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Trials. 2022 Feb 16;23(1):157
The Author(s)
Kautz-Freimuth, Sibylle
Redaèlli, Marcus
Isselhard, Anna
Shukri, Arim
Vodermaier, Andrea
Rhiem, Kerstin
Schmutzler, Rita
Stock, Stephanie
Background Women with BRCA1/2 mutations have a higher risk of developing breast and ovarian cancer compared to women of the general population. Various preventive options are available to deal with the increased risk of developing cancer. These include intensified breast cancer screening and risk-reducing bilateral mastectomy and salpingo-oophorectomy. The choice of a preventive option can lead to increased decisional conflict. To support these women in their decision-making process, two evidence-based decision aids were developed in an upstream research process and adapted to the German healthcare context. These will be evaluated within a randomised controlled trial (RCT) in terms of their effects on decision-making, women’s level of information and psychological outcome variables. Methods A sample of 310 women carrying BRCA1/2 mutations (A) without a history of cancer or (B) with a history of unilateral breast cancer who have received post-test genetic counselling will be enrolled. Upon study consent, women will be randomly assigned to either the intervention or the control group. All participants will receive standard care including a physician’s letter summarising the counselling content. After baseline data collection (t0), the intervention group receives the respective decision aid while the control group receives standard care only. The primary outcome variable assessed at a 3-month follow-up (t1) is the change of extent in decisional conflict (measured with the Decisional Conflict Scale). Secondary outcome variables comprise the stage of decision-making, self-reported symptoms of anxiety, depression and stress due to the genetic test result, and knowledge regarding cancer risks and preventive options. At t1, the extent of preparation for decision-making and acceptability of the decision aids will also be examined. Another secondary outcome variable assessed at 6-month follow-up (t2) is the extent of decision regret. Discussion These will be the first decision aids available for BRCA1/2 mutation carriers in Germany to be evaluated regarding their effectiveness and acceptability in clinical use within an RCT. Subsequently, they are to be integrated into the care concept of the centres of the German Consortium for Hereditary Breast and Ovarian Cancer and the affiliated breast centres. Trial registration {2a} DRKS DRKS00015823 . Retrospectively registered on 14 June 2019
STUDY PROTOCOL Open AccessEvaluation of two evidence-based decisionaids for female BRCA1/2 mutation carriersin Germany: study protocol for arandomised controlled parallel-group trialSibylle Kautz-Freimuth1* , Marcus Redaèlli1, Anna Isselhard1, Arim Shukri1, Andrea Vodermaier1,2, Kerstin Rhiem3,Rita Schmutzler3 and Stephanie Stock1AbstractBackground: Women with BRCA1/2 mutations have a higher risk of developing breast and ovarian cancercompared to women of the general population. Various preventive options are available to deal with the increasedrisk of developing cancer. These include intensified breast cancer screening and risk-reducing bilateral mastectomyand salpingo-oophorectomy. The choice of a preventive option can lead to increased decisional conflict. To supportthese women in their decision-making process, two evidence-based decision aids were developed in an upstreamresearch process and adapted to the German healthcare context. These will be evaluated within a randomisedcontrolled trial (RCT) in terms of their effects on decision-making, women’s level of information and psychologicaloutcome variables.Methods: A sample of 310 women carrying BRCA1/2 mutations (A) without a history of cancer or (B) with a historyof unilateral breast cancer who have received post-test genetic counselling will be enrolled. Upon study consent,women will be randomly assigned to either the intervention or the control group. All participants will receivestandard care including a physician’s letter summarising the counselling content. After baseline data collection (t0),the intervention group receives the respective decision aid while the control group receives standard care only. Theprimary outcome variable assessed at a 3-month follow-up (t1) is the change of extent in decisional conflict(measured with the Decisional Conflict Scale). Secondary outcome variables comprise the stage of decision-making,self-reported symptoms of anxiety, depression and stress due to the genetic test result, and knowledge regardingcancer risks and preventive options. At t1, the extent of preparation for decision-making and acceptability of thedecision aids will also be examined. Another secondary outcome variable assessed at 6-month follow-up (t2) is theextent of decision regret.Discussion: These will be the first decision aids available for BRCA1/2 mutation carriers in Germany to be evaluatedregarding their effectiveness and acceptability in clinical use within an RCT. Subsequently, they are to be integratedinto the care concept of the centres of the German Consortium for Hereditary Breast and Ovarian Cancer and theaffiliated breast centres.