
==== Front
Ther Adv Rare Dis
Ther Adv Rare Dis
TRD
sptrd
Therapeutic Advances in Rare Disease
2633-0040
SAGE Publications Sage UK: London, England

10.1177/26330040241270369
10.1177_26330040241270369
Addendum
Addendum To: Study protocol of the HD-MED study aiming to personalize drug treatment in Huntington’s disease: a longitudinal, observational study to assess medication use and efficacy in relation to pharmacogenetics
https://orcid.org/0000-0002-1160-0920
Feleus Stephanie Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Conceptualization Data curation Formal analysis Funding acquisition Investigation Methodology Project administration Resources Software Validation Visualization Writing – original draft Writing – review & editing
van der Lee Maaike Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
Data curation Formal analysis Writing – review & editing
https://orcid.org/0000-0002-3965-5552
Swen Jesse J. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
Conceptualization Methodology Supervision Writing – review & editing
Roos Raymund A. C. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
Conceptualization Funding acquisition Methodology Supervision Writing – review & editing
https://orcid.org/0000-0002-3512-2468
de Bot Susanne T. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
Conceptualization Funding acquisition Methodology Project administration Resources Supervision Visualization Writing – review & editing
s.feleus@lumc.nl
13 9 2024
Jan-Dec 2024
5 263300402412703693 5 2024
13 6 2024
© The Author(s), 2024
2024
SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
CYP2C19
CYP2D6
drug type
Huntington’s disease
medication use
medication efficacy
pharmacogenetics
pharmacogenomics
pharmacovigilance
Private HD community donations cover-dateJanuary-December 2024
typesetterts1
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pmcFrom the authors: As the HD-med study progressed, we realized that the current statistical methods in our article 1 were outdated. In the analysis, we will no longer combine the extremes of the pharmacogenetic profile (poor metabolizers (PMs) and ultra-rapid metabolizers (UMs)). Furthermore, we will no longer determine negative medication effects and definite prescription changes using the primary outcome definitions given in the original manuscript 1 . Instead, we decided to proceed with a simplified data preprocessing approach, as described below.

With this addendum paper, we provide transparency on our updated methodology. Currently, recruitment and data collection are ongoing. We have not yet seen the final data. No changes in data collection procedures have been made. The updated approach has no relevant impact on the required sample size.

PMs are at risk of experiencing more side effects, while UMs are at risk of experiencing no or less effect of a given drug. By grouping PMs and UMs in the same category of “divergent phenotype,” the true effect might be averaged out. Therefore, we thought it would be better not to combine these groups and just record the CYP2C19 and CYP2D6 genotype-predicted phenotype (PM, intermediate metabolizer (IM), normal metabolizer (NM) or UM). Depending on the actual number of subjects in each group, we may combine IMs and NMs in the analysis to increase power.

In addition, actionable drugs are clustered in pharmacogenetic groups, either CYP2C19 or CYP2D6. Prodrugs are examined separately. We will count how often adverse drug reactions and lack of efficacy occur, compared to the control group (=no adverse drug reactions nor lack of efficacy) per genotype-predicted phenotype for each pharmacogenetic group. Results will be analyzed with ANalysis Of VAriance (ANOVA) or its non-parametric counterpart, depending on the distribution of the data. Causality of adverse events is rated by the Liverpool Adverse Drug Reaction Causality Assessment Tool 2 by two independent investigators. Only possible, probable, and definite causality assessments are included in the analysis. Disagreements are resolved by consensus. Lack of efficacy is reported according to Figure 2 of the original manuscript, 1 where each “negative medication effects” is replaced by “lack of efficacy.” The “Drug change due to side effects?” box in Figure 2 of the original manuscript 1 has therefore become redundant. The new standardized operating procedure to determine the lack of efficacy is included in this addendum (Figure 1). Drug–drug interactions and corresponding co-medication-induced phenoconversion are taken into account when present, according to the previously reported predictions in Table 2 of the original manuscript. 1

Figure 1. Standardized operating procedure to determine lack of efficacy. To complete separately for actionable drug–gene interactions in CYP2C19 and CYP2D6.

The primary objective and main outcome are redefined to reflect these changes.

Primary objective: To classify the effect of the pharmacogenetic profile of CYP2C19 and CYP2D6 in Huntington’s disease gene expansion carriers.

Main outcome: Number of adverse events and lack of efficacy per CYP2C19 and CYP2D6 genotype-predicted phenotype.

Not applicable.

Declarations

ORCID iDs: Stephanie Feleus https://orcid.org/0000-0002-1160-0920

Jesse J. Swen https://orcid.org/0000-0002-3965-5552

Susanne T. de Bot https://orcid.org/0000-0002-3512-2468

Ethics approval and consent to participate: This study will be conducted according to the World Medical Association of Helsinki and has been approved by the MREC Leiden Den Haag Delft based in the Leiden University Medical Center under number NL70391.058.19. All subjects have provided written informed consent.

Consent for publication: Not applicable.

Author contributions: Stephanie Feleus: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Validation; Visualization; Writing – original draft; Writing – review & editing.

Maaike van der Lee: Data curation; Formal analysis; Writing – review & editing.

Jesse J. Swen: Conceptualization; Methodology; Supervision; Writing – review & editing.

Raymund A. C. Roos: Conceptualization; Funding acquisition; Methodology; Supervision; Writing – review & editing.

Susanne T. de Bot: Conceptualization; Funding acquisition; Methodology; Project administration; Resources; Supervision; Visualization; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The HD-med study is supported by private HD community donations. We received no funding from commercial or not-for-profit parties. HD-MED is an investigator-initiated study set up by the Department of Neurology and Department of Clinical Pharmacy and Toxicology of the Leiden University Medical Center.

Leiden University Medical Center receives grants from the European Huntington’s Disease Network (EHDN) and Cure HD Initiative (CHDI), participates in an EU Horizon 2020 project: Innovative Medicines Initiative (IMI) 2 (IDEA_FAST), and participates in clinical trials sponsored by PRILENIA, PTC Therapeutics, WAVE and VICO Therapeutics. R.A.C. Roos is a member of the DSMB uniQure CT-AMT 130, DSMB Enroll-HD, and is on the advisory board of JEITO Pharm. The aforementioned sponsors had no role in the design, execution, interpretation, or writing of this current study protocol. Authors Maaike van der Lee and Jesse J. Swen declare no conflicts of interest.

Availability of data and materials: The final results of the HD-MED study, irrespective of findings, will be submitted for publication in scientific journals and therewith publicly disclosed according to current international and local academic standards. Study data from the HD-MED protocol will not be publicly released, since this study is still ongoing. Parties that wish to collaborate on data generated by this study protocol are encouraged to contact the corresponding author.
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References

1 Feleus S van der Lee M Swen JJ , et al . Study protocol of the HD-MED study aiming to personalize drug treatment in Huntington’s disease: a longitudinal, observational study to assess medication use and efficacy in relation to pharmacogenetics. Ther Adv Rare Dis 2023; 4 : 26330040231204643.
2 Gallagher RM Kirkham JJ Mason JR , et al . Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool. PLoS One 2011; 6 : e28096.
