features of Pompe disease identified via NBS

4. To document parental coping and anxiety/emotional distress overtime using quality of life questionnaires after a child is diagnosed with late onset Pompe disease via NBS

Description:

Late-Onset Pompe Disease(LOPD) is an inherited disorder caused by lack of or defect in the enzyme acid alpha-glucosidase (GAA). GAA enzyme deficiency causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. In LOPD, subtle and overt disease-specific features may go unrecognized in childhood without vigilant clinical examination and assessments with appropriate functional tests. In our clinical experience, children with the "late-onset" GAA variant may present much earlier in life and adult patients with LOPD consistently report a much earlier symptom onset and a significant diagnostic delay. These patients have shown improvement after initiation of ERT but have motor impairments adversely affecting their quality of life and growth from early childhood. Therefore, earlier diagnosis and initiation of ERT is crucial in these patients. Instituting ERT at an ideal time may prevent/reduce these irreversible musculoskeletal impairments and lead to a better quality of life and less disease burden as these children age.

Our team of Pompe disease experts will perform detailed clinical evaluations, physical therapy evaluations, cardiac assessments, speech and swallow evaluations, biochemical tests, sleep questionnaire, and hearing assessments on these patients. These assessments will allow use to capture and describe the earlier clinical phenotype in these patients and provide insights into the early signs and symptoms of LOPD.This study will provide and evidence-based approach to clinical management of newborns with LOPD to primary care physicians and geneticists, leading to improves patient outcomes.

The investigators will enroll 20 infants and children at Duke that has screened for LOPD. This study involves minimal risk to the patient and offers a potential benefit of improved disease management. For infants, the initial visit will be as soon as possible after a confirmed LOPD diagnosis and follow up visits will be at 6 months and 12 months. The investigators will continue to gather clinical information on patients and monitor clinical status beyond assessment at three time points. For children of ages 24 months to 54 months, there will be baseline, year 1 and year 2 visits.

The study has four goals:

1. To study and record disease specific clinical symptoms in newborns, infants and children with Pompe disease without cardiomyopathy (disease of the heart muscle) in the first year of life identified through newborn screening (NBS)

2. To devise an approach to characterize early musculoskeletal (muscles and joints) involvement in subjects with the "late-onset" GAA variant identified by NBS including ability to collect research information via virtual health platforms.

3. To determine criteria to start preventative therapies including enzyme replacement therapy (ERT) in patients with clinical features of Pompe disease identified via NBS

4. To document parental coping and anxiety/emotional distress overtime using quality of life questionnaires after a child is diagnosed with late onset Pompe disease via NBS

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 54 Months

Eligibility

Inclusion Criteria:

• Subject has been diagnosed via newborn screening

• Subject has a confirmed and documented diagnosis of Pompe disease and absence of cardiac involvement

• Subject has predicted "late-onset" GAA variants such as c.-32-13T>G, c.2188G>T, c.1935C>A, c.1726G>A, c.118C>T etc. in homozygosity or compound heterozygosity

• Subject must be between 3 and 20 months for infant study or between 24 and 54 months (+/- 3 months) for children study at time of enrollment.

Related Conditions & MeSH terms

• GAA Deficiency
• Glycogen Storage Disease Type II
• Pompe Disease
• Pompe Disease (Late-onset)

Intervention

Other:
• Observational
This study is a systematic investigation of the natural history of late-onset Pompe disease in infancy and childhood

Locations

Country	Name	City	State
United States	Duke University	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

References & Publications (13)

Chien YH, Chiang SC, Zhang XK, Keutzer J, Lee NC, Huang AC, Chen CA, Wu MH, Huang PH, Tsai FJ, Chen YT, Hwu WL. Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics. 2008 Jul;122(1):e39-45. doi: 10.1542/peds.2007-2222. Epub 2008 Jun 2. — View Citation

Chien YH, Hwu WL, Lee NC. Pompe disease: early diagnosis and early treatment make a difference. Pediatr Neonatol. 2013 Aug;54(4):219-27. doi: 10.1016/j.pedneo.2013.03.009. Epub 2013 Apr 28. — View Citation

Chien YH, Lee NC, Chen CA, Tsai FJ, Tsai WH, Shieh JY, Huang HJ, Hsu WC, Tsai TH, Hwu WL. Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. J Pediatr. 2015 Apr;166(4):985-91.e1-2. doi: 10.1016/j.jpeds.2014.10.068. Epub 2014 Nov 4. — View Citation

Chien YH, Lee NC, Thurberg BL, Chiang SC, Zhang XK, Keutzer J, Huang AC, Wu MH, Huang PH, Tsai FJ, Chen YT, Hwu WL. Pompe disease in infants: improving the prognosis by newborn screening and early treatment. Pediatrics. 2009 Dec;124(6):e1116-25. doi: 10.1542/peds.2008-3667. — View Citation

Feeney EJ, Austin S, Chien YH, Mandel H, Schoser B, Prater S, Hwu WL, Ralston E, Kishnani PS, Raben N. The value of muscle biopsies in Pompe disease: identifying lipofuscin inclusions in juvenile- and adult-onset patients. Acta Neuropathol Commun. 2014 Jan 2;2:2. doi: 10.1186/2051-5960-2-2. — View Citation

Hagemans ML, Hop WJ, Van Doorn PA, Reuser AJ, Van der Ploeg AT. Course of disability and respiratory function in untreated late-onset Pompe disease. Neurology. 2006 Feb 28;66(4):581-3. doi: 10.1212/01.wnl.0000198776.53007.2c. — View Citation