© The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: sibylle.kautz-freimuth@uk-koeln.de1Institute of Health Economics and Clinical Epidemiology, The UniversityHospital of Cologne, Gleueler Straße 176-178, 50935 Cologne, GermanyFull list of author information is available at the end of the articleKautz-Freimuth et al. Trials (2022) 23:157 https://doi.org/10.1186/s13063-022-06081-7Trial registration {2a}: DRKS DRKS00015823. Retrospectively registered on 14 June 2019Keywords: BRCA1 mutation, BRCA2 mutation, Decision aid, Decision-making, Evaluation study, Familial breast andovarian cancer, Hereditary breast and ovarian cancer (HBOC), Preventive measures, Preference-sensitive decisions,Patient-centred careAdministrative informationNote: The numbers in curly brackets in this protocolrefer to SPIRIT checklist item numbers. The order ofthe items has been modified to group similar items (seehttp://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).Title {1} Evaluation of two evidence-based de-cision aids for female BRCA1/2 muta-tion carriers in Germany: studyprotocol for a randomised controlledparallel-group trialTrial registration {2a, 2b} DRKS-ID: DRKS00015823. Registered14 June 2019 - Retrospectivelyregistered, http://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015823.Protocol version {3} Study protocol version No. 1 [23/12/2020]Funding {4} This trial is funded by theLandeszentrum GesundheitNordrhein-Westfalen (LZG.NRW),Gesundheitscampus 10, 44801 Bo-chum, Germany.Authors and Affiliations {5a} Kautz-Freimuth S1, Redaèlli M1,Isselhard A1, Shukri A1, VodermaierA1,3, Rhiem K2, Schmutzler R2, Stock S1Affiliations1 Institute of Health Economics andClinical Epidemiology, The UniversityHospital of Cologne, Gleueler Straße176-178, 50935 Cologne, Germany.2 Centre for Familial Breast andOvarian Cancer, Centre for IntegratedOncology (CIO), The UniversityHospital of Cologne, Kerpener Straße62, 50937 Cologne, Germany.3School of Population and PublicHealth, The University of BritishColumbia, 2206 East Mall, Vancouver,BC C6T 1Z3, Canada.Name and ContactInformation for the TrialSponsor {5b}The University Hospital of Cologne,Kerpener Straße 62, 50937 Cologne,Germany.Role of Study Sponsor andFunder {5c}Neither the study sponsor nor thefunder is involved in the studydesign, data collection, datamanagement, data analyses andinterpretation, report writing, decisionto submit this report for publicationor the writing of this publication.IntroductionBackground and rationale {6a}Women with a pathogenic germline mutation in theBRCA1 or BRCA2 gene face a high risk of developingbreast cancer (BC) and ovarian cancer (OC). Theaverage cumulative life-time risk for BC increases withage [1, 2], reaching about 70% by the age of 80 [1]. Theaverage cumulative lifetime risk for OC is around 44%(BRCA1 mutation) and 17% (BRCA2 mutation) [1].Compared to women affected by sporadic BC or OC,BRCA1/2 mutation carriers without a history of cancer,in the following referred to as ‘previvors’ [3], develop BCor OC about 20 years earlier in their life. Those with ahistory of unilateral BC, in the following referred to as‘survivors’ [4], face an average cumulative 20- to 25-yearrisk of contralateral BC of about 40 to 44% (BRCA1 mu-tation) or around 26 to 33.5% (BRCA2 mutation) [1, 5].Newly diagnosed BRCA1/2 mutation carriers areoffered various preventive options to counter theirincreased cancer risks. These include an intensifiedbreast cancer screening programme for previvors or anintensified breast cancer screening and aftercareprogramme for survivors and risk-reducing surgeries ofthe breasts and the adnexa for both groups. Intensifiedbreast cancer screening (breast magnetic resonance im-aging (MRI), breast ultrasound and mammography) en-ables BC to be detected at an early, potentially curablestage in 85% of cases [6], but does not reduce the risk ofdeveloping BC. Women who opt for screening in thefirst place can postpone their final decision to have sur-gery. Due to the limited specificity of the MRI, screeningoften yields false-positive results [6] which can lead tofurther often more invasive diagnostic tests (e.g. re-imaging or breast biopsies) which may later prove un-necessary and may trigger transient anxiety in women[7]. In contrast, risk-reducing bilateral mastectomy sig-nificantly decreases the risk of developing BC [8] forprevivors and provides a survival benefit to BRCA1 mu-tation carriers [9]. Risk-reducing contralateral mastec-tomy lowers the risk of contralateral BC and reducesoverall mortality in survivors [10]. However, removal ofthe breasts is an irreversible decision that affects physicalintegrity and requires further decisions, e.g. which formof surgery or whether and, if so, which breast recon-struction the woman would prefer. For survivors, thedecision-making process may be even more complexKautz-Freimuth et al. Trials (2022) 23:157 Page 2 of 14because they may face competing risks (e.g. risk of BCrecurrence on the affected side) that may have to beweighed against the benefits of risk-reducing surgery onthe non-affected side.In the absence of an effective screening method forthe adnexa [11–14], the only preventive option tocounter the risk of OC is risk-reducing bilateralsalpingo-oophorectomy. It reduces both the risk of