General practitioner–pharmacist collaboration to enhance deprescribing of psychotropics, sedatives, and anticholinergics among older polypharmacy patients in primary care: study protocol of a cluster-randomized controlled trial (PARTNER)

Annette Haerdtlein; Kerstin Bernartz; Sophie Peter; Laura K Lepenies; Svetlana Puzhko; Yvonne Eberhardt; Michaela Maas; Stephanie Picker-Huchzermeyer; Vita Brisnik; Diana Falomir; Jochen Gensichen; Tim Steimle; Gunnar Huppertz; Michael Koller; Florian Zeman; Patrizio Vanella; Hanna M Seidling; Achim Mortsiefer; Christiane Muth; Tobias Dreischulte

doi:10.1177/20420986251400042

. 2026 Jan 8;17:20420986251400042. doi: 10.1177/20420986251400042

General practitioner–pharmacist collaboration to enhance deprescribing of psychotropics, sedatives, and anticholinergics among older polypharmacy patients in primary care: study protocol of a cluster-randomized controlled trial (PARTNER)

Annette Haerdtlein ¹, Kerstin Bernartz ², Sophie Peter ³, Laura K Lepenies ⁴, Svetlana Puzhko ⁵, Yvonne Eberhardt ⁶, Michaela Maas ⁷, Stephanie Picker-Huchzermeyer ⁸, Vita Brisnik ⁹, Diana Falomir ¹⁰, Jochen Gensichen ¹¹, Tim Steimle ¹², Gunnar Huppertz ¹³, Michael Koller ¹⁴, Florian Zeman ¹⁵, Patrizio Vanella ¹⁶, Hanna M Seidling ¹⁷, Achim Mortsiefer ¹⁸, Christiane Muth ¹⁹, Tobias Dreischulte ^20,^✉

¹Institute of General Practice and Family Medicine, LMU University Hospital, LMU Munich, Munich, Germany

²Department of General Practice and Family Medicine, Medical School OWL, Bielefeld University, Bielefeld, Germany

³Institute of General Practice and Primary Care (iamag), Witten/Herdecke University, Witten, Germany

⁴Internal Medicine IX: Department of Clinical Pharmacology and Pharmacoepidemiology/Cooperation Unit Clinical Pharmacy, Medical Faculty, University Hospital of Heidelberg, University of Heidelberg, Heidelberg, Germany

⁵Department of General Practice and Family Medicine, Medical School OWL, Bielefeld University, Bielefeld, Germany

⁶Center for Clinical Studies, University Hospital Regensburg, Regensburg, Germany

⁷Institute of General Practice and Primary Care (iamag), Witten/Herdecke University, Witten, Germany

⁸Department of General Practice and Family Medicine, Medical School OWL, Bielefeld University, Bielefeld, Germany

⁹Institute of General Practice and Family Medicine, LMU University Hospital, LMU Munich, Munich, Germany

¹⁰Institute of General Practice and Family Medicine, LMU University Hospital, LMU Munich, Munich, Germany

¹¹Institute of General Practice and Family Medicine, LMU University Hospital, LMU Munich, Munich, Germany

¹²TK Health Insurance Fund, Hamburg, Germany

¹³Center for Clinical Studies, University Hospital Regensburg, Regensburg, Germany

¹⁴Center for Clinical Studies, University Hospital Regensburg, Regensburg, Germany

¹⁵Center for Clinical Studies, University Hospital Regensburg, Regensburg, Germany

¹⁶Department of Health Monitoring and Biometrics, aQua Institute, Goettingen, Germany

¹⁷Internal Medicine IX: Department of Clinical Pharmacology and Pharmacoepidemiology/Cooperation Unit Clinical Pharmacy, Medical Faculty, University Hospital of Heidelberg, University of Heidelberg, Heidelberg, Germany

¹⁸Institute of General Practice and Primary Care (iamag), Witten/Herdecke University, Witten, Germany

¹⁹Department of General Practice and Family Medicine, Medical School OWL, Bielefeld University, Bielefeld, Germany

²⁰Institute of General Practice and Family Medicine, LMU University Hospital, LMU Munich, Nußbaumstraße 5, Munich 80336, Germany

^✉

Email: tobias.dreischulte@med.uni-muenchen.de

Roles

Annette Haerdtlein: Conceptualization, Investigation, Project administration, Visualization, Writing – original draft, Writing – review & editing

Kerstin Bernartz: Investigation, Project administration, Writing – review & editing

Sophie Peter: Investigation, Project administration, Writing – review & editing

Laura K Lepenies: Formal analysis, Investigation, Writing – review & editing

Svetlana Puzhko: Investigation, Project administration, Writing – review & editing

Yvonne Eberhardt: Data curation, Formal analysis, Validation, Writing – review & editing

Michaela Maas: Investigation, Writing – review & editing

Stephanie Picker-Huchzermeyer: Investigation, Writing – review & editing

Vita Brisnik: Conceptualization, Writing – review & editing

Diana Falomir: Investigation, Writing – review & editing

Jochen Gensichen: Conceptualization, Writing – review & editing

Tim Steimle: Conceptualization, Funding acquisition, Writing – review & editing

Gunnar Huppertz: Formal analysis, Validation, Writing – review & editing

Michael Koller: Conceptualization, Funding acquisition, Methodology, Writing – review & editing

Florian Zeman: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Patrizio Vanella: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Hanna M Seidling: Conceptualization, Funding acquisition, Methodology, Writing – original draft, Writing – review & editing

Achim Mortsiefer: Conceptualization, Funding acquisition, Methodology, Writing – review & editing

Christiane Muth: Conceptualization, Funding acquisition, Methodology, Writing – review & editing

Tobias Dreischulte: Conceptualization, Funding acquisition, Methodology, Supervision, Visualization, Writing – original draft, Writing – review & editing

PMCID: PMC12783581 PMID: 41522713

Abstract

Background:

Appropriate deprescribing of psychotropic, sedative, and anticholinergic potentially inappropriate medication (PSA-PIM) in older adults with polypharmacy can reduce the risk of adverse drug reactions, but is inconsistently implemented in primary care. The PARTNER intervention was designed to address challenges in PSA-PIM deprescribing at both provider and patient levels.

