PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 1 / 30 OPEN ACCESS Citation: Koller C, Blanchard M, Hügle T (2025) Assessment of digital therapeutics in decentralized clinical trials: A scoping review. PLOS Digit Health 4(6): e0000905. https://doi. org/10.1371/journal.pdig.0000905 Editor: Calvin Or, The University of Hong Kong, HONG KONG Received: March 26, 2024 Accepted: May 25, 2025 Published: June 23, 2025 Copyright: © 2025 Koller et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data availability statement: All relevant data are within the paper and its Supporting Information files. Funding: The author(s) received no specific funding for this work. Competing interests: I have read the journal's policy and the authors of this manuscript RESEARCH ARTICLE Assessment of digital therapeutics in decentralized clinical trials: A scoping review Cinja Koller *, Marc Blanchard, Thomas Hügle Department of Rheumatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland * Cinja.koller@unil.ch, Cinja.koller@chuv.ch Abstract This scoping review aims to identify the necessary and practical considerations for the design, conduct and safety of decentralized clinical trials (DCTs) that test digi- tal therapeutics (DTx) or software as a medical device (SaMD). The review follows the framework of Arksey & O’Malley. A search strategy with the keywords “Digital therapeutics” or “Software as Medical Device” AND “decentralized clinical trial” or synonyms was applied to Cochrane CENTRAL, EMBASE, MEDLINE and Web of Science databases with the latest search on the 25th of April 2025. We selected peer- reviewed articles reporting about fully or partly DCTs using apps or devices that were classified as DTx or SaMD. Studies using general health software or not focus- ing on the design or experiences of the DCT were excluded. Main study characteris- tics were extracted and the articles thematically coded with the qualitative software Atlas.ti. 335 results were assessed for title and abstract screening and 113 articles were identified for full-text screening, of those 41 fulfilled inclusion criteria. DTx used in the trials were mainly targeting depression. The clinical trial design differed sig- nificantly in the number of study arms (1–16), participants (11─5602) and blinding. E-recruitment (78%), e-eligibility screening (73%), e-informed consent (68%), inclu- sion of electronic- patient reported outcomes (e-PROs) (88%), passive data collection (59%) and use of reminders (59%) were key reoccurring features of the studies. Effective access and inclusion of participants, but low adherence and engagement is highlighted in most studies. In some cases, only 40% of participants installed the app and significant drop-out rates of about 50% are reported. A framework for DCTs eval- uating DTx is provided. In summary, DCTs for DTx are unstandardized, heterogenous and characterized by low adherence. Further research on how to tackle the engage- ment problem, along with clearer guidance and regulatory frameworks, is required to standardize this trial type in the future. http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pdig.0000905&domain=pdf&date_stamp=2025-06-23 https://doi.org/10.1371/journal.pdig.0000905 https://doi.org/10.1371/journal.pdig.0000905 http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0009-0009-4612-4221 mailto:Cinja.koller@unil.ch mailto:Cinja.koller@chuv.ch PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 2 / 30 Author summary We systematically reviewed the literature and analyzed 41 articles that investi- gated digital therapeutics (DTx) or a software as a medical device (SaMD) with a decentralized clinical trial (DCT) or its benefits and challenges. Characteristics such as trial design, health area under investigation, methodology or outcomes were summarized and compared. Although trials varied, overlapping themes between the included articles were identified, namely e-recruitment, e-eligibility screening, e-consent, patient-reported outcomes, reminders and passive data collection. Based on these themes, we provided a framework for DCTs testing DTx to standardize future trials. The main advantages reported in the included studies were better reach, access and faster recruitment than with traditional trials, often resulting in diverse participant samples. The predominant mentioned difficulty of this trial type was engagement with the DTx. Therefore, more re- search is needed to develop strategies to address this problem. Introduction In the rapidly evolving landscape of digital health, digital therapeutics (DTx) are being frequently used and developed, especially for self-management in chronic diseases. Typically, they provide information, monitor patient reported outcomes (PROs), and often incorporate psychological and behavioral therapy approaches [1,2]. DTx are highly accessible, given that a majority of people use the internet and own a mobile phone. Moreover, they can easily be personalized with a patient-centered approach [2,3]. The term DTx is defined by the Digital Therapeutics Alliance [4] as: “Digital ther- apeutics deliver to patients evidence-based therapeutic interventions that are driven by high quality software programs to treat, manage, or prevent a disease or disorder. They are used independently or in concert with medications, devices, or other thera- pies to optimize patient care and health outcomes.”. In the United States (U.S.), DTx fall under the rules and concepts of software as a medical device (SaMD) [5,6]. The International Medical Device Regulators Forum defines SaMD as software designed for one or more medical purposes, capable of fulfilling these purposes independently of a hardware medical device [7]. While in the U.S. all DTx qualify as SaMD, this does not apply vice versa, as they do not neces- sarily deliver a therapeutic intervention to the patient. For example, rapid large vessel occlusion (LVO), a Food and Drug Administration cleared software for identification of suspected large vessel occlusions [8], is used by physicians to help with decision making but is not used by patients themselves as a therapeutic intervention. The distinction between a DTx and other educational health or wellness apps can be made through the clinical evaluation [2]. A DTx is designed to have a meaningful effect on treatment or management of a specific disease, rather than providing purely informational content, and must therefore undergo clinical evaluation to ensure its effectiveness and safety [2,4,6,9]. After demonstrating safety and efficacy in a clinical have the following competing interests: Marc Blanchard and Thomas Hügle are shareholders of ATREON Société Anonyme. Thomas Hügle is scientific advisor of Vtuls. PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 3 / 30 trial, a DTx can seek regulatory approval—such as registration as a DiGA (Digitale Gesundheitsanwendungen) in Ger- many—and may be reimbursed by health insurers in an increasing number of countries [4,10]. However, the clinical trial process that underpins this regulatory pathway is often resource-intensive, time-consuming, and limited in reach. Traditional controlled clinical trials are characterized by substantial financial and time expenditures, restricted access, a poor retention rate and limited generalizability of results [11,12]. The COVID-19 pandemic acceler- ated the use of digital technologies in healthcare and provoked a shift in the way clinical trials are conducted [13]. Major changes in clinical trials are reflected in increased online recruitment, adoption of electronical consent, the shipment of samples or devices to and from the patients home and telemedicine consultations [1,13,14]. These changes are particularly relevant when discussing decentralized clinical trials (DCTs). The Clinical Trials Transfor- mation Initiative defines DCTs as “those in which some or all study assessments or visits are conducted at locations other than the investigator site via any or all of the following DCT elements: tele-visits; mobile or local healthcare providers, includ- ing local labs and imaging centers; and home delivery of investigational products.” [15]. DCTs can be completely remote or partially decentralized with hybrid approaches via study centers. The latter requires some visits on site, while other visits or assessments can be performed at a home or within a local care community. In fully remote trials, patients have no required site visits [15]. Existing evidence on DCTs is diverse, with studies focusing on different technologies and evaluation meth- ods. Much of the literature explores specific digital elements used in DCTs, such as e-recruitment and e-consent; however, challenges related to data privacy, accuracy, and integration into existing healthcare infrastructures remain insufficiently addressed [1]. DCTs have been proposed to accelerate patient recruitment, broaden participant diversity by overcoming geo- graphical distance, improve patient retention due to a lower participation burden, decrease the costs of the trial and produce data which is much closer to the real-world [3,11,13,16–18]. A systematic review on DCT methods found that there is insuffi- cient evidence to establish a best practice method, and the experiences of staff and participants are underrepresented [3]. In this context, DTx are particularly well suited for DCTs as their evaluation ideally involves a randomized clinical trial (RCT). Since DTx are used in remote settings, their evaluation with a DCT is closer to the real-world use than with a traditional trial, which could potentially improve the applicability of the results. Furthermore, they often provide the user interface for the collection of PROs and the therapeutic intervention, making them inherently compatible with remote data collection. DTx also typically require fewer interactions with healthcare providers and do not bring along complex supply chain management issues [13,19]. DCT and DTx are both facilitating access by bringing the research or the treatment to the patients home rather than