Hagemans ML, Winkel LP, Van Doorn PA, Hop WJ, Loonen MC, Reuser AJ, Van der Ploeg AT. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain. 2005 Mar;128(Pt 3):671-7. doi: 10.1093/brain/awh384. Epub 2005 Jan 19. — View Citation

Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D; Infantile-Onset Pompe Disease Natural History Study Group. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006 May;148(5):671-676. doi: 10.1016/j.jpeds.2005.11.033. — View Citation

Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J, Marsden D, Martins AM, Millington DS, Nicolino M, O'Grady G, Patterson MC, Rapoport DM, Slonim A, Spencer CT, Tifft CJ, Watson MS. Pompe disease diagnosis and management guideline. Genet Med. 2006 May;8(5):267-88. doi: 10.1097/01.gim.0000218152.87434.f3. No abstract available. Erratum In: Genet Med. 2006 Jun;8(6):382. ACMG Work Group on Management of Pompe Disease [removed]; Case, Laura [corrected to Case, Laura E]. — View Citation

Kroos MA, Pomponio RJ, Hagemans ML, Keulemans JL, Phipps M, DeRiso M, Palmer RE, Ausems MG, Van der Beek NA, Van Diggelen OP, Halley DJ, Van der Ploeg AT, Reuser AJ. Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype. Neurology. 2007 Jan 9;68(2):110-5. doi: 10.1212/01.wnl.0000252798.25690.76. — View Citation

Laforet P, Laloui K, Granger B, Hamroun D, Taouagh N, Hogrel JY, Orlikowski D, Bouhour F, Lacour A, Salort-Campana E, Penisson-Besnier I, Sacconi S, Zagnoli F, Chapon F, Eymard B, Desnuelle C, Pouget J; French Pompe Registry Study Group. The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease. Rev Neurol (Paris). 2013 Aug-Sep;169(8-9):595-602. doi: 10.1016/j.neurol.2013.07.002. Epub 2013 Sep 3. — View Citation

Rairikar MV, Case LE, Bailey LA, Kazi ZB, Desai AK, Berrier KL, Coats J, Gandy R, Quinones R, Kishnani PS. Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant. Mol Genet Metab. 2017 Nov;122(3):99-107. doi: 10.1016/j.ymgme.2017.09.008. Epub 2017 Sep 19. — View Citation

Wokke JH, Escolar DM, Pestronk A, Jaffe KM, Carter GT, van den Berg LH, Florence JM, Mayhew J, Skrinar A, Corzo D, Laforet P. Clinical features of late-onset Pompe disease: a prospective cohort study. Muscle Nerve. 2008 Oct;38(4):1236-45. doi: 10.1002/mus.21025. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Medical records will be tracked for up to 4.5 years to document subtle musculoskeletal signs of Pompe disease.	This outcome measure will be tested individually by a formal physical therapy assessment, Alberta Infant Motor Scale (AIMS), Gross Motor Functional Measure (GMFM), Hammersmith Functional Motor Scale Expanded(HFMSE),Modified Hammersmith Functional Motor Scale Extend(MHMFS-EXTEND), and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders(CHOP INTEND) to give a combined assessment score.	4.5 years
Primary	Medical records will be tracked for up to 4.5 years years to document Pompe-specific clinical symptoms.	This outcome measure will be tested individually by physical examination, nutritional evaluation and functional assessment to give a combined analysis of Pompe-specific symptoms.	4.5 years
Primary	Medical records will be tracked for 4.5 years to document elevation in Pompe-specific biomarkers from blood and urine samples.	This outcome measure will be tested by comparing lab results to lab-specific ranges.	4.5 years
Secondary	Medical records will be tracked for 4.5 years to document sleep quality.	This outcome measure will be tested qualitatively by questionnaire.	4.5 years
Secondary	Medical records will be tracked for 4.5 years to document auditory capacity.	This outcome measure will be tested individually by visual reinforcement audiology (VRA) and distortion product optoacoustic emissions (DPOAE) to give a combined assessment score.	4.5 years
Secondary	Medical records will be tracked for 4.5 years to document cardiac involvement.	This outcome measure will be analyzed by echocardiogram and electrocardiogram results.	4.5 years
Secondary	Medical records will be tracked for 4.5 years to document muscle architecture of the calves, para-spinal muscles and tongue	This outcome measure will be tested qualitatively by simple ultrasound examination.	4.5 years
Secondary	Medical records will be tracked for 4.5 years to document speech and swallow progression	This outcome measure will be tested individually by using videofluoroscopic study, Preschool Language Scale-Fourth Edition(PLS4), Receptive-Expressive Emergent Language Test Third Edition(REEL3), Pediatric Eating Assessment Tool (PEDI EAT-10), Functional Oral Intake Scale(FOIS) and serial photographs to give a combined assessment score.	4.5 years
Secondary	Change in parental coping overtime using quality of life questionnaires after a child is diagnosed with late onset Pompe disease via NBS.	BRIEF COPE is completed by the patient's parent or guardian. BRIEF COPE is rated on a scale of 1-4 with 1 = 'I haven't been doing this at all' and 4 = 'I've been doing this a lot'.	yearly, up to 4.5 years
Secondary	Change in parent's emotional distress overtime using PROMIS questionnaire	The PROMIS questionnaire is completed by the patient's parent or guardian. Emotional distress is rated on a scale of 1-5 with 1=never and 5=always.	yearly, up to 4.5 years