Objectives:

To evaluate the effectiveness and cost-effectiveness of the PARTNER intervention, and to understand the mechanisms of its effects.

Design:

Multicenter, two-arm cluster-randomized controlled trial.

Methods and analysis:

The study aims to recruit at least 44 clusters and 352 patients (⩾65 years old with polypharmacy (⩾5 drugs) and use of ⩾1 PSA-PIM for ⩾6 months) across three study sites in Germany. Clusters consist of one general practice and one or more community pharmacies, randomly allocated to either the PARTNER intervention or control group. The PARTNER intervention includes: (A) education for general practitioners (GPs) and pharmacists on PSA-PIM deprescribing, (B) an interprofessional workshop, (C) drug-specific empowerment brochures for patients, (D) a patient-pharmacist consultation to enhance patient empowerment, and (E) a GP-patient consultation focusing on shared decision-making. The control group receives enhanced usual care, comprising a one-off patient-pharmacist consultation for medication safety checks without a specific focus on PSA-PIM deprescribing. The intervention’s focus on PSA-PIM deprescribing is blinded to control group clusters throughout the study. The primary endpoint is a reduction in PSA-PIM exposure at 6 months (⩾0.15-point decrease in the Drug Burden Index). Secondary endpoints include falls, quality of life, healthcare utilization, and costs. The primary analysis will use a generalized linear mixed model to estimate the odds ratio for achieving the primary endpoint, adjusting for study center, age, sex, and pre-randomization PSA-PIM type and count. The process evaluation will explore the understanding of how and why the intervention succeeded or failed.

Discussion:

The PARTNER trial will provide evidence on the intervention’s effectiveness, efficiency, and appropriateness, informing its potential for broader implementation.

Trial registration:

The trial has been registered with ClinicalTrials.gov (NCT05842928) on May 6, 2023; https://clinicaltrials.gov/search?term=NCT05842928.

Keywords: clinical trial, deprescribing, general practice, interprofessional collaboration, patient empowerment, polypharmacy, potentially inappropriate medication

Plain language summary

Improving medication safety: does collaboration between doctors and pharmacists help reduce psychotropic, sedative and anticholinergic drugs in older adults?

Older adults often take multiple medications, including psychotropic (affecting the mind), sedative (sleep-inducing), and anticholinergic (e.g. certain drugs used in the treatment of incontinence) drugs. While these drugs can be beneficial, they may also cause harmful side effects. Especially if used for a long time, the risks can outweigh the benefits. When possible, deprescribing (stopping or reducing those medications) can lower the risk of adverse effects, but can be challenging. The PARTNER study was designed to address deprescribing challenges of these target drugs by enhanced collaboration between general practitioners (GPs) and pharmacists.

The study will include at least 44 clusters, each consisting of one GP practice and one or more community pharmacies, across three German regions. The aim is to recruit at least 352 patients aged 65 years or older who are taking five or more medications, including at least one target drug for six months or longer. The clusters are randomly assigned to either the PARTNER intervention or a control group.

The PARTNER intervention includes four components: (1) education for GPs and pharmacists on deprescribing, (2) joint workshop between GPs and pharmacists, (3) drug-specific empowerment brochures for patients, (4) patient-pharmacist consultation to enhance patient empowerment, and (5) GP-patient consultation focusing on shared decision-making. In the control group, patients consult with pharmacists for general medication safety checks, without a specific focus on deprescribing target drugs.

The primary goal is to see if the PARTNER intervention can reduce patients’ exposure to target drugs after six months. Further goals include assessing intervention effects on falls, quality of life, healthcare utilization, and costs.

If effective, the PARTNER intervention could provide a practical approach to safely reducing psychotropic, sedative and anticholinergic drugs in older adults through enhanced GP-pharmacist collaboration. This could improve patient safety and health outcomes.

Introduction

Polypharmacy, which is commonly defined as the simultaneous use of five or more drugs,¹ is predominantly managed in primary care and substantially increases the risk of adverse drug reactions (ADRs), which may cause serious harm. For instance, a recent meta-analysis found that 8.3% of emergency hospital admissions are due to ADRs, half of which were deemed preventable.²

To mitigate the risks associated with polypharmacy, guidelines recommend comprehensive medication reviews to evaluate the need, effectiveness, safety, and patient-centeredness of medication regimens in the context of individualized treatment goals.^3,4 Such medication reviews can lead to deprescribing—the process of discontinuing or reducing the dose of drugs that provide limited benefit to the patient or expose them to unacceptable risks. Deprescribing, supervised by a healthcare professional, aims to manage polypharmacy and improve outcomes.^5–7

Over the last three decades, numerous lists of potentially inappropriate medication (PIM) have been developed. These include drugs that should be avoided in older people, either because their risks outweigh their benefits overall or in specific clinical situations, and may therefore be prioritized targets for deprescribing.⁸

However, deprescribing remains underutilized in primary care. A number of interventions to promote deprescribing (where appropriate) have been developed and evaluated with mixed results.⁹ For example, the German RIME intervention provided education on a broad range of PIMs to general practitioners (GPs) and practice teams, as well as paper-based reminder cards, but showed no effect on the use of 80 PIMs.¹⁰ Similarly, the Irish SPPiRE trial reported no impact of GP education on polypharmacy reviews in reducing the use of 34 PIMs.¹¹ In contrast, the Scottish DQIP intervention, which focused solely on nonsteroidal anti-inflammatory drugs and antiplatelets, demonstrated significant reductions in targeted prescribing and associated clinical outcomes. This was achieved through an IT-based case-finding tool combined with education and financial incentives for prescribers.¹² Yet, a similar intervention in Scotland targeting antipsychotics showed no impact on PIM rates.¹³ The EMPOWER trial found that provision of empowerment brochures to long-term users of benzodiazepines led to significantly higher cessation rates in the intervention versus the usual care control arm.¹⁴ These findings may suggest that prescriber education alone may not be sufficient, that interventions targeting a narrower range of PIMs may be more effective than those with a broader scope, and that deprescribing interventions may be effective for certain PIMs but not for others.

