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. 2025 Aug 7;20(1):408.
doi: 10.1186/s13023-025-03900-3.

Establishing a core outcome set for creatine transporter deficiency and guanidinoacetate methyltransferase deficiency

Affiliations

Establishing a core outcome set for creatine transporter deficiency and guanidinoacetate methyltransferase deficiency

Zahra Nasseri Moghaddam et al. Orphanet J Rare Dis. .

Abstract

Background: Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients with either condition commonly exhibit intellectual and developmental disabilities, often accompanied by behavior problems, delayed speech, seizures, and motor impairments. There is currently no efficacious treatment for CTD, while current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements. Efforts to conduct clinical trials on potential treatments for these disorders are made more difficult by the lack of clinical and patient-derived meaningful outcomes. A core outcome set (COS) can facilitate consistent use of outcomes in studies. The current effort included patient and caregiver perspectives into the outcome selection of a COS for CTD and GAMT.

Results: We partnered with caregivers and health professionals to establish the first COS for CTD and GAMT. The COS developed includes seven outcomes ("Adaptive Functioning", "Cognitive Functioning", "Emotional Dysregulation", "MRS Brain Creatine", "Seizure/Convulsions", "Expressive Communication", and "Fine Motor Functions") for both CTD and GAMT, and an additional outcome for GAMT ("Serum/Plasma Guanidinoacetate") that are important to stakeholders and consequently should be considered for measurement in every clinical trial. Caregivers were valued partners throughout the COS development process, which increased community engagement and facilitated caregiver empowerment.

Conclusions: Development of this COS illustrates a patient-centered approach for clinical trial readiness for CTD and GAMT that if utilized will make clinical trial results comparable, minimize bias in clinical trial outcome selection, and promote efficient use of resources.

Keywords: Core outcome set (COS); Creatine transporter deficiency; Guanidinoacetate methyltransferase deficiency; Patient focused drug development; Patient-centered research; Rare disease.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All focus groups and Delphi surveys received institutional review board (IRB) approval from the North Star Review Board (protocols NB200065, NB300094; https://learningirb.org/ ). Informed consent was obtained from all focus group and Delphi survey participants prior to participation. Consent for publication: Not applicable. Competing interests: ZNM reports a stipend and travel support from ACD for this project. BKP reports a grant from INFORM RARE which receives industry matching research funds from Takeda, Biomarin, Ultragenyx, and Perkin Elmer. NL reports the following: clinical trial support for Amgen/Horizon, Amicus Therapeutics, Audentes/Astellas, BioMarin, Chiesi/Protalix, Genzyme/Sanofi, Jnana, Moderna, PTC Therapeutics, Takeda, and Ultragenyx; serves on advisory boards for Amgen/Horizon, Amicus Therapeutics, Audentes/Astellas, BioMarin, Chiesi/Protalix, Genzyme/Sanofi, Ipsen, Jaguar Gene Therapy, Jnana, Leadiant Biosciences, Moderna, Nestle Pharma, PTC Therapeutics, Reneo, and Ultragenyx Data Safety; serves on monitoring boards for Applied Therapeutics, iEcure, and Regeneron. GSL reports grant and travel support funding from ACD. JSM reports a consulting agreement with Ultragenyx and Johnson & Johnson, and has done legal consultation for a variety of cases. AS reports receiving consultation fees from Ceres Brain. EKR, AT, MS, CG, BHT, SAB, DAB, RB, JB, RC, DPC, TJDG, VH, SM-A, MP, GSS, CPW, KFW, SPY, JL, SB, TS, SS-I, and HW declare they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Outcome selection process for COS development for CTD and GAMT. During the candidate outcome selection phase, the total number of candidate outcomes gathered at each stage were identified. During the project's remaining phases, the total number of remaining outcomes at the end of each stage were identified. The total number of CTD and GAMT responses from the CreatineInfo data were identified, along with the total number of patients/caregivers and health professionals from the focus groups, Delphi surveys, and consensus workshop
Fig. 2
Fig. 2
Outcomes remaining after each Delphi survey round and the consensus workshop. Column headers reflect the Delphi round and each set of inclusion criteria. The inclusion criteria for each round were as follows: Delphi 1, rated ≥ 3 by ≥ 70% of any stakeholder group; Delphi 2, rated ≥ 7 by ≥ 70% of any stakeholder group; Delphi 3–1, rated ≥ 7 by ≥ 70% of any stakeholder group; Delphi 3–2, mean rating ≥ 7 for any stakeholder group; Delphi 3–3, ranked in top 10 by ≥ 15% of any stakeholder group; Consensus (C), ≥ 50% of workshop participants voted outcome as “1-Definitely In”. Stakeholders meeting the inclusion criteria for each outcome are identified by color: patients/caregivers (yellow), health professionals (blue), both patients/caregivers and health professionals (green), outcome did not meet the criteria and was excluded (gray). Some outcomes were combined and/or changed throughout the process: “Developmental Delay” and “Intellectual Disability” were combined into “Intellectual and Developmental Disability”, “Adaptive Functioning” and “Daily Living Skills” were combined into “Adaptive Functioning”, and “Expressive Language” was changed to “Expressive Communication”. Outcomes marked with ◼ came exclusively from the focus groups. Outcomes marked with ▲ were introduced by the project team during the pruning phase. Outcomes marked with ◯ were removed by the project team because they are typically already included in clinical trial designs. Outcomes marked with ◆ did not meet the consensus workshop inclusion criteria but were later included after unanimous agreement among participants. Outcomes marked with + are not included in the COS, but are worth measuring alongside the COS
Fig. 3
Fig. 3
Distribution of locations for the participants (n = 150) who completed the Delphi surveys. Represented countries were categorized into three groups: 1–5 participants (light orange, n = 22), 6–10 participants (orange, n = 4), and 11 or more participants (dark orange, n = 1)

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