the other way around [2,15]. Lastly, DTx trials in remote settings appear to be safe, with minimal risk of serious adverse events compared to pharmacological interventions [2]. Together, these factors make DCTs an appropriate approach for evaluating DTx. While various countries and entities have issued guidance on DCTs, these recommendations are not specifically tai- lored for DTx trials [20–22]. Research on DTx trials has examined aspects such as design, quality, and evaluation. DTx evaluation is resembling drug trials and increasingly incorporates digital biomarkers and real-world data [23]. Studies have noted inconsistencies in the definition of control conditions and recommended the use of large-scale, real-world effective- ness trials [6]. Despite these identified biases in the evaluation, most DTx efficacy studies were designed as RCTs [10]. A recent systematic review characterizing DTx trials revealed that they are typically short in duration and, like drug trials, tend to lack inclusivity in terms of participant diversity and eligibility criteria [24]. However, no systematic or scoping review focusing on the combination of DCTs with DTx has been identified, prompt- ing the need for this review to fill this research gap. Therefore, this scoping review aims to identify insights from existing literature and practice on the use of DCT methods in evaluating DTx. The objectives are to address the key aspects and practical considerations when planning, designing, conducting or monitoring DCTs with DTx or SaMD, summarize current knowledge and challenges faced during these trials. Moreover, as running a DCT with DTx is still in its infancy, the article aims to identify research gaps, the type of evidence currently available and what trends, key terms or concepts are used in the literature. PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 4 / 30 Methodology The scoping review follows the framework for scoping reviews provided by Arksey and O’Malley [25] and Levac et al. [26], and is structured along the PRISMA-ScR checklist [27]. The literature research was guided by a structured search strategy. Different terms for DCTs (“virtual”, “remote”, “end-to-end”, “web-based”, “ehealth”) were included based on the systematic review on DCTs conducted by Rogers et al. [3]. The term “mHealth” (mobile health), was included as the term “DTx”, as defined by the DTx Alliance is relatively new. This could have led to the exclusion of articles using other terms that would fall under the definition of a DTx or SaMD. Moreover, many DTx come in form of an mHealth application. The protocol and PRISMA-ScR checklist for this scoping review can be accessed under Supporting information (S1 and S2 Files). Inclusion criteria Fully or partially DCTs, investigating DTx/SaMDs with intention to treat, manage or prevent a disease as per definition of the DTx Alliance, unrelated to planned regulatory approval are included in the review. Also, the protocols, trial design reports or articles reporting experiences about DCTs or a part of it evaluating a DTx/SaMD are considered for inclusion. A fully DCT requires no in-person visit by the patient at the research center, the clinic or a pharmacy while a partially DCT includes at least one physical visit of participants. Exclusion criteria Articles that are not focused on the design, planning, conduct or monitoring or its related learnings (difficulties, benefits and advantages compared to classical trials) of the DCT were not included in this review (reason 1, Fig 1). Only peer- reviewed articles were considered for inclusion whereas abstracts were excluded (reason 2, Fig 1). If the DTx of interest was a wellness or well-being app or a device that is not focused on the treatment, management or prevention of a disease or if the use of the DTx was not discussed, the article was not considered (reason 3, Fig 1). Studies were excluded if the software did not have a specific medical purpose, but instead focused on general health advice, health literacy or symp- tom reporting (reason 4, Fig 1). Articles with study designs other than clinical trials, for example cross-sectional studies were not considered either (reason 5, Fig 1). Full texts not available in English, French or German were excluded (reason 6, Fig 1). Databases and search strategy For the identification of peer-reviewed articles, the databases Web of Science, MEDLINE, EMBASE and Cochrane CEN- TRAL were searched with a structured search strategy which was composed together with a librarian. The last search was conducted on 25th of April 2025. The search strategy, with the Boolean operators OR and AND, was applied in the four databases. The following presentation of the search strategy was used in EMBASE: ((DCT OR DCTs OR VCT OR VCTs OR (trial* NEAR/3 (decentrali* OR de-centrali* OR remote* OR virtual* OR web- based OR ehealth OR end-to-end OR hybrid))):ab,ti,kw) AND (‘mobile health application’/exp OR (“digital therapeutic*” OR DTx OR SAMD* OR (software NEAR/5 “medical device*”) OR Mhealth OR DIGA OR “digital health application*” OR “mobile health” OR (“mobile app*” NEAR/3 treat*)):ab,ti,kw) No limitations such as language restrictions or year of publication were used. Additionally, the references of the articles found with the systematic search strategy were screened for matching articles. Screening process and data extraction After applying the search strategy to the four chosen databases, the 608 results were imported in EndNote 20 and deduplicated with Deduklick, which led to 332 results [28]. The remaining articles were imported in Rayyan for eligibility PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 5 / 30 Fig 1. Selection process of literature – PRISMA flowchart. https://doi.org/10.1371/journal.pdig.0000905.g001 https://doi.org/10.1371/journal.pdig.0000905.g001 PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 6 / 30 screening [29]. 3 articles were found by bibliography screening of the included articles. Articles were first included or excluded based on abstract screening by two reviewers (CK & MB). Afterwards full text screening was done by the same two reviewers using beforehand defined eligibility criteria. In case of disagreement or uncertainty for in- or exclusion of articles the reviewers resolved the issue by discussion. During the abstract screening no conflicts occurred but 7 articles were labeled as “maybe” and then resolved by consensus. Round two based on full text screening led to (10/113) dis- agreements and (7/113) uncertainty. Data extraction was done by two reviewers based on the articles and the information provided in the trial’s registry. Analysis of selected literature As suggested by Levac et al. [26], the selected literature was reviewed with qualitative coding to identify reoccurring themes across the articles. Two rounds of coding by one researcher with the software Atlas.ti, resulted in 42 codes [30]. Coding was oriented towards the research question with predefined code groups (inductive coding) but went beyond the topics of design, planning, conducting and monitoring (deductive coding). The emerging codes were grouped into five pro- spectively defined code groups, namely design, planning, conducting, challenges and benefits. The five code groups were selected by two researchers. After one round of coding, the same two researchers discussed new codes and text sections that were coded with the predefined code groups, to ensure consensus and that they followed the intended scope before proceeding to the second round. Some codes remained without being assigned to a group as a semi-structured approach was used. Articles were grouped by disease or condition targeted and were reviewed along key aspects of the studies and the data was charted in a Microsoft Excel spreadsheet. Results of the Excel were summarized and illustrated in Table 1 and Fig 2. When using the term DCT, the study refers to the definition of the DCTs working group from the Clinical Trials Transformation Initiative and for the term DTx to the DTx Alliance definition. Results Fig 1 represents the selection process of sources scanned and included for this review. In total 335 articles were screened and 41 included by two reviewers. Among the included articles are thirteen study protocols [31–43], eighteen clinical trials [44–61], three clinical trial design reports [62–64], two mixed method studies [65,66], two reviews [1,67] and three articles discussing a specific part or adaption of a clinical trial [68–71]. Characteristics of sources A summary of references, type of the article and targeted disease/condition, intervention types, study populations, the methodologies used, the aim of the studies, the outcome measures, and other important results of all the articles included in this scoping review are presented in Table 1 below. Synthesized results from Table 1 A total of 41 articles were reviewed with 29 originating from the U.S., 7 from Europe, 2 from Canada, 1 from Brazil, 1 from Japan and 1 from New Zealand. All studies were published between 2015 and 2025. Types of DTx tested or discussed were mainly targeting mental health (12/41) [53,70] out of which 10 specifically focused on depression [31,34,42,46–48,51,55,56,61], or substance use disorders (7/41) [1,32,39,40,60,62]. Other targeted conditions were cardiovascular diseases (7/41) [35,36,44,57,64,66,69], stroke/ aphasia (3/41) [37,45,58] and pelvic floor issues such as urinary incontinence (5/41) [38,52,54,59,63], illustrated in Fig 2. The studies discussing a trial varied in the design regarding arms, blinding, type of control/comparator, duration, sample size and population. Most trials (34/38) included a control group, and the number of arms ranged between 1 and 16. Trials with multiple arms used randomization tech- niques. Open-label, single and double blinding was used, and trial phases were described as either feasibility pilot study, early-phase or phase 3 trial. The duration of the intervention varied from 3 hours to 6 months and the sample size ranged PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 