OC[15] and the overall and OC specific mortality [16].However, consequences include the definite loss of fer-tility and possible premature menopause; the latter cancause menopausal symptoms such as hot flashes, as wellas long-term consequences such as cardiovascular dis-ease and osteoporosis [17].Each preventive option is accompanied with distinctadvantages and disadvantages that each mutation carrierwill judge and weigh individually depending on herpersonal experiences, values and preferences. The sameapplies to the several options of breast reconstructionsafter mastectomy, to family planning or to steps to betaken to treat undesired effects of an option [18]. Forexample, to counter the negative consequences ofsurgical menopause after a risk-reducing bilateralsalpingo-oophorectomy, temporary hormone replace-ment therapy might be considered for premenopausalwomen [11]. Hence, BRCA1/2 mutation carriers faceseveral so-called preference-sensitive decisions [19, 20].These can lead to considerable decisional conflicts thatcan be associated with delays of decisions, dissatisfac-tion, decision regret or blaming of healthcare providers[21–26]. These negative consequences might be furthercomplicated by lacking knowledge and understanding ofthe individual risk constellation and available options orby personal stressors and psychosocial, family and/orpsychological factors [20, 26–29].In order to support BRCA1/2 mutation carriers duringtheir complex decision-making process in choosing apreventive option and the right time to do so, a numberof supportive tools, in particular, decision aids (DAs),have been developed internationally [30–36]. A system-atic review on DAs for women with BRCA1/2 mutationsidentified four RCTs and one pretest-post-test study thatassessed the effectiveness of DAs on decision-, know-ledge- and health-related criteria. The analysis showedthat DAs support these women most likely by improvingdecision-related outcomes: Women who received a DAexperienced lower decisional conflict were more likely tocome to a decision and were more satisfied with the de-cision made compared to women who did not receive aDA [37]. Favourable effects of DAs on decision-relatedfactors as well as on knowledge are reported by a previ-ous Cochrane Review that analysed 105 RCTs involvinga total of 31,043 participants with regard to the effects ofDAs on patients facing treatment or screening decisionsacross different indications. High-quality evidence wasfound for the following effects: DAs improve knowledgeabout the available options, lower decisional conflictsresulting from the feeling of not being informed andsupport clarification of values and preferences of the ad-dressees [38].In Germany, following receipt of the genetic testresult, women with a pathogenic BRCA1/2 mutationreceive personalised counselling from a medicalspecialist at one of the specialised GC-HBOC centres ortheir affiliated breast centres. The post-test geneticcounselling and care concept (in the following referredto as ‘standard care’) includes detailed non-directive in-formation on the women’s mutation status, their individ-ual risk prediction, risks and benefits of the availablerisk-adapted prevention options and their consequences[11, 39–41], provision of written information, e.g. onself-help or psychological support options, along with aphysician’s letter summarising the contents of the con-sultation. So far, no additional structured intervention isused to provide women carrying BRCA1/2 mutationswith targeted support for making high-quality decisionsdefined as being informed by the best available scientificknowledge and based on the women’s values and prefer-ences [42, 43].For this reason, two evidence-based DAs (one for pre-vivors (DA-A), one for survivors (DA-B) with BRCA1/2mutations) that correspond to the evidence-based guide-lines and consented procedures in the German health-care system were developed in an upstream researchprocess [44]. The development of the DAs followed astructured, quality-controlled procedure according tothe International Patient Decision Aid Standards Collab-oration [45–47]. Both DAs follow the same structureand share the same content for all aspects that are validfor both target groups (e.g. information on genetic muta-tions, methods of breast cancer screening). Yet, they dif-fer in aspects where the respective target group needsand/or wishes distinct information. For example, previ-vors need information on the risk-reducing bilateral re-moval of healthy breasts, while survivors needinformation on BC in the affected breast and on therisk-reducing removal of the non-affected breast. Beforethe newly developed DAs can be incorporated intostandard care, it is required to evaluate these in terms oftheir effectiveness and acceptability in clinical use [45,48]. In order to fulfil this final quality criterion, the DAswill be evaluated in the randomised controlled trial(RCT) described here in detail.Objectives {7}The aim of this study is to evaluate two newly developedevidence-based DAs for women with pathogenicBRCA1/2 mutations in Germany with regard to theirKautz-Freimuth et al. Trials (2022) 23:157 Page 3 of 14effectiveness on decision-, psychological- andknowledge-related factors in clinical use and their ac-ceptability with the