The PARTNER project focuses on psychotropic, sedating, and anticholinergic PIMs (PSA-PIMs). PSA-PIMs have in common that they can trigger or worsen geriatric syndromes, such as falls/fractures, cognitive impairments/delirium, and malnutrition, all of which significantly affect quality of life for older people.^8,9,15 While deprescribing PSA-PIMs may therefore offer substantial benefits, it also poses distinct challenges.¹⁵ Although these drugs may provide subjective relief, some PSA-PIMs (e.g., hypnotics used to treat insomnia) are addictive.^16,17 In addition, abrupt cessation of all PSA-PIMs may cause withdrawal symptoms, including symptom rebound (e.g., insomnia), which initially prompted their use.^18–20 As a consequence, patients may be reluctant to agree to PSA-PIM deprescribing or to stop deprescribing attempts prematurely, while GPs may be reluctant to engage in a complex and time-consuming deprescribing process.

The PARTNER intervention is a complex intervention targeting PSA-PIMs, aiming to support deprescribing of these drugs via healthcare provider education, patient empowerment, and interprofessional collaboration. This study protocol describes the evaluation of the PARTNER intervention through (1) a cluster-randomized controlled trial (cRCT) to evaluate its effectiveness and potential undesired consequences, (2) a health economic evaluation to examine benefits in relation to costs, and (3) a process evaluation to explore why and how the intervention succeeded or failed.

Methods

Cluster-randomized controlled trial

The protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 statement²¹ (see Supplemental Material). The study protocol of the cRCT has been developed, and the findings will be reported in line with the Consolidated Standards of Reporting Trials (CONSORT) statement: extension to cluster-randomized trials, respectively.^22,23

Aims and objectives

The primary objective of the cRCT is to evaluate the effectiveness of the PARTNER intervention in reducing the exposure to PSA-PIMs at the patient level at 6 months follow-up, with 1 month being defined as 30 days. Secondary objectives comprise evaluation of the intervention effect on PSA-PIM exposure at 12 months, on different groups of PSA-PIMs, on prevalent (“old”) and incident (“new”) prescribing of PSA-PIMs, on other (non-PSA) PIMs and potential prescribing omissions (PPOs), and desired and undesired patient-reported and clinical outcomes.

Study design

The trial uses a multicenter, cluster-randomized design with two parallel arms and a 1:1 allocation ratio. The intervention arm receives the PARTNER intervention, while the control arm undergoes enhanced treatment as usual (eTAU). To minimize patient selection bias, clusters are blinded to their treatment allocation and the intervention’s focus on PSA-PIMs until patient recruitment is finalized in each cluster. After randomization, only the intervention arm will be unblinded. The PARTNER intervention includes cluster-level components (outlined below), and a patient-randomized design was deemed unsuitable due to the high risk of contamination in the control arm, making cluster randomization the preferred approach.

Blinding

To avoid patient selection bias, the clusters are blinded to the target drugs (PSA-PIM) of the intervention until they are informed of their allocated treatment arm. To reduce contamination bias, control arm clusters remain unaware of the intervention’s specific focus on PSA-PIMs throughout the trial. In the intervention arm, the blinding is broken as soon as clusters are informed of their allocated group and provided access to educational material targeting PSA-PIM deprescribing.

Participants

The clusters (i.e. the units of randomization) are collaboration units formed for the purposes of this trial. Each cluster consists of one GP practice and one or more community pharmacies, which provide care for a patient enrolled in this trial.

Cluster eligibility criteria

GP practices are recruited in three study regions in Germany (Upper Bavaria with study center Munich, Western Westphalia with study center Witten, Eastern Westphalia with study center Bielefeld). Community pharmacies located in the vicinity of recruited GP practices are invited to participate in the study. To avoid contamination between the study arms, the recruited cooperation units are selected in such a way that overlap of clusters (i.e., patients being managed by more than one participating cluster) can be ruled out, for example by maintaining sufficient geographic distance between recruited clusters. Table 1 provides detailed eligibility criteria for GP practices and pharmacies.

Table 1.

Eligibility criteria for clusters (cooperation units of one GP practice and one or more community pharmacies).

Inclusion criteria	Exclusion criteria
A. GP practices
• Provision of medical care to patients under statutory (public) health insurance • Practice size/structure, which is expected to have a sufficient number of eligible patients	• Specialist practice for unconventional medical treatments • Specialist practice for special indications (e.g., HIV)
B. Community pharmacies
• —	• No suitable premises for conducting confidential patient consultations

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GP, general practitioner.

Patient eligibility criteria

Eligible patients are recruited by GP practices, who are instructed to recruit between 6 and 15 patients (to confine heterogeneity of cluster sizes). The target population comprises older people with polypharmacy receiving outpatient care from GP practices and community pharmacies, who take at least one PSA-PIM, and who are mobile and able to provide information for the study via telephone. Table 2 lists the detailed eligibility criteria.

Table 2.

Eligibility criteria for patients.

Inclusion criteria

Exclusion criteria

• Age ⩾65 years
• Patient is capable of giving consent
• GP contact in the quarter prior to inclusion
• Current use of ⩾5 active substances, including ⩾1 PSA-PIM^* with a treatment duration of ⩾6 months
• Willingness to select a regular pharmacy for the duration of the study
• Consent to data exchange between GP and community pharmacy

• Terminal illness (life expectancy <6 months)
• Current treatment of pain associated with cancer
• Other serious physical illness or mental distress (e.g., bereavement) that makes participation in the study impossible (according to the GP’s assessment)
• Psychiatric illness or addiction that makes participation in the study impossible (according to the GP’s assessment)
• Unable to meet the requirements of the study (participation in telephone or written questionnaires, visits to the GP practice or community pharmacy, alone or with the help of caregivers for physical infirmity)
• Current participation in research projects on medication safety or geriatric medicine

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Hypnotics (benzodiazepines, z-drugs), opioids, gabapentinoids, antipsychotics, antidepressants, anticholinergic urospasmolytics. Where PSA-PIMs are prescribed as required, the inclusion criterion is met if the patient takes the drug at least twice per week.

GP, general practitioner; PSA-PIM, psychotropic, sedating, and anticholinergic potentially inappropriate medication.