7 / 30 Ta b le 1 . S u m m ar y o f ke y d at a o f in cl u d ed s tu d ie s. A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s S ch w ei ge r et a l. 20 22 M is so ur i, U .S . [3 1] P ro to co l D ep re ss io n 1st A rm ( E xp er im en ta l): D ev ic e: M in df ul M y W ay N o co m pa ra to r 18 w ee ks O ld er a du lts ( 65 + ) w ith c ur re nt m aj or de pr es si on N = 2 3 S in gl e ar m , o pe n- la be l e ar ly -p ha se cl in ic al tr ia l F ul ly r em ot e Te st o nl in e m in df ul - ne ss tr ai ni ng E co lo gi ca l M om en ta ry A ss es sm en t (E M A ) D ep re s- si on S ca le E xe m pl ifi es in no - va tiv e cl in ic al tr ia l d es ig ns b y us in g sm ar tp ho ne te ch no lo gy P ra ta p et a l. 20 18 C al ifo rn ia , U .S . [4 6] C lin ic al tr ia l re po rt D ep re ss io n 1st A rm ( A ct iv e C om pa ra to r) : T he ra pe ut ic v id eo g am e ta rg et in g co gn iti ve c on tr ol ne tw or k 2nd A rm ( E xp er im en ta l): P ro bl em S ol vi ng T he ra py 3rd A rm ( A ct iv e co m pa ra to r) : B as ic h ea lth p us h ap p 4 w ee ks P eo pl e 18 a nd o ld er w ho h av e sy m pt om s of d ep re ss io n E nr ol le d: N = 1 04 0 A ct iv e us er s: N = 3 48 F ea si bi lit y pi lo t st ud y ra nd om iz ed , op en -la be l c lin ic al tr ia l F ul ly r em ot e F ea si bi lit y of c on du ct - in g fu tu re r an do m iz ed co nt ro lle d tr ia l c om - pa rin g th re e m ob ile m en ta l h ea lth a pp s fo r de pr es si on S he eh an D is ab ili ty A ss es sm en t S ca le Lo ng -t er m e ng ag e- m en t a k ey is su e. Im pr ov ed o ut co m es di d no t v ar y by tr ea t- m en t a pp A re an e t a l. 20 16 S an F ra nc is co , U .S . [4 7] C lin ic al tr ia l re po rt D ep re ss io n 1st A rm : B eh av io ra l: P ro bl em - so lv in g th er ap y 2nd A rm : B eh av io ra l: C as e m an ag em en t ( C M ) a nd 3rd A rm : c on tro l a pp fo r m oo d 12 w ee ks P eo pl e ol de r 60 su ffe rin g fr om m aj or un ip ol ar d ep re ss io n N = 6 26 O pe n- la be l r an do m - iz ed c on tr ol le d tr ia l F ul ly r em ot e C om pa re u se p at te rn s an d cl in ic al o ut co m es be tw ee n 3 di ffe re nt se lf- gu id ed m ob ile ap ps fo r de pr es si on D ep re ss io n [T im e F ra m e: M ea su re d at pr et re at m en t an d W ee ks 3 , 6, 9 , 1 2, a nd 24 ] D ep re ss io n ap ps ha ve g re at es t i m pa ct on p eo pl e w ith m or e m od er at e le ve ls o f de pr es si on A ng ue ra e t a l. 20 16 S an F ra nc is co , U .S . [4 8] C lin ic al tr ia l re po rt D ep re ss io n 1st A rm : A c og ni tiv e tr ai ni ng ap pl ic at io n, ba se d on p ro bl em -s ol vi ng th er ap y. 2nd A rm : C on tr ol a pp fo r m oo d 12 w ee ks P eo pl e ol de r 60 su ffe rin g fr om m aj or un ip ol ar d ep re ss io n N = 1 09 8 O pe n- la be l r an do m - iz ed c on tr ol le d tr ia l F ul ly r em ot e A ss es s fe as ib ili ty fu lly m ob ile r an do m iz ed co nt ro lle d tr ia l u si ng as se ss m en ts a nd tr ea tm en ts d el iv - er ed th ro ug h m ob ile de vi ce s A cc es s (s am - pl e re pr es en - ta tiv en es s) , en ga ge m en t an d co st s to c om pl et e st ud y S tu dy e ng ag em en t hi gh d ur in g th e fir st 2 w ee ks o f t re at m en t, fa lli ng to 4 4% a dh er - en ce b y th e 4t h w ee k F ur m an e t a l. 20 23 S an F ra nc is co , U .S . [3 4] P ro to co l D ep re ss io n 1st A rm ( E xp er im en ta l): A ct iv e in te rv en tio n 5 w ee ks ap p pr og ra m 2nd A rm ( C on tr ol ): N o in te r- ve nt io n, u su al c ar e 5 w ee ks P ar tic ip an ts a ge d 13 –2 1 w ith s ym pt om s of d ep re ss io n N = 2 20 2 A rm r an do m iz ed , pa ra lle l a ss ig ne d, si ng le -b lin d tr ia l F ul ly r em ot e E va lu at e th e ef fe ct iv en es s of a se lf- gu id ed , c og ni tiv e be ha vi or al th er ap y (C B T )- ba se d m ob ile ap p + a ss es sm en t- en ha nc ed U su al C ar e (e U C ) co m pa re d to eU C a lo ne a s an in te rv en tio n D ep re ss iv e sy m pt om se ve rit y at p os t- in te rv en tio n N ot a pp lic ab le (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 8 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s M cC lo ud e t a l. 20 20 U ni te d K in gd om [5 5] C lin ic al tr ia l re po rt D ep re ss io n 1st A rm ( E xp er im en ta l): F ee l s tr es s fr ee m ob ile ap pl ic at io n 2nd A rm ( C on tr ol ): N o in te r- ve nt io n, w ai tli st 12 w ee ks S tu de nt s (1 8+ ) w ith an xi et y or d ep re ss iv e sy m pt om s N = 1 68 2 A rm p ar al le l- as si gn ed r an do m - iz ed o pe n- la be l t ria l F ul ly r em ot e Te st th e ef fe ct iv en es s of a n ap pl ic at io n- ba se d co m pu te riz ed C B T in te rv en tio n na m ed “ F ee l S tr es s F re e” a t r ed uc in g de pr es si on a nd an xi et y sy m pt om s in a sa m pl e of U K u ni ve r- si ty s tu de nt s H os pi ta l A nx ie ty a nd D ep re ss io n S ca le F ee l S tr es s F re e ap p re du ce d de pr es si on sy m pt om s at w ee k 6 K ul ik ov e t a l. 20 23 S an F ra nc is co , U .S . [5 1] C lin ic al tr ia l re po rt D ep re ss io n 1st A rm ( E xp er im en ta l): Li m bi x S pa rk , C B T- ba se d in te rv en tio n 2nd A rm ( A ct iv e C om pa ra - to r) : P sy ch oe du ca tio n 5 w ee ks A do le sc en ts w ith de pr es si on a ge 1 3– 21 N = 6 0 2 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, op en -la be l t ria l F ul ly r em ot e E va lu at e th e cl in ic al ef fe ct iv en es s an d sa fe ty o f a C B T- ba se d di gi ta l t re at - m en t f or a do le sc en t de pr es si on ( Li m bi x S pa rk ) re la tiv e to ps yc ho ed uc at io n) C ha ng e in de pr es si on sy m pt om s, P ar tic ip an t- / pa re nt -r at ed A nx ie ty S ym pt om s an d G lo ba l F un ct io ni ng , nu m be r of pa rt ic ip an ts in re m is si on R ob us tn es s of on lin e re cr ui tm en t te ch ni qu es , s tr on g en ga ge m en t w ith a nd po te nt ia l t he ra pe ut ic be ne fit o f S pa rk , a nd ef fe ct iv en es s of th e no ve l s af et y pr ot oc ol to m on ito r an d en su re pa tie nt s af et y. S ig ni f- ic an t m ai n ef fe ct o f tim e, a ss oc ia te d w ith de cr ea se d P H Q -8 sc or es o ve r tim e M ob er g et a l. 20 19 S an F ra nc is co , U .S . [5 6] C lin ic al tr ia l re po rt D ep re ss io n 1st A rm ( In te rv en tio n) : M ob ile a pp lic at io n P ac ifi ca (C B T ) + tr ea tm en t a s us ua l 2nd A rm ( C on tr ol ): N o in te r- ve nt io n, w ai tli st + tr ea tm en t as u su al 4 w ee ks A du lts ( 18 + ) w ith m ild to m od er at e sy m p- to m s of d ep re ss io n or an xi et y N = 5 00 2 A rm , f ac to ria l as si gn ed o pe n- la be l tr ia l F ul ly r em ot e E xa m in e th e ef fic ac y of a m ob ile a pp lic at io n im pl em en ta tio n of ex is tin g be st p ra ct ic es in m en ta l h ea lth tr ea t- m en t f or m an ag in g st re ss , a nx ie ty , a nd de pr es si on C ha ng e in D ep re ss io n, A nx ie ty , S tr es s [T im e F ra m e: 2 w ee ks , 1 m on th , 3 m on th s] P ac ifi ca g ro up e xp e- rie nc ed s ig ni fic an t ch an ge fr om p re to po st fo r ea ch v ar i- ab le . C ha ng e in th e P ac ifi ca g ro up w as gr ea te r th an c ha ng e in th e w ai tli st g ro up R ot hm an e t a l. 20 24 Te xa s, U .S . [4 2] P ro to co l D ep re ss io n 1st A rm : A pp -b as ed D T x (C T- 15 2) , c og ni tiv e- em ot io na l a nd b eh av io ra l in te rv en tio n 2nd A rm : S ha m D tx 6 w ee ks A du lts w ith m aj or de pr es si ve d is or de r ag ed 2 2– 64 y ea rs N = 3 86 2 A rm , p ha se 3 r an - do m iz ed , p ar al le l- as si gn ed , b lin de d an d co nt ro lle d tr ia l H yb rid C om pa re th e ef fe c- tiv en es s of 2 D T x in a du lts d ia gn os ed w ith m aj or d ep re ss iv e di so rd er w ho a re on a nt id ep re ss an t th er ap y C ha ng e fr om ba se lin e to w ee k 6 in th e M on tg om - er y– Å sb er g D ep re ss io n R at in g S ca le an d G en er al A nx ie ty D is - or de r 7 to ta l sc or e M et ho do lo gi ca lly ro bu st tr ia l, in co rp o- ra tin g m an y as pe ct s of a c on ve nt io na l ph ar m ac eu tic al p ha se 3 tr ia l Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 9 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s A ke ch i e t a l. 20 24 Ja pa n [6 1] C lin ic al tr ia l re po rt D ep re ss iv e sy m pt om s 1st A rm : A pp w ith p sy ch oe d- uc at io n, a ss er tiv e tr ai ni ng , pr ob le m -s ol vi ng , b eh av io ra l ac tiv at io n 2nd - 16 th A rm : A pp w ith p sy - ch oe du ca tio n + a ll di ffe re nt co m bi na tio ns o f t he th re e co m po ne nt s in A rm 1 8 w ee ks A du lts ( 20 + ) w ith ca nc er d ia gn os is N = 3 59 P ar al le l-g ro up , r an - do m iz ed , o pe n- la be l, fa ct or ia l t ria l F ul ly r em ot e D ev el op a n ef fic ie nt an d ef fe ct iv e sm ar t- ph on e ps yc ho th er ap y co m po ne nt to a dd re ss de pr es si ve s ym pt om s C ha ng e in pa tie nt h ea lth qu es tio nn ai re -9 an d G en er al - iz ed A nx ie ty D is or de r 7 be tw ee n ba se lin e an d w ee k 8. S ig ni fic an t r ed uc - tio n of d ep re ss iv e sy m pt om s bu t n on e of th e th re e ap p in te r- ve nt io n co m po ne nt s co nt rib ut ed to a dd iti ve si gn ifi ca nt r ed uc - tio n of d ep re ss iv e sy m pt om s H au n et a l. 20 23 U .S . [7 0] R ep or t o f re cr ui tm en t an d at tr iti on in a c lin ic al tr ia l P os ttr au - m at ic S tr es s D is or de r (P T S D )/ M us cu lo - sk el et al C hr on ic P ai n 1st A rm ( A ct iv e C om pa r- at or ): M is si on R ec on ne ct se lf- di re ct ed m ob ile a pp in te rv en tio n th at te ac he s co m pl em en ta ry a nd in te gr a- tiv e he al th s ki lls . 2nd A rm ( P la ce bo c on tr ol ): W ai tli st 8 w ee ks V et er an s w ith m us cu - lo sk el et al c hr on ic p ai n or P T S D N = 3 64 2 A rm r an do m - iz ed , s in gl e gr ou p as si gn m en t, w ai tli st co nt ro lle d, o pe n- la be l t ria l H yb rid D es cr ib e th e re cr ui t- m en t, on bo ar di ng ph as e, a nd a ttr iti on o f a fu lly r em ot e ra nd om - iz ed c on tr ol le d tr ia l as se ss in g th e ef fic ac y of a s el f- di re ct ed m ob ile a nd w eb - ba se d in te rv en tio n fo r ve te ra ns w ith P T S D an d th ei r pa rt ne rs . M is si on R ec on ne ct ef fe ct iv en es s fo r ph ys ic al , P T S D , a nd ps yc ho lo gi ca l sy m pt om s, gl ob al h ea lth O f t he 3 64 r ec ru ite d dy ad s, 9 7 (2 6. 