addressees. We hypothesise that theuse of these DAs on top of standard care will reduce theextent of decisional conflict regarding the choice of apreventive option compared to standard care alone (pri-mary outcome). Furthermore, it will be examinedwhether the use of the DAs can reduce possible symp-toms of anxiety, depression or psychological strain asso-ciated with the genetic test result, the risk of BC and OCand the available preventive options. Lastly, we hypothe-sise that at 6-month-follow-up, the intervention group(IG) will feel less regret regarding the choice made com-pared to the control group (CG).Trial design {8}The trial is designed as a monocentric randomisedcontrolled parallel-group superiority trial with a 1:1 allo-cation ratio.MethodsThe study protocol is based on the Standard Protocol:Recommendations For Intervention Trials (SPIRIT 2013Statement) [49].Study setting {9}All participants will be recruited by the medicalspecialist team supported by a study nurse (recruitingteam) at the Centre for Familial Breast and OvarianCancer at the University Hospital of Cologne (recruitinginstitution). All data will be collected and analysed bythe research team consisting of physicians, healthcareresearchers, and a statistician at the Institute for HealthEconomics and Clinical Epidemiology at the UniversityHospital of Cologne (data evaluation institution).Eligibility criteria {10}All participants must meet the inclusion criteria forgenetic testing according to the German Consortium forHereditary Breast and Ovarian Cancer (GC-HBOC) [50]and have undergone a genetic testing. Included in thestudy are women with a positive genetic test result for apathogenic BRCA1/2 mutation who have received post-test genetic counselling and have not yet made a finaldecision on at least one preventive measure. This in-cludes both mutation carriers immediately after thepost-test genetic counselling and those later on afterpost-test genetic counselling who have initially decidedto participate in the intensified breast cancer screening(and aftercare) programme but do not yet know, whenand for which alternative they will finally opt.Further inclusion criteria are as follows: (A) Not affected by cancer or (B) affected byunilateral BC (stage I, II or III) Age 18 to 70 years No medical reasons against possible risk-reducingsurgeries Given written consent to participate in the study Sufficient knowledge of the German languageExclusion criteria are as follows: Affected by advanced BC, e.g. local recurrence ordistant metastasis Affected by ovarian cancer or other types of cancerother than unilateral BC Age under 18 years and over 70 years Medical reasons against possible risk-reducingsurgery Not able to give informed consent/not giveninformed consent to participate in the study Insufficient knowledge of the German languageConsent to participate {26a}The recruiting physicians will obtain the informedwritten consent of potential trial participants after theyhave been informed about the study and are willing toparticipate. Informed consent will be obtained from allstudy participants.Additional consent provisions {26b}In the consent form, the participants will also be askedto agree that in the event of withdrawal from the study,their data collected up to that point may be processed.No further consent provisions will be requested.InterventionsChoice of comparators {6b}The participants of the CG will receive standard care.Standard care was chosen as the comparator, because itis offered for all women with pathogenic BRCA1/2mutations seeking advice by the specialised GC-HBOCcentres as part of post-test genetic counselling and iscurrently considered the gold standard.Standard care in the GC-HBOC centres is as follows:In a medical non-directive consultation mutation, car-riers receive detailed individual information on theirgenetic test results, their lifetime, age- and/or time-dependent risks of BC and OC and the risk-adapted pre-ventive options available to them. In addition, furtherwritten information may be provided, e.g. on the Ger-man self-help organisation BRCA network (BRCA-Netz-werk e.V.) or on psychological counselling options.Following a detailed physician’s consultation, eachwoman receives a personal physician’s letter summaris-ing the contents of her consultation by regular mail.Kautz-Freimuth et al. Trials (2022) 23:157 Page 4 of 14This includes information about the identified mutation,the calculated individual risks for breast and ovariancancer, the intensified breast cancer screeningprogramme with pros and cons, the risk-reducing sur-geries of the breast and ovaries and fallopian tubes withpros and cons, possible further cancer risks, the signifi-cance of the genetic test result for a possible desire tohave children, the probability of passing on the mutationto the offspring and a summary of the result of thecounselling interview.Intervention {11a}Participants in the IG will also receive standard care asdescribed above. After the return of the baselinequestionnaire (t0), participants of the IG will be sent theDAs as a brochure by regular mail. Participants of theCG will not receive a DA.Criteria for discontinuing or modifying allocatedinterventions {11b}No known unfavourable side effects of theimplementation of DAs are reported in