Cluster recruitment

During recruitment, clusters are provided with the following information: “The PARTNER study aims to enhance medication safety for elderly patients with multiple medications and potential medication risks by fostering closer collaboration between GP practices and one or more partnering pharmacies. In both the intervention (IG) and control groups (CG), patients will receive an evaluation of their current medication and a risk assessment during a planned visit to the pharmacy. In the intervention group, there will also be an interprofessional workshop involving both the GP practices and pharmacies, as well as an additional patient visit to the GP practice.” This communication is designed to generate interest while maintaining blinding by not disclosing the intervention’s specific focus on PSA-PIM deprescribing.

Patient screening and recruitment

GP practices will generate screening lists of patients meeting all the following inclusion criteria: age ⩾65 years, at least one GP visit in the quarter prior to inclusion, and use of ⩾5 active substances. The patient’s current medication will then be entered into a software tool, which applies an algorithm to identify the use of ⩾1 PSA-PIM. The software only notifies the GP practice whether the patient meets the inclusion criteria, without specifying the qualifying medication. To minimize selection bias, the remaining eligible patients are randomly assigned numbers and listed in ascending order. Starting with the first patient on the list, the GP verifies the exclusion criteria. Patients who remain eligible are then invited by the GP practice to participate in the study. If interested, informed consent will be obtained by the GP.

Interventions

The cRCT compares the PARTNER intervention with an intervention that is consistent with eTAU. Figure 1 shows the intervention components in the PARTNER intervention and eTAU control arms.

Rationale and components of the PARTNER intervention arm

The PARTNER intervention has been designed to address key barriers to deprescribing PSA-PIMs. One such barrier is inertia, that is, in this context, a reluctance to deprescribe PSA-PIMs without an acute reason, such as ADRs.^24,25 At the level of healthcare professionals, this is exacerbated by competing priorities, time pressure, and a lack of knowledge on how best to deprescribe (e.g., the design and practical implementation of tapering schemes) as well as patient resistance.^26,27 The latter can be fueled by patient misconceptions about the benefits and risks of PSA-PIMs.²⁸ To overcome these barriers, the PARTNER intervention includes components aiming to educate and motivate healthcare professionals (via a web-based continuing professional development (CPD) portal and a moderated live CPD session) as well as patients (via empowerment brochures). In addition, there are components aiming to facilitate its practical implementation via tools, interprofessional case conferences, and delegation of patient empowerment to community pharmacies.

GPs and pharmacists volunteer to participate and to implement either the PARTNER intervention or the control intervention. While no financial incentives are provided as components of the intervention itself, GPs and pharmacists are compensated for their time and effort. Specifically, GP practices and community pharmacies in the intervention group receive €180 per patient enrolled in their cluster, while those in the control group receive €120 per patient. The higher compensation in the intervention group reflects the additional time, documentation requirements, and complexity associated with the intervention. Participating providers in the intervention group are required to complete a short questionnaire for each intervention component, enabling monitoring of compliance with the study protocol. However, it is important to note that the study protocol does not compel participants in either arm to undertake a deprescribing attempt.

Table 3 maps the intervention components to specific functions and elements of the COM-B model.²⁹ According to COM-B, behavior (e.g., of healthcare professionals or patients) is a result of the interaction between three essential components: Capability (C), Opportunity (O), and Motivation (M), which together determine whether a Behavior (B) will occur. This categorization facilitates a higher-level understanding of which interventions are suitable and effective for addressing particular healthcare challenges.

Table 3.

Mapping components of the PARTNER intervention to the COM-B model.²⁹.

COM-B component	Intervention element (target group)	Intervention function and rationale
Psychological capability (C-Ps)	- Web-based CPD portal/screencasts (HCP) - Interprofessional workshops (HCP) - Training in shared decision-making (HCP)	Education: Improves healthcare professionals’ knowledge and skills in deprescribing, enhancing their psychological capability to make informed decisions
Social opportunity (O-So)	- Interprofessional workshops (HCP) - Collaboration between GPs and community pharmacies (HCP)	Environmental restructuring: Creates opportunities for healthcare professionals to collaborate and share knowledge, fostering a supportive environment for deprescribing
Physical opportunity (O-Ph)	- Web-based tapering support tool (HCP) - Pharmacy consultations (HCP)	Environmental restructuring: Provides healthcare professionals with tools and resources to implement deprescribing practically, such as tapering support tools and consultation frameworks
Reflective motivation (M-Re)	- Motivational screencasts (HCP) - Empowerment brochures (Pat) - Shared decision-making processes in GP consultations (HCP/Pat)	Education: Motivates both healthcare professionals and patients by increasing awareness about the benefits and risks of deprescribing, prompting reflective decision-making
Automatic motivation (M-Au)	- Empowerment brochures emphasizing gradual tapering benefits (Pat) - Positive emotional framing in pharmacy consultations (Pat)	Incentivization: Engages patients’ automatic motivation by focusing on emotional benefits and reinforcing positive associations with deprescribing, making the process feel less intimidating

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COM-B, Capability, Opportunity, Motivation—Behavior; HCP, healthcare professionals; Pat, patients.

Web-based CPD portal (cluster level).

Clusters randomized to the intervention arm receive access to a web-based portal with the following resources on PSA-PIM deprescribing:

Screencasts aiming to overcome inertia and increase motivation for deprescribing. This is achieved by emphasizing the importance of a primary prevention approach to avoid PSA-PIM-associated harm and by explaining how the PARTNER intervention provides resources to facilitate it. Five short screencasts (between 5 and 12 min) are provided, in which an academic GP and an academic pharmacist provide information and guidance on (i) the rationale of the intervention’s focus on PSA-PIMs, (ii) intervention components and procedures, (iii) PSA-PIM tapering schemes, (iv) tools for communication with patients (including teach back and shared decision-making), (v) tools for conducting medication reviews.
Downloadable/printable educational material (brief and detailed versions) on PSA-PIM benefits and risks, when to deprescribe them and when not to, as well as PSA-PIM withdrawal symptoms and how to manage them.
Link to a (i) web-based tapering support tool that offers general information about tapering PSA-PIM and synthesized information on current guidelines and recommendations, and calculates possible tapering schemes and (ii) the accompanying PSA-PIM list, which provides an overview of the oral dosage forms, dosage strengths, and divisibility of pharmaceutical products available in Germany and is intended to support the practical implementation of the planned tapering schemes. Downloadable/printable guidance to support community pharmacists in conducting medication reviews, including a PIM/PPO checklist.