6% ) fa ile d to c om pl et e on bo ar di ng a ct iv iti es . R ea so ns fo r fa ilu re in cl ud e lo ss o f s el f- el ec te d pa rt ne r bu y- in (n = 8 , 8 % ), d iff ic ul tie s w ith u si ng r em ot e da ta c ol le ct io n m et h- od s an d in te rv en tio ns (n = 3 0, 3 1% ), a nd ad ve rs e he al th e xp e- rie nc es u nr el at ed to s tu dy a ct iv iti es (n = 2 3, 2 4% ) B en -Z ee v et a l. 20 21 W as hi ng to n, U .S . [5 3] C lin ic al tr ia l re po rt S er io us m en ta l ill ne ss 1st A rm ( E xp er im en ta l): C O R E s m ar tp ho ne a pp 2nd A rm ( A ct iv e C om pa ra - to r) : W ai tli st c on tr ol 4 w ee ks A du lts ( 18 + ) di ag - no se d w ith a s er io us m en ta l i lln es s N = 3 15 2 A rm r an do m iz ed w ai tli st -c on tr ol le d, cr os so ve r, op en - la be l t ria l F ul ly r em ot e E va lu at e ac ce pt ab il- ity a nd p re lim in ar y ef fic ac y of C O R E , a sm ar tp ho ne in te rv en - tio n th at c om pr is es da ily e xe rc is es de si gn ed to p ro m ot e re as se ss m en t o f d ys - fu nc tio na l b el ie fs C ha ng e in de pr es si ve sy m pt om s, pa ra no id th in k- in g, a nx ie ty sy m pt om s, ps yc ho tic sy m pt om s an d pa rt ic ip an t ac ce pt ab ili ty (a fte r 1 an d 2 m on th s) F ea si bi lit y of r em ot e di gi ta l h ea lth a pp tr ia l. Te st ed C O R E a pp is us ab le , a cc ep ta bl e, ef fe ct iv e fo r re du ci ng sy m pt om s in p eo pl e w ith s er io us m en ta l ill ne ss Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 10 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s P ar k et a l. 20 22 U .S . [3 9] P ro to co l A lc oh ol u se di so rd er s 1st A rm ( A ct iv e C om pa ra to r) : S el f- m on ito re d sm ar tp ho ne ap p A -C H E S S 2nd A rm ( E xp er im en ta l): P ee r su pp or te d sm ar tp ho ne ap p A -C H E S S 3rd A rm ( E xp er im en ta l): C lin - ic al ly in te gr at ed s m ar tp ho ne ap p A -C H E S S 12 w ee ks A du lts a ge d > 21 ye ar s w ith r is ky d rin k- in g pa tte rn N = 3 57 , e nr ol lm en t su sp en de d du e to C O IV D -1 9 3 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, op en -la be l t ria l H yb rid D et ec t t he e ffe ct iv e- ne ss o f a n m H ea lth in te rv en tio n by as se ss in g di ffe re nc es in s el f- re po rt ed r is ky dr in ki ng p at te rn s an d qu al ity o f l ife be tw ee n pa rt ic ip an ts in th re e st ud y gr ou ps (s el f- m on ito re d, pe er -s up po rt ed , a nd cl in ic al ly in te gr at ed ) N um be r of ris ky d rin ki ng da ys ( 1y ea r) N ot a pp lic ab le K au fm an e t a l. 20 23 U .S . [6 2] C lin ic al tr ia l d es ig n re po rt F et al A lc oh ol S pe ct ru m D is or de r P re ve nt io n 1st A rm ( E xp er im en ta l): m H ea lth in te rv en tio n W Y S E C H O IC E S p re ve nt io n pr og ra m 2nd A rm ( C on tr ol ): N o in te r- ve nt io n, u nr el at ed p ro gr am to a lc oh ol e xp os ed p re g- na nc y (A E P ) pr ev en tio n 3 ho ur s A m er ic an In di an a nd A la sk a N at iv e (A IA N ) W om en a ge 1 6– 20 ye ar s 2 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, op en -la be l t ria l F ul ly r em ot e Te st th e ef fe ct iv en es s of a c ul tu ra lly a da pt ed m H ea lth in te rv en tio n to p re ve nt A E P, u si ng so ci al m ed ia to r ec ru it A IA N y ou ng w om en N um be r of da ys in p as t 30 d ay s w ith at le as t o ne al co ho lic dr in k, e ffe ct iv e co nt ra ce pt iv e us e N ot a pp lic ab le K au fm an e t a l. 20 25 U .S . [6 0] C lin ic al tr ia l r ep or t (o ne m on th ou tc om es ) F et al A lc oh ol S pe ct ru m D is or de r/ A lc oh ol - ex po se d pr eg na nc y 1s t A rm ( E xp er im en ta l): N at iv e W Y S E C H O IC E S A pp 2nd A rm ( C on tr ol ): A lte rn a- tiv e ap p, fi na nc ia l l ite ra cy / bu dg et in g 4 w ee ks F em al e, a ge d 16 –2 0 ye ar . A m er ic an In di an or A la sk a N at iv e an d liv in g in a to w n or c ity N = 4 39 2 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, op en -la be l t ria l F ul ly r em ot e E va lu at e th e ef fe ct iv en es s of th e m H ea lth tr an sl at io n of A m er ic an In di an Y ou th C H O IC E S fo r pr ev en t- in g al co ho l- e xp os ed pr eg na nc y an d fe ta l al co ho l s pe ct ru m di so rd er A lc oh ol a nd co nt ra ce pt iv e us e in th e la st 3 0 da ys m ea su re d at 2, 6 a nd 1 2 m on th s N at iv e W ys e C H O IC E S a pp in flu en ce d ch an ge s in k no w le dg e an d be ha vi or a t o ne m on th . T ria l o ng oi ng Lu de re r et a l. 20 22 N ew Y or k, U .S . [3 2] P ro to co l O pi oi d/ su b- st an ce u se di so rd er 1st A rm ( A ct iv e co m pa ra to r) : D ev ic e: r eS E T- O 2nd A rm ( E xp er im en ta l): D ev ic e: P E A R -0 08 12 w ee ks In di vi du al s w ith op io id u se d is or - de r, bu pr en or ph in e tr ea tm en t E nr ol lm en t o ng oi ng D ec en tr al iz ed , ra nd om iz ed s in gl e bl in de d co nt ro lle d tr ia l H yb rid In ve st ig at e in te ra ct io n w ith D T x ne w c on te nt de liv er y fo rm at . E va lu at in g tr ea tm en t s uc ce ss E va lu at e P ar tic ip an t E ng ag em en t D at a E va lu at e th e nu m be r of a ct iv e se ss io ns p er w ee k be tw ee n P E A R -0 08 a nd re S E T- O N ot y et a va ila bl e Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 11 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s R os a et a l. 20 15 U .S . [1 ] R ev ie w E - te ch no lo gi es in c lin ic al tr ia ls e xe m - pl ifi ed w ith op io id /s ub - st an ce u se di so rd er N ot a pp lic ab le N ot a pp lic ab le Li te ra tu re r ev ie w P ro vi de a g en er al ov er vi ew o f t he u se of e -t ec hn ol og ie s in cl in ic al tr ia ls r es ea rc h N ot a pp lic ab le P ot en tia l o f e- te ch no lo gi es to r ea ch a w id e au di en ce , m ak in g tr ia ls m or e ef fic ie nt , re du ci ng c os ts Lo eb en be rg et a l. 20 23 U ni te d K in gd om [6 8] C as e st ud y of a r em ot e tr ia l A lc oh ol ab us e/ D et ec tin g & m an ag in g pa rt ic ip an t de ce pt io n 1st A rm : D rin k Le ss a pp 2nd A rm : N at io na l h ea lth se rv ic e A lc oh ol a dv is e w eb pa ge to r ed uc e dr in ki ng 6 m on th s A du lts ( 18 + ) w ith ha za rd ou s/ ha rm fu l al co ho l c on su m pt io n N = 5 60 2 2 A rm p ar al le l- as si gn ed , r an do m - iz ed tr ia l F ul ly r em ot e E va lu at in g th e ef fe c- tiv en es s of a n al co ho l re du ct io n ap p, D rin k Le ss . H ig hl ig ht a nd di sc us s th e is su es w ith p ar tic ip an t d ec ep - tio n af fe ct in g re m ot e re se ar ch tr ia ls w ith fin an ci al c om pe ns a- tio n; a nd th e im po r- ta nc e of r ig or ou s da ta m an ag em en t t o de te ct an d ad dr es s th es e is su es C ha ng e be tw ee n ba se lin e an d 6‐ m on th fo llo w ‐u p in se lf‐ re po rt ed w ee kl y al co ho l co ns um pt io n es tim at ed o ve r th e la st m on th . N um be r of pa rt ic ip an t de ce pt io n O f t he 1 14 2 pa rt ic i- pa nt s w ho e nr ol le d in th e fir st 2 m on th s of re cr ui tm en t, 75 .6 % (n = 8 63 ) of th em w er e id en tif ie d as bo ts d ur in g da ta sc re en in g. M an ua l pa rt ic ip an t d ec ep tio n oc cu rr ed th ro ug ho ut th e st ud y. O f t he 5 95 6 pa rt ic ip an ts ( ex cl ud - in g bo ts ) w ho e nr ol le d in th e st ud y, 2 98 ( 5% ) w er e id en tif ie d as fa ls e pa rt ic ip an ts G la ss e t a l. 20 23 W as hi ng to n, U .S . [4 0] P ro to co l S ub st an ce us e di so rd er 1st A rm ( A ct iv e C om pa ra to r) : S ta nd ar d im pl em en ta tio n re se t & r es et -O 2nd A rm ( E xp er im en ta l): S ta nd ar d im pl em en ta - tio n + h ea lth c oa ch in g 3rd A rm ( E xp er im en ta l): S ta nd ar d im pl em en ta - tio n + p ra ct ic e fa ci lit at io n 4th A rm ( E xp er im en ta l): S ta nd ar d im pl em en ta - tio n + h ea lth c oa ch in g + p ra c- tic e fa ci lit at io n 12 w ee ks P rim ar y ca re c lin ic s w ith a t l ea st o ne re S E T /r es et -O tr ai ne d cl in ic ia n A du lts ( 18 + ) w ith un he al th y su bs ta nc e us e in p rim ar y ca re 4 A rm c lu st er - ra nd om iz ed , 2 x2 fa ct or ia l-a ss ig ne d si ng le -b lin d tr ia l H yb rid E st im at e th e ef fe ct of p ra ct ic e fa ci lit at io n an d he al th c oa ch in g im pl em en ta tio n st ra te - gi es in in cr ea si ng th e re ac h an d fid el ity o f a D T x fo r su bs ta nc e us e di so rd er s in p rim ar y ca re c lin ic s R ea ch o f th e D T x to pa tie nt s in th e pr im ar y ca re cl in ic & F id el ity of p at ie nt s’ us e of th e D T x to c lin ic al re co m m en da - tio ns N ot a pp lic ab le Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 12 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s W ou te rs e t a l. 20 22 B el gi um [4 4] C lin ic al tr ia l re po rt C ar di ac m on ito r- in g, a tr ia l fib ril la tio n 1st A rm : D ev ic e: s ev en -d ay E C G H ol te r & 2 4- ho ur bl oo d pr es su re m on ito r on sm ar tp ho ne 2nd A rm ( C om pa ra to r) ; D ev ic e: s ev en -d ay E C G H ol te r & 2 4- ho ur b lo od p re s- su re m on ito r on s m ar tw at ch 6 m on th s C ry pt og en ic s tr ok e an d tr an si en t i sc h- em ic a tta ck ( T IA ) pa tie nt s, o ld er th an 18 y ea rs N = 4 4 2 A rm d ou bl e bl in d ra nd om iz ed p ar al le l as si gn m en t c lin ic al tr ia l F ul ly r em ot e D em on st ra te th e ad de d va lu e of m H ea lth to d et ec t at ria l f ib ril la tio n (A F ) ea rly in ( T IA ) pa tie nt s A F d et ec tio n w ith m H ea lth ve rs us IL R – P er ce nt ag e P er ce nt ag e of pa tie nt s w ith A F d et ec te d P P G -b as ed m H ea lth ab le to d et ec t A F in a pa tie nt in w hi ch A F w as c on fir m ed o n th e IC M . M an y fa ls e- po si tiv e A F o n IC M s re gi st ra tio ns Je ga na th an et a l. 20 22 M ic hi ga n, U .S . [3 5] P ro to co l C ar di ac re ha bi lit at io n 1st A rm ( E xp er im en ta