Establishing a Core Outcome Set for Creatine Transporter Deficiency and Guanidinoacetate Methyltransferase Deficiency

Abstract

Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients 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 the current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements. Efforts to develop effective, sustainable treatments for these disorders are limited by the lack of clinical and patient-derived meaningful outcomes. A core outcome set (COS) can facilitate consensus about outcomes for inclusion in studies. Unfortunately, patient and caregiver perspectives have historically been overlooked in the COS development process, thus limiting their input into the outcome selection. 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. We expect this COS will ensure a patient-centered approach for accelerating drug development for CTD and GAMT, 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-centered research; Patient-informed drug development; Rare disease.

Figure 1.

Outcome selection process for COS development for CTD and GAMT. During the candidate outcome selection phase, the total number of candidate outcomes gathered during each stage are identified. During the remaining project phases, the total number of remaining outcomes at the end of each stage are identified.

Figure 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.