Interprofessional workshop (cluster level).

The interprofessional workshop aims to deepen, focus, and strategically plan the collaboration between GP practices and community pharmacies of each cluster randomized to the intervention arm. In preparation for the workshop, clusters are asked to familiarize themselves with the resources provided in the web-based portal (see above), and GPs are asked to provide community pharmacists with relevant clinical information on included patients using standardized templates (medication, diagnoses, selected laboratory results). The workshop itself has a planned duration of up to 2 h and consists of two parts. Part 1 (intervention training) is moderated by the study team. The session aims to ensure that GP practices and community pharmacies understand the rationale behind the intervention’s focus on PSA-PIMs. It facilitates introductions between team members, clarifies their respective roles and responsibilities, and familiarizes participants with the resources and tools available on the web-based portal. This component is designed to be flexible, allowing the study team to adapt the content and emphasize topics of particular relevance to each cluster. Part 2 (case conference), which is conducted independently of the study team, enables GPs and community pharmacists to discuss each study patient. Together, they decide whether deprescribing should be attempted and identify specific drugs to target for deprescribing. This structured yet adaptable approach ensures that each cluster is equipped to collaborate effectively while tailoring the intervention to meet their unique needs.

Empowerment brochures (patient level).

In the PARTNER intervention arm, the GP practice sends drug-specific and layperson-friendly empowerment brochures to patients selected in the interprofessional workshop (see above), unless the respective GP and pharmacist concluded that PSA-PIM deprescribing should not be attempted for a specific patient. To encourage patients to engage with the brochure, each patient also receives a personalized letter from their GP practice asking them to read the brochure at home and bring it along to their pharmacy visit. Seven different brochures with a focus on the following drugs and indications are available:

benzodiazepines and z-drugs
antipsychotics
antidepressants in the treatment of sleeping problems
antidepressants in the treatment of depression
opioids
gabapentinoids in the treatment of chronic pain
anticholinergic antispasmodics in the treatment of incontinence

The content of the empowerment brochures is based on instruments that were successfully used in a Canadian cluster-randomized trial (EMPOWER) on the deprescribing of benzodiazepines¹⁴ and is designed to deliver the following educational messages: (a) patients realistically assess the benefits and risks of PSA-PIM use; (b) patients understand that adverse events following any previous attempts to discontinue PSA-PIM are likely an expression of habituation and are usually temporary in nature; (c) patients understand that there may be effective and sustainable nonpharmacological alternatives for the treatment of symptoms treated with PSA-PIM; (d) patients understand that discontinuing PSA-PIMs gradually can minimize the risk of any adverse withdrawal effects. Information on the extent to which patients engaged with the empowerment brochures and understood their content will be documented in two ways: first, through the pharmacist’s assessment after the patient’s pharmacy visit, including the empowerment conversation; and second, through a patient survey conducted at the end of the study as part of the process evaluation (see below).

Pharmacy consultation (patient level).

All patients are invited to attend a consultation with the designated community pharmacist within the premises of the pharmacy and to bring along all medicines they are currently taking, as well as any empowerment brochures they have received. The consultation is planned to last approximately 1 h and consists of two parts. In part 1 (brown bag review), the community pharmacist checks the current medication for medication-related problems (MRPs) on the basis of the information provided by the GP practices and a structured patient discussion. To support MRP identification, the pharmacist is encouraged to use the PIM/PPO checklist provided in the web-based portal (see above). The pharmacist’s findings of the medication review are documented on standardized templates and sent to the GP practice. In part 2 (empowerment), the community pharmacist draws attention to any empowerment brochures sent to the patient and aims to ensure that their key educational messages are understood by the patient.

GP consultation (patient level).

GP and patient agree on any medication changes and how to implement them (including a tapering and follow-up plan). To increase the chance of successful and sustained PSA-PIM deprescribing, GPs are encouraged (via web-based portal and moderated interprofessional workshop) to apply shared decision-making and to reiterate and emphasize to their patients that withdrawal symptoms are usually mild and temporary, and that tapering schemes can be adapted to minimize any experienced adverse effects.

Rationale and components of the eTAU control arm

The study design and the control intervention were chosen to evaluate the additional benefit of an in-depth, patient-centered collaboration between GPs and pharmacists, focusing on PSA-PIM (PARTNER intervention), compared to a generic approach not focused on particular target drugs and without structured pharmacist-GP collaboration. The control arm was designed to align with enhanced routine practice in Germany, where community pharmacists may be reimbursed for conducting “medication reviews for patients with polymedication” (with or without involving GPs at their discretion) since June 2022,³⁰ although implementation remains patchy.³¹

Pharmacy consultation (patient level).

The only component of the eTAU control arm is a brown bag review (as in the intervention arm). Community pharmacists are instructed to provide a “medication check-up” with any follow-up at their discretion. In contrast to the intervention arm, the study team neither provides guidance nor tools to support these reviews, nor is there a requirement to feed back any findings to GP practices.

Table 4 provides the timeline for intervention components and data collection for each cluster.

Table 4.

Timeline for intervention components and data collection for each cluster.