l): S m ar t w at ch + V A LE N T IN E A pp 2nd A rm ( A ct iv e co m pa ra to r) : U su al c ar e + s m ar t w at ch 6 m on th s C ar di ac r eh ab ili ta tio n pa tie nt s ag e > 1 8 < 7 5 ye ar s 2 A rm r an do m iz ed - co nt ro lle d, o pe n- la be l t ria l H yb rid E va lu at e an m H ea lth in te rv en tio n fo r ca r- di ac r eh ab ili ta tio n C ha ng e in 6 m in ut es w al k di st an ce a nd st ep c ou nt af te r 6 m on th s N ot a pp lic ab le M ag na ni e t a l. 20 21 U .S . [6 9] A da pt io n re po rt o f on go in g cl in ic al tr ia l A tr ia l fib ril la tio n 1st A rm ( E xp er im en ta l): In te rv en tio n re la tio na l ag en t/A liv eC or K ar di a 2nd A rm ( A ct iv e C om pa ra - to r) : U su al c ar e 4 m on th s P at ie nt s liv in g in a ru ra l a re a w ith a tr ia l fib ril la tio n N = 1 30 2 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, si ng le -b lin d tr ia l H yb rid S um m ar iz e tr ia l a da p- ta tio n fr om in -c lin ic to v irt ua l d es ig n in r es po ns e to th e C O V ID -1 9 S uc ce ss fu l ad ap ta tio n to vi rt ua l e ng ag e- m en t a nd re cr ui tm en t D em on st ra te d po te nt ia l t o vi rt ua lly re cr ui t a nd in vo lv e ol de r ad ul ts in tr ia ls o f d ig ita l h ea lth in te rv en tio ns P fa ef fli D al e et a l. 20 15 N ew Z ea la nd [6 6] M ix ed m et ho d st ud y Is ch em ic he ar t di se as e 1st A rm : U su al ca re + m H ea lth a pp lic at io n 2nd A rm ( C on tr ol ): U su al ca re 6 m on th s Is ch em ic h ea rt d is - ea se p at ie nt s N = 1 71 2 A rm H yb rid S tu dy : t o co nd uc t a pr oc es s ev al ua tio n of th e H E A R T in te rv en - tio n to d et er m in e w ha t w or ke d an d w ha t d id no t, as w el l a s ac ce pt - ab ili ty a nd u sa bi lit y. T ria l: In ve st ig at e ef fe ct iv en es s of a n in te rv en tio n de si gn ed to in cr ea se p hy si ca l ac tiv ity a nd th er eb y ex er ci se c ap ac ity P ro ce ss ev al ua tio n: b y m ea ns o f W eb si te u sa ge s ta - tis tic s, q ua nt i- ta tiv e su rv ey s, an d qu al ita tiv e in te rv ie w M ax im al o xy - ge n up ta ke , co m pa re d to us ua l c ar di ac re ha bi lit at io n ca re a lo ne (c on tr ol ) H ig h us ag e ra te s su pp or te d re ce nt ev id en ce th at o ld er ad ul ts d o no t n ec es - sa ril y ex pe rie nc e a di gi ta l d iv id e. H E A R T in te rv en tio n w as w el l re ce iv ed b ut a dd i- tio na l t ai lo rin g co ul d im pr ov e th e pr og ra m Lo kk er e t a l. 20 21 O nt ar io , C an ad a [3 6] P ro to co l H yp er te ns io n 1st A rm ( E xp er im en ta l): In te rv en tio n A pp S ph yg m o B P 2nd A rm ( N o in te rv en tio n) : E du ca tio na l C on tr ol G ro up 6 m on th s A du lts ( 18 + ) w ith hy pe rt en si on 2 A rm p ilo t r an - do m iz ed , p ar al le l- as si gn ed o pe n- la be l tr ia l F ul ly r em ot e Te st th e fe as ib ili ty o f us in g th e w eb r es ea rc h pl at fo rm to c on du ct ef fic ie nt a nd r ig or ou s on lin e ra nd om iz ed co nt ro lle d tr ia ls o f m H ea lth a pp s re le va nt to p at ie nt s w ith c ar di o va sc ul ar r is k fa ct or s P ar tic ip at io n co m pl et io n, C ha ng e fr om ba se lin e bl oo d pr es su re a t 6 m on th s N ot a pp lic ab le Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 13 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s B ilb re y et a l. 20 24 W as hi ng to n D .C . U .S . [5 7] C lin ic al tr ia l re po rt C ar di ac re ha bi lit at io n R ec ov er yP lu s. H ea lth D ig ita l ca rd ia c re ha bi lit at io n pr o- gr am : t el eh ea lth c oa ch in g an d m H ea lth a pp e xe rc is es N o co m pa ra to r 12 w ee ks A du lts ( 45 + ) w ith st ab le c ar di ov as - cu la r di se as e w ith re fe rr al to c ar di ac re ha bi lit at io n N = 7 5 S in gl e ar m , o pe n- la be l, w ith in s ub je ct de si gn tr ia l F ul ly r em ot e A ss es s fe as ib ili ty an d im pa ct o f a ho m e- ba se d ca rd ia c re ha bi lit at io n pr og ra m in p at ie nt s w ith c ar di o- va sc ul ar d is ea se s E ffi ca cy ; ch an ge in 6- m in ut e w al k te st , r es tin g he ar t r at e, qu al ity o f lif e w ith th e 12 -I te m S ho rt F or m H ea lth S ur ve y be fo re an d af te r 12 w ee ks T he h om e- ba se d ca rd ia c re ha bi lit at io n pr og ra m s ho w ed fe a- si bi lit y an d ef fic ac y T un is e t a l. 20 24 U .S . [6 4] C lin ic al tr ia l d es ig n re po rt C ar di ov as - cu la r di s- ea se ; H ea rt fa ilu re 1st A rm : S en so r- co nt ro lle d di gi ta l g am e, s m ar t c al e an d ac tiv ity tr ac ke r 2nd A rm ( C on tr ol ): S en so r on ly 24 w ee ks O ld er a du lts w ith he ar t f ai lu re N = u nr ep or te d 2 A rm r an do m iz ed cl in ic al tr ia l H yb rid E xa m in e ch al le ng es an d op po rt un iti es o f di gi ta l h ea lth in te rv en - tio ns th at a ffe ct h ea lth eq ui ty . A ss es s ef fic ac y of d ig ita l h ea lth to ol s fo r im pr ov in g ad he re nc e to s el f- ca re be ha vi or s in p at ie nt s w ith h ea rt fa ilu re H ea lth e qu ity in th e bi ol og - ic al , b eh av - io ra l, ph ys ic al en vi ro nm en t, so ci o- cu ltu ra l an d he al th y sy st em do m ai n. H ea rt fa ilu re p ro xi - m al o ut co m es an d di st al ou tc om es D em on st ra te d st ra te - gi es fo r di gi ta l h ea lth in te rv en tio ns e .g . D C Ts to e ffe ct iv el y ad dr es s he al th e qu ity vi a a fr am ew or k en co m pa ss in g so ci al an d di gi ta l d et er m i- na nt s of h ea lth . T ria l o ng oi ng B ra le y et a l. 20 21 M as sa ch us et ts , U .S . [4 5] C lin ic al tr ia l re po rt S pe ec h th er ap y fo r ap ha si a in po st -s tr ok e pa tie nt s 1st A rm ( E xp er im en ta l): P C T 2nd A rm ( A ct iv e co m pa ra to r) : C on ve nt io na l w or kb oo k th er ap y 10 w ee ks A du lts > 1 8y ea rs w ith co gn iti ve , s pe ec h, o r la ng ua ge d is or de rs du e to s tr ok e N = 3 6 O pe n- la be l, ra n- do m iz ed p ar al le l as si gn m en t t ria l F ul ly r em ot e A ss es s fe as ib ili ty a nd cl in ic al e ffi ca cy o f a vi rt ua l s pe ec h, la n- gu ag e, a nd c og ni tiv e D T x W es te rn A ph as ia B at - te ry R ev is ed , A ph as ia Q uo tie nt (W A B -A Q ) C T- R g ro up h ad W A B -A Q s co re s 6. 43 h ig he r th an th e w or kb oo k gr ou p K im e t a l. 20 21 C an ad a [3 7] P ro to co l A ph as ia 1st A rm ( E xp er im en ta l): V oi ce A da pt In te rv en tio n 2nd A rm ( C on tr ol ): N o in te rv en tio n 13 w ee ks P at ie nt s w ith p os t- st ro ke a ph as ia ag e > 1 8 ye ar s 2 A rm r an do m iz ed , w ai tli st -c on tr ol le d, cr os so ve r si ng le - bl in d tr ia l H yb rid E xa m in e im pa ct o f ad ap tiv e sp ee ch - la ng ua ge tr ea tm en t ap p C ha ng e in na m in g on th e B os to n N am in g Te st N ot a pp lic ab le Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 14 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s Le i e t a l. 20 25 M is so ur i, U .S . [5 8] C lin ic al tr ia l re po rt S tr ok e/ po st -s tr ok e fu nc tio ni ng 1st A rm : i nt er ac tiv e se lf- m an ag em en t a ug m en te d by re ha bi lit at io n te ch no lo gi es (iS M A R T ) in te rv en tio n, te ch no lo gy - b as ed s ki ll- bu ild in g ed uc at io n, h um an co ac hi ng & te xt m es sa gi ng 2nd A rm ( C on tr ol ): S ta n- da rd o f C ar e, P os t- st ro ke in fo rm at io n 12 w ee ks A du lts ( 18 + ) 3m on th s po st is ch em ic o r he m or rh ag ic s tr ok e w ith m ild -t o- m od er at e se ve rit y N = 2 4 2 A rm r an do m iz ed pa ra lle l-a ss ig ne d, op en -la be l t ria l F ul ly r em ot e E xa m in e tr ea tm en t sa tis fa ct io n, u se r ex pe rie nc e an d in iti al ef fe ct o f t he iS M A R T in te rv en tio n on p os t- st ro ke fu nc tio ni ng A cc ep ta bi lit y, ap pr op ri- at en es s, fe as ib ili ty a nd sa tis fa ct io n at 1 2 w ee ks . S el f- ef fic ac y an d fu nc tio n- in g vi a st ro ke im pa ct s ca le at w ee k 0 an d 12 iS M A R T e nh an ce d po st -s tr ok e fu nc - tio ni ng a nd s up po rt s st ro ke s ur vi vo rs m an ag in g ch ro ni c co nd iti on s M ar kl an d et a l. 20 23 U .S . [3 8] P ro to co l U rin ar y in co nt in en ce 1st A rm ( A ct iv e co m pa ra to r) : M yh ea lth eb la dd er , m H ea lth ed uc at io n & b eh av io ra l st ra te gi es 2nd A rm ( A ct iv e C om pa r- at or ): V A V id eo c on ne ct , te le he al th v is its 8 w ee ks W om en v et er an s (1 8+ ) w ith u rin ar y in co nt in en ce 2 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, si ng le -b lin d tr ia l F ul ly r em ot e D et er m in e th e op tim al m et ho d fo r re m ot e de liv er y of b eh av - io ra l t he ra py fo r U I to w om en V et er an s. C om pa re M yH ea l- th eB la dd er to a b es t us ua l c ar e m od el de liv er ed b y a cl in i- ci an w ith U I e xp er tis e vi a vi rt ua l v id eo C ha ng e in In te rn at io na l C on su lta tio n on In co n- tin en ce Q ue st io nn ai re U rin ar y In co n- tin en ce S ho rt F or m N ot a pp lic ab le M er lo t e t a l. 20 23 B or de au x, F ra nc e [5 2] C lin ic al tr ia l re po rt E nd om et ri- os is r el at ed pe lv ic p ai n 1st A rm ( E xp er im en ta l): E nd oc ar e co ns is tin g of vi su al a nd a ud ito ry th er a- pe ut ic p ro ce du re s 2nd A rm ( A ct iv e co m pa ra to r) : D ig ita l C on tr ol 5 da ys W om en ( 18 + ) w ith en do m et rio si s N = 1 02 2 A rm r an do m iz ed , pa ra lle l-a ss ig ne d, sh am -c on tr ol le d, fu ll bl in d tr ia l F ul ly r em ot e E va lu at e th e ef fe ct s of E nd oc ar e co m pa re d to a d ig ita l c on tr ol o n th e m ea n ch an ge in pa in in te ns ity 1 , 2 , an d 3 ho ur s af te r da ily us e du rin g th e 5 m os t pa in fu l c on se cu tiv e da ys o f t he m on th in w om en w ith c hr on ic pe lv ic -p er in ea l p ai n P ai n in te ns ity ch an ge fr om be fo re to a fte r tr ea tm en t du rin g 5 da ys F ea si bi lit y an d ef fe ct iv en es s of V R so ftw ar e us e w ith ou t m ed ic al s up er vi - si on ( at h om e) . T he de cr ea se o f a na lg e- si c us e an d of p ai n in te ns ity p ro vi de s ev id en ce fo r th e in te gr at io n of V R in m ul tim od al c hr on ic pe lv ic p ai n tr ea tm en t st ra te gi es Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 15 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s W ei ns te in e t a l. 20 22 U .S . [5 4] C lin ic al tr ia l r ep or t (o f d es ig n re po rt b el ow W ei ns te in e t al . 