the literature.Nevertheless, all participants will be offered to set up anappointment with the clinical psychologist at therecruiting institution in case stressful feelings orthoughts will be coming up. They will also be offered anadditional specialist appointment at the centre if theneed to clarify further issues arises. Participants will beinformed that participation is completely voluntary andthat they can leave the study at any time without givingany reason or having to fear negative consequences.Strategies to improve adherence to intervention protocols{11c}Participants of the IG are encouraged to read throughthe DAs and engage with them by filling out theattached work sheets and discuss its contents withpersons of their confidence. No special strategy wasdefined to facilitate the use of the DAs. To supportphysicians’ assistance to recruit eligible participants intothe study, a study nurse will be involved. The studynurse will review the patient files with upcomingappointments every day and will place the enrolmentdocuments in the files of eligible women.Concomitant care or interventions {11d}Not applicable. No concomitant care or interventionsare planned. No concomitant care or interventions areexplicitly prohibited.Outcomes {12}Baseline measures at t0 will be obtained within 2 weeksafter enrolment in the study, t1 measures 3 months andt2 measures 6 months after enrolment (see Table 1). Atbaseline (t0), the following variables will be collected:decisional conflict as measured with the DecisionalConflict Scale (DCS) [51], stage of decision-making asmeasured with the Stage of Decision Making Scale,SDM-S [52], anxiety and depressive symptoms asTable 1 Outcome parameters and time points for outcome measurementsKautz-Freimuth et al. Trials (2022) 23:157 Page 5 of 14measured with the Hospital Anxiety and DepressionScale, HADS [53, 54], impact of genetic test result asmeasured with the Impact of Event Scale-Revised, IES-R[55] and knowledge criteria as measured with a set of fif-teen knowledge questions.The primary outcome at 3-month follow-up (t1) is thechange in the extent of decisional conflict measured withthe DCS. Secondary outcome variables at t1 includechanges in SDM-S, HADS, IES-R and knowledge. Add-itionally, at t1, the items addressing the preparation fordecision-making as measured with the Preparation forDecision Making Scale (PrepDMS) [56, 57] and the ac-ceptability of the DAs compared to control by the par-ticipants as measured with an acceptability instrument[30, 58] are collected. Secondary outcome variables at t2comprise SDM-S, DCS, HADS and the extent of regretfor the decision made as measured with the Decision Re-gret Scale (DRS) [59]. It is possible that no final decisionhas been made at t2 or that the decisions made at t2 areonly temporary.The evaluation instruments are described below.Decisional conflictDecisional conflict is measured using the DecisionalConflict Scale (DCS) [51, 60]. It comprises five subscaleswith a total of 16 items, which are assessed on a 5-pointLikert scale (from 1 = strongly agree to 5 = strongly dis-agree). The subscales concern the following topics: beinginformed, clarification of personal values, support orpressure from others, uncertainty about the decision andthe assessment of one’s own decision-making. The Ger-man version of the DCS has been shown to have goodpsychometric properties, with a reported internalconsistency of Cronbach’s alpha = 0.78 or higher [60].The DCS is administered at t0, t1 and t2.Stage of decision-makingThe stage of decision-making is measured using theStage of Decision Making Scale (SDM-S) [52]. It consistsof a single item with four or six response categories. Inthis study, an adapted German version with a four-answer category is used [61]. The categories used are (1)‘I have not yet thought about the options’, (2) ‘I am con-sidering the options’, (3) ‘I am close to choosing one op-tion’ and (4) ‘I have already made a choice’. The SDM-Sis administered at t0, t1 and t2.Anxiety and depressive symptomsTo measure the symptoms of anxiety and depression,the German version of the Hospital Anxiety andDepression Scale (HADS-D) [53, 54] is used. It measuresthe level of anxiety and depressive symptoms in the lastweek by self-assessment. The HADS-D consists of twosubscales (anxiety, depression) with seven items each,which are assessed on a 4-point Likert scale. The toolis widely used and shows good psychometric proper-ties, with most studies reporting an internalconsistency of Cronbach’s alpha = 0.8 or higher. Ithas been shown to be well suited for measuring emo-tional stress in cancer patients [62]. The HADS-D isadministered at t0, t1 and t2.Subjective stress symptoms because of the genetic testresultTo determine the impact of the genetic test result ofhaving a pathogenic BRCA1/2 mutation on subjectivestress symptoms the German version of the Impact ofEvent Scale-Revised (IES-R) is used [63]. The IES-R con-tains a total of 22 items in three subscales referred to asintrusion, avoidance and hyperarousal. They are assessedusing a 4-point Likert scale (from 0 = not at all to 5 =often). The values of the three subscales can be used tocalculate the probability of diagnosing a post-traumaticstress disorder. The IES-R is administered at t0 and t1.Knowledge on