Time	Activity	Parties involved in activity
Time	Activity	Research team	GP	Pharmacy	Patients
Minus 5 months	Recruitment of GP practice and collaborating community pharmacy	✓
Minus 3 months	Study training		✓	✓
Minus 3 months	Patient screening		✓
Minus 2 months	Patient recruitment		✓
Minus 1 month	Randomization	✓
Minus 1 month	Data collection at T₀: Medication, Health-Related Resource Use^a, HRQoL^b, Insomnia^c, Cognition^d, Adverse Drug Reactions^e	✓			✓
Minus 1 month	Provide access to educational portal^*	✓
Minus 1 month	Familiarization with educational portal content^*		✓	✓
Minus 2 weeks	Interprofessional workshop^*	✓	✓	✓
Minus 2 weeks	Postage of empowerment brochures^*		✓
Reference	Pharmacy consultation			✓	✓
Plus 2 weeks	GP consultation^*		✓	✓
Plus 3 months	Data collection at T₁: Health-Related Resource Use^a, HRQoL^b	✓			✓
Plus 6 months	Data collection at T₂: Medication, Health-Related Resource Use^a, HRQoL^b, Insomnia^c, Cognition^d, Adverse Drug Reactions^e	✓			✓
Plus 9 months	Data collection at T₃: Health-Related Resource Use^a, HRQoL^b	✓			✓
Plus 12 months	Data collection at T₄: Medication, Health-Related Resource Use^a, HRQoL^b, Insomnia^c, Cognition^d, Adverse Drug Reactions^e	✓			✓

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Measurement tools: ^aQuestionnaire for Health-Related Resource Use in an Elderly Population (FIMA), ^bEuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire, ^cRegensburg Insomnia Scale (RIS), ^dVerbal Fluency Test, ^ePatient-reported ADR questionnaire.

Intervention arm only.

GP, general practitioner; HRQoL, Health-Related Quality of Life.

Outcomes

Data collection

Participating GP practices, pharmacies, and patients serve as data sources. GP practices document relevant data to characterize the patient collective upon inclusion in the study, and GP practices and pharmacies document all study-related patient contacts during the follow-up in the intervention group. All study endpoints listed in Tables 4 to 9 are collected by trained study personnel via patient interviews. The follow-up period is 12 months, with data collection taking place at five points in time:

Table 9.

Secondary outcomes—clinical outcomes.

No.	Source population	Parameter	Time of measurement^*
SO21	All study participants	Number of falls (reported in fall diaries) in source population	• T₁, T₂, T₃, T₄
SO22	All study participants	Number of emergency hospital admissions due to falls in source population	• T₁, T₂, T₃, T₄
SO23	All study participants	Number of adverse drug reactions in source population	• T₀, T₂, T₄

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Data collection for T₀ is at randomization. T₁, T₂, T₃, and T₄ are defined as 3, 6, 9, and 12 months after the pharmacy consultation in each arm, respectively. In case the pharmacy consultation does not take place within 3 months after randomization (protocol deviation), T₁, T₂, T₃, and T₄ are defined as 6, 9, 12, and 15 months after randomization.

SO, secondary outcomes.

Data collection for T₀ is at randomization.
T₁, T₂, T₃, and T₄ are defined as 3, 6, 9, and 12 months after the pharmacy consultation in each arm, respectively.
In case the pharmacy consultation does not take place within 3 months after randomization (protocol deviation), T₁, T₂, T₃, and T₄ are defined as 6, 9, 12, and 15 months after randomization.

Hospitalizations, use of medical services, and quality of life estimates are collected at all five time points. Falls/fall injuries, hospital admissions (with outpatient or inpatient care), and contacts with GPs or specialist doctors are also documented in patient diaries to minimize recall bias. The use of a patient diary is regularly checked by study personnel. All other endpoints are recorded at T₀, T₂, and T₄ (see Tables 5–10). Participant retention and complete follow-up are promoted by the regular phone calls (in intervals of 3 months) to collect primary and secondary outcome data. In case of study discontinuation, the stated reason(s) will be documented.

Table 5.

Primary outcome—PSA-PIM deprescribing.

No.	Source population	Parameter	Time of measurement^*
Impact on DBI response
Primary outcome	All study participants	Number of patients in source population with a reduction in the DBI (including all PSA-PIMs) of ⩾0.15	T₂ vs T₀

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The outcome is the rate of parameter/source population in the intervention versus the control arm.

DBI, Drug Burden Index; PSA-PIM, psychotropic, sedating, and anticholinergic potentially inappropriate medication.

Table 6.

Secondary outcomes (SO)—PSA-PIM deprescribing and use.

No.	Source population	Parameter	Time of measurement^*
Sustained and stratified impact on DBI response
SO1	All study participants	Number of patients in source population with a reduction in the DBI (including all PSA-PIMs) of ⩾0.15	• T₄ vs T₀
SO2	Study participants with chronic pain psychotropics at baseline	Number of patients in source population with a reduction in the DBI (including chronic pain psychotropics only) of ⩾0.15	• T₂ vs T₀ • T₄ vs T₀
SO3	Study participants with mental health psychotropics at baseline	Number of patients in source population with a reduction in the DBI (including mental health psychotropics only) of ⩾0.15	• T₂ vs T₀ • T₄ vs T₀
SO4	Study participants with sedative-hypnotics at baseline	Number of patients in source population with a reduction in the DBI (including sedative-hypnotics only) of ⩾0.15	• T₂ vs T₀ • T₄ vs T₀
SO5	Study participants with anticholinergic urological antispasmodics at baseline	Number of patients in source population with a reduction in the DBI (including anticholinergic urological antispasmodics only) of ⩾0.15	• T₂ vs T₀ • T₄ vs T₀
Impact on overall number of PSA-PIMs
SO6	All study participants	Number of PSA-PIMs taken by patients in source population	• T₂ vs T₀ • T₄ vs T₀
Impact on baseline PSA-PIM use
SO7	All study participants	Patients in source population with reduced number of “old” (i.e., present at baseline) PSA-PIMs	• T₂ vs T₀ • T₄ vs T₀
Impact on new PSA-PIM prescribing
SO8	All study participants	Patients in source population with “new” (i.e., different from baseline) PSA-PIMs	• T₂ vs T₀ • T₄ vs T₀

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The outcome is the rate of parameter/source population in the intervention versus the control arm, unless specified otherwise

DBI, Drug Burden Index; PSA-PIM, psychotropic, sedating, and anticholinergic potentially inappropriate medication; SO, secondary outcomes.

Table 7.

Secondary outcomes—other PIMs and PPOs.