2 02 1) S tr es s ur in ar y in co nt in en ce 1st A rm : L ev a P el vi c D ig ita l H ea lth S ys te m 2nd A rm : K eg el p el vi c flo or m us cl e ex er ci se s 8 w ee ks A du lts ( 18 + ) w ith se lf- re po rt ed s tr es s ur in ar y in co nt in en ce N = 3 63 2 A rm r an do m iz ed , co nt ro lle d, d ou bl e- bl in de d tr ia l F ul ly r em ot e E va lu at e w he th er pe lv ic fl oo r m us cl e tr ai ni ng u si ng a m ot io n- ba se d di gi ta l in tr av ag in al d ev ic e is m or e ef fe ct iv e th an ho m e pe lv ic fl oo r m us cl e tr ai ni ng fo r tr ea tm en t o f s tr es s or st re ss - p re do m in an t m ix ed u rin ar y in co nt in en ce U ro ge ni ta l D is tr es s In ve nt or y, B la dd er d ia rie s ev al ua tin g th e av er ag e nu m - be r of s tr es s- in co nt in en ce ep is od es in 3 da ys T he m ed ia n nu m be r of S U I e pi so de s on th e 3- da y bl ad de r di ar y w as s ig ni fi- ca nt ly r ed uc ed in th e in te rv en tio n gr ou p co m pa re d w ith c on tr ol gr ou p, r es pe ct iv el y. A s ig ni fic an tly g re at er nu m be r of p ar tic i- pa nt s in th e in te r- ve nt io n gr ou p th an in th e co nt ro l g ro up re po rt ed th ey w er e “m uc h im pr ov ed ” or “v er y m uc h im pr ov ed ” on th e P G I- I W ei ns te in e t a l. 20 21 U .S . [6 3] C lin ic al tr ia l d es ig n re po rt S tr es s ur in ar y in co nt in en ce 1st A rm : L ev a P el vi c D ig ita l H ea lth S ys te m 2nd A rm : K eg el p el vi c flo or m us cl e ex er ci se s 8 w ee ks A du lts ( 18 + ) w ith se lf- re po rt ed s tr es s ur in ar y in co nt in en ce N = 3 63 2 A rm r an do m iz ed , co nt ro lle d, d ou bl e- bl in de d tr ia l F ul ly r em ot e E va lu at e w he th er p el vi c flo or m us cl e tra in in g us in g a m ot io n- ba se d di gi ta l i nt ra va gi na l de vi ce is m or e ef fe ct iv e th an h om e pe lv ic fl oo r m us cl e tra in in g fo r tre at m en t o f s tre ss o r st re ss - p re do m in an t m ix ed u rin ar y in co nt in en ce U ro ge ni ta l D is tr es s In ve nt or y, B la dd er d ia rie s ev al ua tin g th e av er ag e nu m - be r of s tr es s- in co nt in en ce ep is od es in 3 da ys N ot a pp lic ab le V ile la e t a l. 20 24 B ra zi l [5 9] C lin ic al tr ia l re po rt S tr es s ur in ar y in co nt in en ce 1st A rm : M y P el vi c F lo or m ob ile a pp 2nd A rm : B oo kl et 12 w ee ks W om en ( 18 + ) w ith st re ss u rin ar y an d/ o r m ix ed in co nt in en ce N = 1 04 2 A rm r an do m iz ed , co nt ro lle d, d ou bl e- bl in de d tr ia l F ul ly r em ot e V er ify th e ef fe ct s of us in g a m ob ile a pp on p el vi c flo or m us cl e tr ai ni ng in w om en w ith s tr es s ur in ar y in co nt in en ce In co nt in en ce Q ue st io nn ai re - S ho rt F or m an d th e K in g’ s H ea lth Q ue st io nn ai re P el vi c flo or m us cl e tr ai ni ng r ed uc ed sy m pt om s vi a th e us e of th e m ob ile a pp an d th e bo ok le t ( bo th gr ou ps ) C hr is to fo ro u et a l. 20 17 Lo nd on , U ni te d K in gd om [5 0] C lin ic al tr ia l re po rt A go ra ph ob ia 1st A rm ( In te rv en tio na l): A go ra ph ob ia F re e, p ro vi de s an in te ra ct iv e ga m e- ba se d in te rv en tio n us in g co gn iti ve be ha vi or al te ch ni qu es 2nd A rm ( A ct iv e C on tr ol ): G en er ic s tr es s an d an xi et y re du ct io n ap p 12 w ee ks A du lts ( 18 + ) su ffe rin g fr om a go ra ph ob ia N = 1 70 2 A rm r an do m iz ed pa ra lle l-a ss ig ne d, as se ss or -b lin de d tr ia l F ul ly r em ot e Te st th e cl in ic al ef fe ct iv en es s of a no ve l m ob ile a pp fo r ag or ap ho bi a in a co m m un ity - b as ed sa m pl e. S ev er ity o f ag or ap ho bi c an d pa ni c sy m pt om s ar e m ea su re d us in g th e P an ic a nd A go ra ph ob ia S ca le a t b as e- lin e, 6 a nd 1 2 w ee ks . P ar tic ip an ts w ho re ce iv ed A go ra - ph ob ia F re e di d no t im pr ov e m or e th an th os e w ho r ec ei ve d th e S tr es s F re e ap p. B ot h gr ou ps sh ow ed r ed uc tio ns in st at is tic al ly s ig ni fic an t sy m pt om s ev er ity . A ttr iti on w as h ig h Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 16 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s C at el la e t a l. 20 22 U .S . [4 9] C lin ic al tr ia l re po rt F ib ro m ya lg ia 1st A rm (A ct iv e co m pa ra to r) : D ig ita l A cc ep ta nc e an d C om m it- m en t T he ra py ( A C T ) 2n d A rm ( A ct iv e C om pa r- at or ): D ig ita l S ym pt om T ra ck er 12 w ee ks F ib ro m ya lg ia p at ie nt s ag ed 2 2– 75 N = 6 7 2 A rm r an do m iz ed , ac tiv e co nt ro lle d, ph as e 2 op en -la be l, pi lo t t ria l H yb rid F ea si bi lit y of a pr ed om in an tly v irt ua l cl in ic al tr ia l i n an F M po pu la tio n an d pr el im - in ar y ev id en ce fo r th e sa fe ty a nd e ffi ca cy o f a di gi ta l A C T p ro gr am fo r F M ( F M -A C T ) M ea n ch an ge of R ev is ed F ib ro m ya lg ia Im pa ct Q ue s- tio nn ai re T ot al S co re fr om ba se lin e to 1 2 w ee ks F M -A C T d em on - st ra te d im pr ov ed ou tc om es c om pa re d to F M -S T, w ith h ig h en ga ge m en t a nd lo w at tr iti on in b ot h ar m s B is ch of e t a l. 20 22 Lü be ck , G er m an y [3 3] P ro to co l In te rn et u se di so rd er 1st A rm ( In te rv en tio n) : S te pp ed -c ar e ap pr oa ch (a pp , t el ep ho ne c ou ns el in g, on lin e th er ap y 2nd A rm ( C on tr ol ): P la ce bo , pr ev en tio n m od ul e in a pp 17 w ee ks P ar tic ip an ts b et w ee n 16 –6 7y ea rs 2 A rm r an do m iz ed , ob se rv er -b lin d, p ar - al le l g ro up tr ia l F ul ly r em ot e E va lu at io n of a co m pr eh en si ve a nd ec on om ic c ar e sy st em ba se d on a s te pp ed ca re a pp ro ac h fo r in te rn et u se d is or de r N um be r of cr ite ria fo r pr ob le m at ic in te rn et u se ad ap te d to th e ga m in g di s- or de r cr ite ria in D S M -5 a nd IC D -1 1 af te r 6 m on th s N ot a pp lic ab le D on ne lly e t a l. 20 18 D ub lin , I re la nd [6 5] M ix ed m et ho d st ud y (C lin ic al tr ia l re po rt + q ua l- ita tiv e S tu dy ) B al an ce di so rd er s an d ot he r co nd iti on s re la te d to hi gh r is k of fa lls A fa lls p re ve nt io n pr og ra m in a n ur si ng h om e w ith su pp or tin g te ch no lo gi ca l so lu tio ns N o co m pa ra to r 8 w ee ks N ur si ng h om e st af f & re si de nt s S ta ff (N = 1 0) R es id en ts ( N = 1 1) P ar tic ip at or y de si gn ap pr oa ch , 8 w ee ks tr ia l, se m i-s tr uc tu re d in te rv ie w s, q ua lit a- tiv e st ud y H yb rid E xp lo re b ur de n as so - ci at ed w ith a r em ot e tr ia l i n a nu rs in g ho m e se tti ng o n bo th s ta ff & re si de nt s Li ve e xp er i- en ce / b ur de n as so ci at ed to re m ot e tr ia l pa rt ic ip at io n S ta ff re po rt ed ex te ns iv e bu rd en to su pp or t a ct iv iti es o f th e tr ia l. R es id en ts le ss b ur de n H un t e t a l. 20 23 U .S . [6 7] R ev ie w A st hm a N ot a pp lic ab le A st hm a pa tie nt s N ot a pp lic ab le R ep or t e xa m pl es o f re m ot e as th m a cl in ic al st ud ie s, e xp lo re th e be ne fit s an d po te nt ia l dr aw ba ck s of v irt ua l cl in ic al in ve st ig at io n, po te nt ia l i m pa ct o n eq ui ty a nd r ep re - se nt at io n in a st hm a re se ar ch , p ro vi de su gg es tio ns fo r D C T im pl em en ta tio n N ot a pp lic ab le Im pl em en tin g D C Ts us in g m H ea lth te ch no lo gy is a fe as ib le a nd e nc ou r- ag ed a lte rn at iv e to tr ad iti on al in -p er so n cl in ic al a st hm a st ud - ie s an d ca n en ha nc e eq ui ty in r es ea rc h re pr es en ta tio n Ta b le 1 . (C on tin ue d) (C on tin ue d) PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 17 / 30 A u th o r( s) , y ea r o f p u b lic at io n , st u d y lo ca ti o n , C it at io n Ty p e o f ar ti cl e Ta rg et ed d is ea se / co n d it io n In te rv en ti o n t yp e, a n d co m p ar at o r (i f an y) ; d u ra - ti o n o f th e in te rv en ti o n S tu d y p o p u la ti o n s (c ar er g ro u p ; ca re re ci p ie n t g ro u p ) N u m b er o f p ar ti ci p an ts M et h o d o lo g y S tu d y d es ig n : F u lly re m o te o r h yb ri d A im s o f th e st u d y O u tc o m e m ea su re s Im p o rt an t re su lt s T ho rn di ke e t a l. 20 21 U .S . [4 1] P ro to co l C hr on ic in so m ni a 1st A rm ( E xp er im en ta l): D T x S om ry st P E A R -0 03 A N o co m pa ra to r 9 w ee ks P at ie nt s w ith c hr on ic in so m ni a ag ed 2 2– 75 S in gl e gr ou p as si gn ed , o pe n- la be l tr ia l F ul ly r em ot e A ss es s th e po te nt ia l be ne fit s of tr ea tin g in so m ni a w ith a n as yn ch ro no us , m ob ile , ta ilo re d pr es cr ip tio n D T x C ha ng e in In so m ni a S ev er ity In de x E va lu at e P E A R -0 03 A E ng ag em en t an d A dh er - en ce D at a N ot a pp lic ab le B er ub e et a l. 20 24 N ew Y or k, U .S . [4 3] P ro to co l Ty p 2 D ia be te s 1st A rm : P er so na liz ed G ui d- an ce , D ay Tw o ap p 2nd A rm : S ta nd ar di ze d 3rd A rm : U su al C ar e C on tr ol 6 m on th s A du lts ( 21 + ) w ith ea rly s ta ge T yp 2 D ia - be te s, th re e m on th s av er ag e bl oo d gl u- co se le ve l, he m og lo - bi n (H bA 1c )< 8% w ith m et fo rm in u se P ar al le l, ra nd om - iz ed , s in gl e- bl in d, th re e ar m tr ia l F ul ly r em ot e D et er m in e th e ef fic ac y of a p er so na liz ed be ha vi or al a pp ro ac h fo r di et ar y m an ag e- m en t o f t yp e 2 di ab e- te s, v s. a s ta nd ar di ze d be ha vi or al in te rv en tio n M ea n A m pl i- tu de o f G ly ce - m ic E xc ur si on an d H bA 1c Le ve ls a fte r 3 an d 6 m on th s N ot a pp lic ab le ht tp s: //d oi .o rg /1 0. 