cancer risks and preventive optionsKnowledge about cancer risks associated with theBRCA1/2 mutations and the available preventive optionsconveyed by the present DAs will be tested with a set offifteen statements that can be classified as ‘true’, ‘nottrue’ or ‘don’t know’. In preparation for this study, thisinstrument was developed by a team of medical experts,psychologists and healthcare researchers working in thefield of hereditary breast and ovarian cancer (HBOC).The topics covered by this instrument are addressed inthe DAs and distributed as follows: four items each dealwith the risks of BC/OC and risk-reducing breast sur-gery, three items each deal with the intensified breastcancer screening (and aftercare) programme and withrisk-reducing adnexal surgery. One item concerns atopic that is explained in a section addressing ‘questionsand answers’ of the DAs. Women’s level of knowledge isassessed at t0 and t1.Preparation for decision-makingThe German version of the Preparation for DecisionMaking Scale (PrepDMS) [57, 64, 65] will be used tomeasure the extent to which the participants feelprepared for the decision by the additional DA. Theinstrument consists of the two subscales ‘preparation forthe decision’ and ‘preparation for the physician’sconsultation’ and comprises a total of ten items, whichare rated on a 5-point Likert scale (from 1 = not at all to5 = a great deal). This instrument is validated, showsgood internal consistency (Cronbach’s alpha = 0.95 fortotal score) and is recommended for the evaluation ofDAs [65]. The PrepDMS is administered at t1.Kautz-Freimuth et al. Trials (2022) 23:157 Page 6 of 14AcceptabilityAcceptability of the DAs among participants of the IG ismeasured by an acceptability scale. Participants of theCG will judge the written information received as part ofstandard care with the same instrument. The tool isadapted from an acceptability tool developed byO’Connor and Cranney [58] and from an approach totest acceptability described in a study by Metcalfe et al.[30]. It consists of seven items in which personalassessments of the following characteristics of thereceived DA are queried: (1) scope, (2) amount ofinformation, (3) comprehensibility, (4) usefulness inmaking a decision on a preventive measure, (5)satisfaction with the DA, (6) sufficient information tomake an appropriate decision and (7) likelihood ofrecommending the DA to other women in her situation.Items (1), (2), (6) and (7) are assessed with adichotomous response format; items (3), (4) and (5) arescored with a 3-step ordinal response format. The ac-ceptability scale is administered at t1.Decision regretTo assess the participants’ level of distress and regret interms of the final decision made, the Decision RegretScale (DRS) [21, 59, 66] is used. It consists of five itemsto be rated on a 5-point Likert scale (from 1 = stronglyagree to 5= strongly disagree). The instrument was vali-dated in a sample of BC patients and showed good in-ternal consistency with a Cronbach’s alpha = 0.81 to0.92. It is strongly negatively correlated with decisionsatisfaction and overall quality of life and positively cor-related with decisional conflicts [21]. The DRS is admin-istered at t2.The outcome parameters and time points for outcomemeasurements are listed in Table 1.Participant timeline {13}The schematic participant timeline is shown in Fig. 1.Enrolment and randomisationRecruitment takes place during a specialist consultationeither (1) directly following the post-test genetic coun-selling or (2) during a medical examination as part ofthe intensified breast cancer screening programme (forprevivors, A) or the intensified breast cancer screeningand aftercare programme (for survivors, B). If the inclu-sion criteria are met, eligible women will be informedabout the study and invited to participate. Women whoagree to do so will be asked to provide informed con-sent. Physicians will complete a recruitment form.Thereafter, participants are randomly assigned to one ofthe two study groups. The allocation is blinded to boththe recruiting physicians and the participants.Baseline data collection at t0After enrolment, all participants receive a package withstudy material (enrolment package). It contains thebaseline questionnaire (t0) with a pre-stamped returnenvelope, brief and detailed information about the studyand a copy of the informed consent document. Partici-pants are invited to fill out the questionnaire at homeand to return it within 2 weeks per regular mail.InterventionOnce the completed baseline questionnaires (t0) havebeen returned to the data evaluation institution, the DAswill be sent by regular mail to those participantsrandomised to the IG with a request to use the DA forinformation and decision support at home. Previvorswill receive DA-A, and survivors will receive DA-B.Outcome data collections at t1 and t2Participants, who have returned the baselinequestionnaire (t0), will receive the follow-up question-naire at t1 at 3-month-follow-up with the request to re-turn the completed questionnaire within two weeks byregular mail. Participants who have returned the ques-tionnaire t1 will receive the next follow-up questionnaireat t2 at 6-month follow-up with the request to returnthe completed questionnaire within two weeks by regu-lar mail.Sample