No.	Source population	Parameter	Time of measurement^*
SO9	All study participants with other PIMs at baseline	Number of resolved PIMs in source population	• T₂ vs T₀ • T₄ vs T₀
SO10	All study participants with PIMs increasing bleeding risk at baseline	Number of resolved PIMs increasing bleeding risk in source population	• T₂ vs T₀ • T₄ vs T₀
SO11	All study participants with PIMs increasing risk of acute kidney injury at baseline	Number of resolved PIMs increasing risk of acute kidney injury in source population	• T₂ vs T₀ • T₄ vs T₀
SO12	All study participants with PIMs increasing risk of cardiac decompensation and/or bradycardia at baseline	Number of resolved PIMs increasing risk of cardiac decompensation and/or bradycardia in source population	• T₂ vs T₀ • T₄ vs T₀
SO13	All study participants with PIMs increasing risk of falls, fractures, delirium at baseline	Number of resolved PIMs increasing risk of falls, fractures, delirium in source population	• T₂ vs T₀ • T₄ vs T₀
SO14	All study participants with PIMs increasing risk of hypoglycemia at baseline	Number of resolved PIMs increasing risk of hypoglycemia in source population	• T₂ vs T₀ • T₄ vs T₀
SO15	All study participants with drug-drug interactions at baseline	Number of resolved drug-drug interactions in source population	• T₂ vs T₀ • T₄ vs T₀
SO16	All study participants with drug-risk factor interactions at baseline	Number of resolved drug-risk factor interactions in source population	• T₂ vs T₀ • T₄ vs T₀
SO17	All study participants with potential prescribing omissions at baseline	Number of resolved potential prescribing omissions in source population	• T₂ vs T₀ • T₄ vs T₀

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The outcome is the rate of parameter/source population in the intervention versus control arm

DBI, Drug Burden Index; PIM, potentially inappropriate medication; PPO, potential prescribing omission; SO, secondary outcomes.

Table 8.

Secondary outcomes—patient-reported outcomes.

No.	Source population	Parameter	Time of measurement^*
SO18	All study participants	Cognition (Verbal Fluency Test) in source population	• T₀, T₂, T₄
SO19	All study participants	Insomnia (Regensburg Insomnia Scale) in source population	• T₀, T₂, T₄
SO20	All study participants	Quality of life (EQ-5D-5L) in source population	• T₀, T₁, T₂, T₃, T₄

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EQ-5D-5L, EuroQol 5-Dimension 5-Level questionnaire; SO, secondary outcomes.

Table 10.

Health economic outcomes.

No.	Benefit	Cost	Time of measurement^*
HEO1	Primary Outcome (reduction in Drug Burden Index of ⩾0.15)	Questionnaire for Health-Related Resource Use in an Elderly Population (FIMA):	T₀, T₂, T₄
HEO2	Quality of life (EQ-5D-5L Score)	- Outpatient medical care - Inpatient medical care - Drug costs	T₀, T₁, T₂, T₃, T₄
HEO3	Quality of life (EQ-VAS)	- Provision of remedies and aids - Outpatient care/rehabilitation	T₀, T₁, T₂, T₃, T₄
HEO4	Falls (Patient Diary)	- Resources GP practice/pharmacy (personnel, infrastructure, and material)	T₁, T₂, T₃, T₄
HEO5	Cognition (Verbal Fluency Test Score)		T₀, T₂, T₄

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EQ-5D-5L, EuroQol 5-Dimension 5-Level questionnaire; EQ-VAS, EuroQol Visual Analogue Scale; HEO, health economic outcomes.

Primary outcome

The primary endpoint of the cluster-randomized study is a reduction in PSA-PIM exposure at the patient level after 6 months of follow-up, which is measured using the Drug Burden Index (DBI) approach.³² The primary endpoint measures the responder rate in the intervention versus control arm, where response is defined as a reduction in the DBI by ⩾0.15 points (see Table 5).

The DBI quantifies the total exposure to PSA-PIM at the patient level and is calculated from the sum of the DBIs of the individual substances, which in turn are calculated as follows

D B I = \sum \frac{D}{D + δ}

where D is the daily dose, and δ is the minimum effective daily dose for each medication, which is used as an estimate of the DR₅₀ (daily dose required to achieve 50% of maximal contributory effect at steady state).³³ Figure 2 shows that for patients taking the minimum effective daily dose or a higher dose at baseline, a reduction of the DBI by 0.15 points is consistent with a dose reduction of one PSA-PIM by approximately 50%. In patients taking lower daily doses, larger relative dose reductions are required. Given the dose-dependency of sedative and anticholinergic effects, a DBI reduction of ⩾0.15 points is considered to be clinically meaningful.^32,34 The specific PSA-PIMs and minimal effective doses considered to calculate the primary endpoint have been prespecified and are available from the authors upon request.

here is a chart showing how much a drugs dose has to be reduced for the relative effectiveness of the drug to improve. the baseline daily dose is used as a point of comparison. the greater the dose reduction needed, the more effective the reduction is. — Required percentage reduction in daily dose for a DBI change of 0.15 by baseline daily dose.

DBI, Drug Burden Index.

Secondary outcomes

Secondary endpoints are designed to provide a more detailed understanding of intervention effects on deprescribing of PSA-PIMs, other (i.e., non-PSA) PIMs, clinical and patient-reported outcomes, and costs.

Table 6 shows secondary outcomes measuring PSA-PIM deprescribing and use. SO1 to SO5 measure whether the effect on the primary endpoint is sustained at 12 months follow-up (SO1) and whether it differs between different groups of PSA-PIMs, that is, (SO2) chronic pain psychotropics (opioids and gabapentinoids), (SO3) mental health psychotropics (antidepressants and antipsychotics at doses exceeding those used to treat insomnia, see Table S1), (SO4) sedative-hypnotics (benzodiazepines, z-drugs, antihistamines, certain antidepressants and antipsychotics at doses lower than those used to treat mental health conditions), (SO5) anticholinergic urological antispasmodics. The impact of the intervention on the overall number of PSA-PIMs prescribed is measured by SO6, whereas SO7 measures its impact on reductions in baseline PIM use and SO8 its impact on new PSA-PIM prescribing.