13 71 /jo ur na l.p di g. 00 00 90 5. t0 01 Ta b le 1 . (C on tin ue d) https://doi.org/10.1371/journal.pdig.0000905.t001 PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 18 / 30 between 11 and 5602 participants. Interventions were either a DTx or a SaMD in form of mobile apps or combined with wearable devices, medical devices or telehealth. Studies differed in terms of the DCT elements employed. Some only decentralized the delivery of the intervention; others mixed centralized and decentralized elements (hybrid) such as in the recruitment process and some were fully decentralized. Although aims of the studies differed, the majority of them evalu- ated the efficacy or feasibility of the DTx. Due to the diversity of DTx interventions in the trials, outcomes assessed, and important results varied across most of the studies. Therapeutic approaches per disease group Therapeutic approaches used in the DTx are analyzed by disease groups to address the heterogeneity of the studies. Mental illness. All included studies treating depression [31,34,42,46–48,51,55,56,61] and mental illness [53,70] used mHealth applications and the majority of studies were using CBT elements as an intervention. The study of Akechi et al. [61] specifically analyzed the effectiveness of different smartphone-based CBT components and their order in treating depressive symptoms. Substance use disorders. The articles investigating a DTx for substance use disorders [1,32,39,40,60,62,68] were mainly using parts of behavioral therapy. The intervention Kaufman et al. [60,62] provided, was in form of a culturally tailored prevention app with educational content. Two clinical trials will compare the effectiveness of DTx when applying different implementation strategies. Park et al. [39] will investigate different levels of human touch (self-monitored, peer supported and clinically integrated) while Glass et al. [40] will test the introduction of the DTx for health care professionals (HCPs), or health coaching for the DTx on a participant level. Pelvic floor issues. Merlot et al. [52] tested a class 1 medical device, with virtual reality that could be used at home to reduce pain caused by endometriosis. Two studies [38,59] tested an mHealth solution, and Weinstein et al. [54,63] a motion-based DTx device to perform pelvic floor muscle training to improve urinary incontinence. The mHealth solution delivered educational content, behavioral change reinforcement and self-monitoring. Cardiovascular diseases. The articles focusing on cardiovascular diseases [35,36,44,57,64,66,69] were heterogeneous in terms of designed interventions. Wouters et al. [44] conducted a comparative study between a DTx and a smartwatch for detection of AF. Jeganathan et al. [35] designed a virtual cardiac rehabilitation program that included contextually tailored notifications promoting low-level physical activity, exercise tracking, goal setting through the mobile study application and weekly activity summaries via email. A similar study was conducted by Bilbrey et al. [57]. They tested a remotely delivered guideline-concordant cardiac rehabilitation intervention that combined synchronous telehealth Fig 2. Therapeutic indications of DTx or SaMD investigated in the articles. https://doi.org/10.1371/journal.pdig.0000905.g002 https://doi.org/10.1371/journal.pdig.0000905.g002 PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 19 / 30 exercise training via videoconferencing and asynchronous coaching through a mHealth app, supported by remote vital sign monitoring using Bluetooth-enabled sensors. In Lokker et al.’s [36] study, a web-based platform should serve as a tool to test mHealth applications in the area of cardiovascular risk factors with web-based RCTs. Tunis et al. [64] used a digital health equity framework to analyze challenges and opportunities in digital health interventions for heart failure self-care, drawing on their experience from a DCT involving multiple sensors and apps to support behavior adherence, and offering recommendations to promote health equity in future research and practice. The intervention of Magnani et al. [69] included a virtual agent that helped to decrease the feeling of social isolation, a digital health application for education, monitoring, and problem-solving, specifically developed for AF. Pfaeffli Dale et al. [66] designed an intervention that consisted of theory-based exercises and behavioral change text messages. Stroke/aphasia. Braley et al. [45] and Kim et al. [37] conducted a DCT with a DTx for speech therapy in patients with aphasia. The DTx in Braley et al.’s [45] trial delivered structured virtual cognitive, speech and language therapy that would usually be given by a therapist. Kim et al. [37] will test an app to improve lexical retrieval which is aiming to strengthen naming abilities through app-based interactions. A broader DCT was conducted by Lei et al. [58] targeting post-stroke rehabilitation. They used a remote technology-based self-management program combining skill-building education, human coaching, and interactive text messaging to improve post-stroke functioning. Others (mixed diseases). Donelly et al. [65] analyzed the burden of a DCT on participants and staff testing a fall prevention program in a nursing home. Bischof et al. [33] investigated a stepped care approach consisting of app use, telephone counselling and online therapy for internet use disorder. Catella et al. [49] conducted an acceptance and commitment therapy DCT for people living with fibromyalgia. A DTx incorporating CBT for insomnia treatment will be investigated by Thorndike et al. [41] within a real-world evidence setting. Christoforou et al. [50] included in the treatment of agoraphobia a CBT approach with individual goal setting. Hunt et al. [67] reviewed decentralized implementation of mHealth interventions in asthma research and provided a simple framework for it. The study of Berube et al. [43] will enroll adults with type 2 diabetes to evaluate the effects of three dietary counseling approaches—personalized, standardized, and usual care control—over six months, using virtual sessions, a mobile app, and sensor-based glucose monitoring, with all participants receiving mediterranean diet guidance and behavioral support. Challenges Challenges and benefits were coded in Atlas.ti across all included articles, then extracted, synthesized to avoid redun- dancies, and compiled into Table 2. One potential problem discussed by Pratap et al. [46] in a DCT with a DTx or SaMD Table 2. Summary of reported benefits and challenges in DCTs. Benefits Challenges Faster recruitment Adherence/engagement/attrition Improved reach and access to trial and treatment (E.g. bridge waiting times) Ensure safety of participants Diversified participant sample (Including minorities, underrepresented groups) Increased burden for staff or caregiver (E.g. comprehension, time or logistical restraints) Less burden for participants (E.g. fewer administrative tasks) Participant burden (E.g. comprehension or emotional load) Easy data collection (E.g. passive data collection) Organizing all assessments remotely Better generalizability as studies were closer to real-world conditions Data privacy, security and accuracy (Response bias due to self- reported data) Lower costs than traditional trials Technical difficulties/ insufficient digital literacy Due to technology, content can be adapted to participants Blinding of participants Potential to alleviate social isolation Potential to increase social isolation Effectiveness of DTx interventions Fraud in enrollment https://doi.org/10.1371/journal.pdig.0000905.t002 https://doi.org/10.1371/journal.pdig.0000905.t002 PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 20 / 30 that requires downloading the software on a personal device is that people sometimes share a mobile phone. This raises concerns about data privacy or may act as a barrier to seeking treatment or participating in a trial due to the fear of being stigmatized. Braley et al. [45] highlighted the elevated technological support that was requested in such trial designs. Beyond the increased need for support, the DCT with AF detection reported technical difficulties such as unstable Blue- tooth connection, insufficient signal and low data quality [44]. Limited data storage capacity was emphasized as another technical issue. Participants in Bilbrey et al.’s trial [57] encountered technical difficulties using an iPad paired with wireless monitors, largely due to limited digital literacy. Fraudulent behavior such as fake or double enrollment was another chal- lenge faced in these trials [46,68]. Rosa et al. [1] underlined a risk of lacking digital health literacy among participants and the difficulty to verify their identities during the trial. Another notable challenge is the lack of guidance from the regulatory side which could hinder the widespread adoption of these types of trial [67]. Donnelly et al. [65] identified various issues in a DCT involving a DTx that were experienced by staff and residents. Comprehension, time, communication, emotional and cognitive load, engagement, logistical aspects and product accountability were perceived burdens from staff. Partici- pants reported problems of comprehension, adherence, emotional load and interference with their personal space. Safety has been mentioned as a challenge in the literature about DCTs. It has been addressed in some of the analyzed trials but was not reported as a key issue. The most frequent measure to ensure safety was the exclusion of participants with suicidal thoughts during the screening [34,47,49,51]. As in classical trials, adverse events were documented in the DCTs and were classified by physicians. Some trials integrated emergency resources in the applications or used telemonitoring to increase safety [32]. One trial had participants who reported feeling reliant on the application [55] which was described as a potential risk in the literature about DTx [2]. Several articles reported high attrition or low engagement as the most common issues, exemplified with retention rates as low as 26% in some studies [44,50–57,59,65,67,70]. Pratap et al. [46] encountered a significant drop-out rate of 50% from