size {14}The required sample size was calculated based on theeffect size (Cohen’s d) from previous research [30, 67,68]. Since the effect size varies between 0.3 and 0.83, aconservative assumption is made with a small effect sizeof 0.3, α of 0.05, and ß of 0.8. Since numerous studiesprovide evidence that DAs significantly reducedecisional conflict [30, 38, 69], a superiority study with aone-sided t-test is conducted. Using the one-sided t-test,a sample size of 139 patients per group is required. As-suming an average drop-out rate of 10% of BRCA1/2mutation carriers in previous evaluation studies [31, 32,34, 69, 70], the planned sample size is n = 155 partici-pants per group, yielding a total of 310 requiredparticipants.Recruitment {15}The following strategies are used to achieve adequateparticipant enrolment to reach the target sample size:Posters are placed in the waiting room areas of therecruitment centre to publicise the study and inviteinterested women to participate. A study nurse willcheck women’s files who have upcoming appointmentsin the recruiting institution and screen these foreligibility. Then, counselling physicians are requested toactively approach eligible women after post-test geneticKautz-Freimuth et al. Trials (2022) 23:157 Page 7 of 14counselling or during an appointment for the intensifiedbreast cancer screening (and aftercare) programme.Allocation: sequence generation {16a}Study participants will be randomly assigned to eitherIG or CG with a 1:1 allocation. Sequence generation isdone with a computerised random number generator bya member of the research team who is not involved indata analysis.Allocation concealment mechanism {16b}After sequence generation, a member of the researchteam prepares the enrolment packages that contain thestudy documents for eligible participants. There are nodifferences in the enrolment packages between IG andCG. Thus, all packages look exactly the same andcontain the same documents. Each package is markedwith a study ID. Only the members of the research teamat the data evaluation institution know the allocation ofthe study IDs to IG and CG. The participants, therecruiting physicians and the study nurse will not beable to decode the allocation.Implementation {16c}The enrolment packages are prepared and equippedwith a study ID by the data evaluation institution andthen transferred to the recruitment institution. Afterinformed consent, the recruiting physicians enrol eligiblewomen into the study, and each participant receives anenrolment package. As the allocation to IG or CG isFig. 1 Participant timelineKautz-Freimuth et al. Trials (2022) 23:157 Page 8 of 14determined by the study ID, both physicians andparticipants are blinded regarding the assignment of theparticipants to IG or CG.Blinding {17a}Once the completed baseline questionnaire (t0) isreturned to the data evaluation institution, the researchteam will identify study IDs that are assigned to the IGand prepare the sending of the DA in a closed envelope.This envelope will be solely marked with the study ID.An independent entity neither belonging to the researchteam nor the recruiting team will decode the study ID,prepare the envelope with the name and address of theparticipants and send it off. The supervising study nurseremains blinded to the allocation to the study groupthroughout the study. This also applies to the recruitingphysicians. However, it cannot be ruled out that treatingphysicians could be unblinded if participants approachthem about the study at a follow-up appointment. At t0,all trial participants are blinded. The data analysts willbe blinded with regard to group allocation by codinggroup allocation before data analysis.Unblinding {17b}Due to the nature of this study, unblinding for theparticipants will occur as soon as they receive the DAs.The same applies to participants who receive the follow-up questionnaires at t1 and have not received a DA bythen. With the exception of the statistician who is re-sponsible for data analysis, the research team will be ableto assign the evaluated data to the two study groups andtherefore will not be blinded.Data collection, management and analysisData collection methods {18a}The completed questionnaires are sent to the dataevaluation institution, where the research team collectsthe data and transfers them into a digital form on apassword-protected computer. The research team is nei-ther involved in post-test genetic counselling nor in re-cruitment of the participants.Promoting participant retention and complete follow-up{18b}Participants who did not return the questionnaires intime will receive up to two postal reminders with therequest to send the questionnaires back within 1 week.Those who still will not react will be contacted again bytelephone to encourage participant retention. This willbe done by the study nurse who works with therecruiting team.Women assigned to the CG do not receive DAs andmay, therefore, be more likely to drop out of the studythan women assigned to the IG. To counter thispossibility of higher drop-out rates, all women in the CGare offered to request a DA when the last follow-upquestionnaire at t2 is returned. This is to ensure thatthey can participate in the study without beingdisadvantaged.Data management {19}The paper-based