Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review

Pugliese, Michael; Tingley, Kylie; Chow, Andrea; Pallone, Nicole; Smith, Maureen; Rahman, Alvi; Chakraborty, Pranesh; Geraghty, Michael T.; Irwin, Julie; Tessier, Laure; Nicholls, Stuart G.; Offringa, Martin; Butcher, Nancy J.; Iverson, Ryan; Clifford, Tammy; Stöckler, Sylvia; Hutton, Brian; Paik, Karen; Tao, Jessica; Skidmore, Becky; Coyle, Doug; Duddy, Kathleen; Dyack, Sarah; Greenberg, Cheryl R.; Ghai, Shailly Jain; Karp, Natalya; Kronick, Jonathan B.; MacKenzie, Alex; MacKenzie, Jennifer; Maranda, Bruno; Mitchell, John; Potter, Murray A.; Prasad, Chitra; Schulze, Andreas; Sparkes, Rebecca; Taljaard, Monica; Trakadis, Yannis; Walia, Jagdeep S.; Potter, Beth K.

doi:10.1186/s13023-019-1276-1

Cited by 19 publications

(20 citation statements)

References 27 publications

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“…The protocol for the development of COS for MCAD deficiency and PKU has been published elsewhere [10] and results of this process have been published [9,11]. Briefly (see overview, Fig.…”

Section: Cos Development Studymentioning

confidence: 99%

“…Fig. 1 Outline of core outcome set (COS) development process [9,11] in the health care system and was on the executive of the Canadian Organization for Rare Disorders. Together, they co-led the patient engagement strategy along with the principal investigator (BP).…”

Section: : Reportmentioning

confidence: 99%

“…We recently developed the first COS for two rare inherited metabolic diseases (IMDs) in children, mediumchain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) [9][10][11], following the approach recommended by COMET [1]. We found that parent and caregiver participation in the design and conduct process was paramount to capturing patient-important outcomes in both COS for MCAD deficiency and PKU, and also offered key insights which may be transferrable for patient engagement in the development of other COS and future research activities.…”

Section: Introductionmentioning

confidence: 99%

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Patient and family engagement in the development of core outcome sets for two rare chronic diseases in children

Vanderhout

Smith²,

Pallone³

et al. 2021

Res Involv Engagem

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Background Core outcome sets (COS) are lists of consensus-determined outcomes to be measured and reported in all clinical research studies within a disease area. While including patients and families in COS development to improve their relevance and applicability to patient values is key, there is limited literature documenting practical barriers and facilitators to successful patient engagement in COS development. In this paper, as researchers and patient partners, we provide a resource for COS developers to meaningfully and effectively engage patients and families. Main body To establish a consensus-based COS for children with two inherited metabolic diseases (medium-chain acyl-CoA dehydrogenase deficiency and phenylketonuria), we conducted an evidence review, Delphi survey, and workshop. Two adult patient partner co-investigators co-developed the study protocol, co-designed strategies to address challenges with incorporating patient perspectives, and led all patient engagement activities, including communication with a group of family advisors. Seven adult family advisors received training about COS development and subsequently contributed to Delphi survey development, outcome definitions, the consensus workshop, and selection of outcome measurement instruments. Patient partner co-investigators and family advisors were essential to the successful design, conduct, and completion of the two COS. Patient partner co-investigators supported the understanding, inclusion and engagement of family advisors, and helped develop accessible tools to determine patient-oriented outcome measurement instruments. Patient partner co-investigators and family advisors collaborated with the study team to co-develop surveys, modify technical language, and recruit participants to the study. Together, we addressed challenges to patient engagement in COS development such as unfamiliarity with study methods, comprehensibility of materials and ongoing engagement, and power imbalances between team members. Conclusion Our approach to patient and family engagement in COS development for two rare conditions for children was feasible and considered valuable by all study team members, including patients and family members, in improving the relevance of the deliverable to patients. This approach to patient engagement in developing COS can be applied to other paediatric disease contexts, allowing patient and family perspectives to influence the direction of future studies to develop COS.

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“…The protocol for the development of COS for MCAD deficiency and PKU has been published elsewhere [10] and results of this process have been published [9,11]. Briefly (see overview, Fig.…”

Section: Cos Development Studymentioning

confidence: 99%

Section: : Reportmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Patient and family engagement in the development of core outcome sets for two rare chronic diseases in children

Vanderhout

Smith²,

Pallone³

et al. 2021

Res Involv Engagem

Self Cite

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“…These and similar methods have been adopted in rare disease settings 87,88 . Using these methodologies, our group recently has developed COS have been developed for PKU and MCAD deficiency 89 …”

Section: Outcome Researchmentioning

confidence: 99%

Developments in evidence creation for treatments of inborn errors of metabolism

Stöckler‐Ipsiroglu

Potter

Yuskiv

et al. 2020

J of Inher Metab Disea

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Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell‐and gene‐based therapies have become available. Inherent to the rare nature of the single conditions, generating high‐quality evidence for these treatments in clinical trials and under real‐world conditions has been challenging. Guidelines developed with standardized methodologies have contributed to improve the practice of care and long‐term clinical outcomes. Adaptive trial designs allow for changes in sample size, group allocation and trial duration as the trial proceeds. n‐of‐1 studies may be used in small sample sized when participants are clinically heterogeneous. Multicenter observational and registry‐based clinical trials are promoted via international research networks. Core outcome and standard data element sets will enhance comparative analysis of clinical trials and observational studies. Patient‐centered outcome‐research as well as patient‐led research initiatives will further accelerate the development of therapies for IEM.

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“…Treatment non-adherence has an important consequence on the outcome. The most relevant PKU outcome reported in the literature is a biochemical outcome, that of plasma Phe levels [ 12 ]. Medford and colleagues reviewed 29 studies that examined factors related to a poor adherence in children, adolescents, and adult patients with PKU.…”

Section: Introductionmentioning

confidence: 99%

The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria

et al. 2020

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The gold standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet supplemented with Phe-free protein substitutes. Adherence to therapy becomes difficult after childhood. Supplementing with large neutral amino acids (LNAAs) has been proposed as an alternative medication to Phe-free protein substitutes (i.e., amino acid mixtures). The aim of this study was to evaluate adherence to therapy and quality of life (QoL) in a cohort of sub-optimally controlled adult PKU patients treated with a new LNAA formulation. Twelve patients were enrolled in a 12-month-trial of slow-release LNAAs (1g/kg/day) plus a Phe-restricted diet. Medication adherence was measured with the Morisky Green Levine Medication Adherence Scale; the QoL was measured using the phenylketonuria-quality of life (PKU-QoL) questionnaire. Phe, tyrosine (Tyr) levels, and Phe/Tyr ratios were measured fortnightly. Before treatment, 3/12 patients self-reported a ‘medium’ adherence to medication and 9/12 reported a low adherence; 60% of patients reported a full adherence over the past four weeks. After 12 months of LNAA treatment, all patients self-reported a high adherence to medication, with 96% reporting a full adherence. Phe levels remained unchanged, while Tyr levels increased in most patients. The Phy/Tyr ratio decreased. All patients had a significant improvement in the QoL. LNAAs may give patients a further opportunity to improve medication adherence and, consequently, their QoL.

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Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review

Cited by 19 publications

References 27 publications

Patient and family engagement in the development of core outcome sets for two rare chronic diseases in children

Patient and family engagement in the development of core outcome sets for two rare chronic diseases in children

Developments in evidence creation for treatments of inborn errors of metabolism

The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria

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