the first to the fourth week with an earlier drop-out of 2.5 weeks for the minority group compared to the control group. The prob- lem of low adherence started already with downloading the app. In the study of Arean et al. [47] 60% of the participants never installed the app on their device. A significant decline in engagement was observed after just two weeks, along with deviations from the recommended usage outlined in the instructional video. McCloud et al. [55] also pointed out a discrepancy between participants’ high self-reported engagement and actual usage, which was in reality around 30% lower. The use of the device for urine incontinency in Weinstein et al.’s study [54] dropped to 35%, already on day five. For patients in the study of Wouters et al. [44], engagement lasted longer but also experienced a clear deterioration after one month. Donnelly et al. [65] outlined non-adherence among staff and participant being attributing it to a lack of understanding of the trial and the devices used. After conducting attrition interviews, Haun et al. [70] found that participants desired more in-person interaction, as most studies primarily involved contact limited to technical support or study-related questions. The delay in receiving the intervention was suspected to be another potential factor contributing to the low adherence of the DTx usage [46]. To achieve a highly engaged and adherent sample, participants in Weinstein et al.’s trial [54] had to fill in a bladder diary for 3 days, excluding those from the trial who failed to complete this task. Furman et al. [34] and Thorndike et al. [41] required the completion of questionnaires before participants could engage with the application, as a strategy to foster adherence and engagement. Other methods applied to improve engagement or adherence were regular reminders, gamification, reward functions, monetary incentives and check-in features [32,34,38,44,46,47,54,58,61,63,64]. In contrast to most other trials analyzed, Catella et al. [49] had high engagement and adherence to recommended use in both arms of their study, with 92% and 93%, respectively. Benefits The coding analysis revealed important benefits associated with DCTs using DTx. DCT and DTx enhanced the reach and inclusion of minorities like Hispanics [46] or underrepresented groups such as people living in a nursing home [65], thereby facilitating access to both treatment and research [1,32,46,57]. Three studies [47,48,57] achieved a much better representation of the population in their sample than is typical, and Pratap et al. [46] recruited participants much faster PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 21 / 30 than in person. Nevertheless, it brings along the problem of a biased sample if this is the sole strategy of recruiting participants [1]. The use of mHealth, allowed for passive data collection with minimal effort from participants. Beyond recruitment, improved efficiency in screening was cited as a benefit, by means of reaching a high number of participants that could be contacted in a quick way [1]. Cost savings are also anticipated, with Anguera et al. [48] expecting a cost reduction around 50% compared to standardized procedure. This may enable faster testing of new interventions and providing safe and effective treatments on the market, easily accessible for patients. Braley et al. [45] emphasized an ease of engagement with the DTx therapy due to decreased rigid trial and treatment structures. As a fear of being stigma- tized, patients do not always seek treatment or dare to participate in a trial, depending on the disease. Remote delivery of treatment by using mHealth solutions and use of technology rather than interacting with trial staff directly can reduce this barrier [1,46]. Different studies mentioned the advantage of personalizing and tailoring interventions of DTx and tasks of DCTs to participants. Another key benefit is the demonstrated effectiveness of several of the investigated DTx. Effec- tiveness was observed across various disease areas, with improvements in symptoms of depression, anxiety, and stress. Stroke survivors showed enhanced scores on the WAB-AQ test or post-stroke functioning, while the VR software for pel- vic pain successfully reduced pain intensity and the use of analgesics. Also, participants with agoraphobia and those with fibromyalgia exhibited significant reductions in symptom severity. Summary and framework for DCTs investigating DTx To our knowledge, this is the first scoping review that focuses on DCTs in combination with DTx. Even though DTx are very suitable for the conduct of DCTs [72], there is a limited number of articles that discussed or used this combination. By using a structured database search and the application of eligibility criteria, we identified 41 articles that were ana- lyzed regarding trial rollout. Characteristics of planning, conducting, monitoring and trial design as well as important benefits and challenges were extracted through qualitative coding. Some reoccurring concepts derived from the code groups “planning”, “design” and “conduct” were e-recruitment (32/41), e-eligibility screening (30/41), e-informed consent (28/41) and the inclusion of e-PROs (36/41). Other key themes in most of the studies were the integrated reminders (24/41), passive data collection (24/41) and the patient-centered approach by using personalized treatment, feedback mechanisms, participatory design, preferences and burden assessment (25/41). The major problems encountered were high attrition, low adoption, adherence and engagement with trial activities and the DTx/SaMD (18/26). The primary advantages identified in this trial and intervention type were better access to treatment and trials, and faster recruitment than with traditional ways. Identified themes and steps of the analyzed DCTs using a DTx are summarized into a framework shown in Fig 3. It is proposed to take the displayed concepts into account when designing future DCTs with DTx. Step-by-step guidance through the framework Participant-centered design of the interventions and trials. Before initiating the design of a DCT with a DTx, developers should involve patients in the creation of the application. Given that low DTx engagement was identified as the most significant problem in these trials, a participant-centered design of the intervention is essential to get the users to interact with the app. This participant-centered approach should also extend to the design of the DCT, to maximize convenience for the participants, to foster inclusion, prevent drop-outs and increase adherence to the trial protocol. An example is considering participants’ preferred times of the day for completing trial tasks, as stated by them in the beginning [31]. Other examples used in the analyzed studies can be found in S1 Table. Recruitment, screening and inclusion of participants. Once the DTx and the trial are designed, e-recruitment is the first step. E-recruitment methods include the use of social media platforms or even machine learning to optimize participant recruitment. Mixed approaches with traditional methods of recruitment should be considered. Screening of participants can be done either simply online (e-eligibility screening) or in combination with an interviewer over the phone. PLOS Digital Health | https://doi.org/10.1371/journal.pdig.0000905 June 23, 2025 22 / 30 Recruitment and screening should be facilitated by electronic health records or electronic patient registries. They can help to identify potential participants which then can be specifically contacted, e.g., via email or to automate screening for eligibility as many criteria can be checked with the information in the records. In addition, self-reported screening forms can be designed to automatically exclude participants who do not meet eligibility criteria, rather than simply replicating the paper-based form in electronic format. To hinder participation of ineligible patients, introducing a locking function for selected answers in the eligibility screen- ing can become necessary. The same strategy can be used at a later stage in the randomized allocation of the treatment. Additionally, single-use study links for device and per user should be considered to prevent multiple enrollments by the same person. Integration of automated tools to detect participant deception and phone number verification can reduce fake enrollments. Consent can be obtained either fully electronically or in combination with a phone call to clarify remaining questions. Besides the read-only consent information, interactive links, a video about the study, a subsequent quiz to test partic- ipants’ understanding, and follow-up contact in cases of unclarity are options to improve traditional ways of a consent procedure. Additional confidentiality agreements might need to be signed, for example if the clinical trial includes telemed- ical group discussions. An important aspect is to check whether the electronic signature is accepted or not in the country where participants are recruited. Randomization can be automated via a computer randomization tool. Either before or after randomization, a step referred to as “onboarding” of participants is recommended. In the analyzed trials, the term “onboarding” was described as the process of introducing the participants to the DTx (downloading the Fig 3. Identified design, steps and technical features of DCTs with DTx among analyzed articles. Reoccurring steps with features to integrate, to enable DCTs as safe and effective as possible. Locking mechanism: Prevents participants from altering their responses. For example, if a participant reports smoking during e-eligibility screening (an exclusion criterion), they are marked ineligible and cannot revise their answer to qualify. Similarly, the mechanism prevents re-randomization if participants are dissatisfied with their assigned treatment. Secured authentication/data protection: High data protection standards such as double authentication for log-ins into applications. Fraud detection: Mecha