Table 7 shows secondary outcomes SO9 to SO17 related to the use of PIMs other than those specifically targeted by PARTNER, as well as PPOs. The hypothesis to be tested here is that the medication review conducted by community pharmacists in the PARTNER intervention arm leads to optimized detection of MRPs (through the provision of patient information by the GP, the educational material provided in the web-based portal, and use of the PIM/PPO checklist) as well as corrective action to resolve them (through intensified collaboration between community pharmacists and GPs facilitated by the interprofessional workshop and planned feedback of medication review findings to GPs) compared to the eTAU control arm (where no particular tools or guidance are provided to support the medication check-up and feedback to GPs remains at the discretion of community pharmacists). The specific measures for SO9 to SO17 have been prespecified and are available from the authors upon request.

Table 8 shows patient-reported outcomes (SO18 to SO20) measuring any desired impact of the intervention on cognition (measured by the Verbal Fluency Test (VFT)^35,36) and quality of life (EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire³⁷), as well as any undesired impact of the intervention on insomnia (measured by the Regensburg Insomnia Scale (RIS)³⁸).

Table 9 shows clinical outcomes (SO21 to SO23) measuring any desired impact of the intervention on falls with or without subsequent hospital admission. This is measured by FIMA (Questionnaire for Health-Related Resource Use in an Elderly Population)^39,40 and a self-reported patient diary. The ADRs are measured by a ‘Patient-Reported Outcome Measure, Inquiry into Side Effects’ (PROMISE) ADR questionnaire⁴¹ modified for our study.

All patient questionnaires used as secondary outcome measures in our cRCT (see Supplemental Material) have been validated, either through established psychometric procedures (FIMA,^39,40 EQ-5D-5L,^37,42 RIS,³⁸ VFT^35,36) or via content validation involving both patients and clinical experts (ADR questionnaire^41,43).

Sample size

Sample size calculation is based on the primary endpoint, the proportion of patients with a relevant reduction in DBI of at least 0.15 points at T₂ (6 months after T₀) compared to T₀. Based on a Dutch intervention study⁴⁴ and a slight positive effect expected in the control arm, we estimate the proportion of patients with a relevant reduction in DBI in the control arm to be 10%. Based on the successful Canadian EMPOWER study,¹⁴ whose main intervention component (patient empowerment by pharmacists) we adopt in the PARTNER intervention, we expect the proportion of patients with a relevant reduction in DBI to be 25% in the intervention arm. This corresponds to an absolute risk difference of 15% and an odds ratio (OR) of 3. Furthermore, we estimate the intra-cluster correlation coefficient (ICC) to be 0.05 and the average cluster size to be n = 6 patients. To be able to show a difference in responder rates of 10% versus 25% with a power of 80% at a significance level α = 0.05 with an ICC = 0.05, 22 clusters per group with a total of n = 264 patients are required. Under the conservative assumption of a maximum loss-to-follow-up of 25%, 352 patients (8 patients per cluster) will be recruited. Sample size was calculated using R software (version 4.1.1; R Foundation for Statistical Computing, Vienna, Austria).

Randomization

A cluster randomization at the level of the cooperation units, consisting of a GP practice and one or more community pharmacies, will be performed. Thus, all patients within a GP practice belong to the same group (either intervention or control group). The randomization is stratified by study center (Munich, Bielefeld, Witten), and the intervention and control groups are randomized in a 1:1 ratio. The random allocation sequence will be generated by the Center for Clinical Studies Regensburg by block randomization using SAS (version 9.4; SAS Institute Inc., Cary, NC, USA) and the procedure proc plan. Randomization lists will be stored at the Center for Clinical Studies and are concealed from the study centers until the end of the study. Allocation of a cluster to a treatment group will be directly after completion of patient recruitment within the cluster (see Figure 3).

Statistical analysis

A generalized linear mixed model (GLMM) is used for the analysis of the primary binary endpoint (reduction of ⩾0.15 points on the DBI at 6 months follow-up). In this model, the patients are nested under the cooperation units (clusters) with a random intercept for each cluster, whereby the number of degrees of freedom is determined using the between-within method.⁴⁵ The GLMM is adjusted for study center and the known prognostic factors age, sex, and type and number of PSA-PIM at time T₀. ORs with associated 95% confidence intervals are reported as effect sizes. In additional sensitivity analyses, the GLMM is adjusted for other covariates potentially associated with the primary endpoint.⁴⁶ Subgroup analyses are planned to identify any differential effects of the intervention on different PSA-PIM drug groups. The study population for the primary analysis is based on the intention-to-treat principle, with a per-protocol analysis performed as a secondary analysis. Secondary endpoints will be presented descriptively and analyzed exploratively using the appropriate methods. All planned statistical analyses (including handling of missing data) will be prespecified in a Statistical Analysis Plan before the end of the study, which will be accessible at the Center for Clinical Studies Regensburg.

Study organization

The steering committee comprises staff of the LMU University Hospital and lead investigators of all participating study centers, and is responsible for the design, integrity, and progress of the trial. The steering committee is also tasked with implementing any potential protocol modifications.

The risks of the study to patients are considered to be low, as all patients will continue to receive regular care from their GP, regardless of their participation in the study. Nevertheless, a Data Monitoring Committee (DMC) that is independent of the study team and the study sponsor and has no conflicts of interest has been appointed to carry out safety-related tasks. If adverse symptoms occur during a deprescribing attempt, the GP may, at their own discretion, discontinue the attempt at any time and return to the original dose. If any unexpected serious events are identified during data collection by study personnel, these will be documented and forwarded to the DMC for review. The persons responsible for data collection at the respective study center will be trained to recognize these events and report them to the medical study personnel at the respective study center, who will then contact the GP if necessary. The DMC consists of two physicians with specific expertise in clinical pharmacology.

The Center for Clinical Studies Regensburg is responsible for data management and data quality assurance within the study. Details on data management and data protection are outlined in the data protection concept, which was submitted to the ethics committee alongside the ethics application and approved by the data protection officers at all study sites collecting data.

Dissemination

Within 1 year after completion of data collection, we will report results in ClinicalTrials.gov, including a flow chart of study recruitment and dropout, demographic and baseline characteristics of participants, primary and secondary outcomes, statistical test results, and adverse event information, if applicable. To make results available, we will provide the following: (1) Final report of the study results to the funder; (2) publication of study results in peer-reviewed journals; (3) presentations at national and international conferences; (4) plain language summary sent to patient participants.