data from the returned pseudonymisedquestionnaires will be transferred into digital data usingthe software programme Remark Office OMR. For qual-ity control and verification, all the extracted data is alsomanually checked by members of the research team. Ac-cording to the German data protection guidelines, thepaper-based questionnaires are kept in a securely lockedlocation, as are the digital data which is stored on anotebook with password protection and kept in a se-curely locked location. Solely, the members of the re-search team have access to these data.Confidentiality {27}According to the German data protection guidelines,personal information about potential and enrolledparticipants is kept strictly separate from the study datain order to maintain confidentiality before, during andafter the trial. Personal data is only known to therecruiting physicians, the study nurse and oneindependent person who is responsible for sending theDAs to the IG participants (see the ‘Blinding {17a}’section). Only these persons will have a list that allowsthe study IDs to be matched to the personal data of theparticipants. This assignment list will be kept strictlyseparate from the study data collected by the researchteam. The research team will never have access to theparticipants’ personal data but will only receivepseudonymised questionnaires.Biological specimens {33}No biological specimen will be collected.Statistical methodsAnalysing primary and secondary outcomes {20a}Analysis of the baseline data (t0) will be done to ensurethe comparability of the two study groups. Outcomesare measured at t1 and t2. All primary and secondaryeffectiveness variables will be described by statisticalcharacteristics values. Continuous data will be describedby mean, standard deviation, median, minimum andmaximum. Categorical data will be described by usingfrequencies and percentages. The number of non-missing values will also be given.The primary outcome at t1 is decisional conflict. Themean differences of the primary outcome between bothgroups will be compared using the independent t-test incase of normal distribution. In addition, the meanKautz-Freimuth et al. Trials (2022) 23:157 Page 9 of 14differences in the score within the groups between t0and t1 will be compared using a dependent t-test. Non-parametric tests will be used in case of non-normal dis-tribution. Secondary outcomes comprise the mean dif-ferences in scores of the stage of decision-making, stress,anxiety and depressive symptoms between t0, t1 and t2.A further secondary outcome measured at t2 is the re-gret of the decision. For these analyses, a dependent re-spectively independent t-test will be used in case ofnormal distribution, non-parametric tests will be used incase of non-normal distribution. Data will be analysedby using IBM SPSS Statistics for Windows, version 27.0(IBM Corp: Armonk, NY) and R [71]. An alpha level of0.05 is considered significant in all statistical tests.Interim analysis {21b}An exploratory interim analysis of the baseline datacollected at t0 is planned when a total of 70 participantshave been recruited. The aim is to check whether thebaseline data of both study groups are comparable.Access to the analysed interim data will be given to theproject leading member (SKF) and the statistician whoconducts data analysis (AS).Additional analyses {20b}Subgroup analyses are planned to investigate whetherthere are differences in primary and secondary outcomes(1) between BRCA1/2 mutation carriers without apersonal history of cancer and those with a personalhistory of unilateral BC and (2) between womenrecruited directly after the post-test genetic counsellingor later on at an appointment as part of an examinationfor the intensified breast cancer screening (and aftercare)programme. Subgroup analyses will be performed usingthe independent t-test for normally distributed metricvariables, and non-parametric tests will be used in caseof non-normal distributions. The chi-square test or Fish-er’s exact test will be used for categorical variables. Be-yond group allocation, demographic data will be used asthe independent variable.Definition of analysis population {20c}All analyses will be conducted following the intention-to-treat (ITT) principle including all randomised pa-tients. No imputation of missing values will beperformed.Public access {31c}The datasets that will be generated and/or analysedduring the present study will be available from thecorresponding author on reasonable request.Roles and responsibilities {5d}The coordination team includes two scientific staffmembers and the medical director. Their tasks are toprepare the ethics application, produce the studymaterials, train the clinical recruitment units, preparethe reports for the funding institution, coordinate theconsulting experts and obtain the consent forms. Inaddition to the coordination team, the steeringcommittee includes the management of the participatinginstitutions. It reviews progress, discusses interfaceproblems and proposes adjustments if necessary. Datamanagement is organised by two study nurses and tworesearch assistants who work spatially and structurallyseparate from the coordination team. They are dividedinto two units. One takes over pseudonymisation,dispatch and reminder functions. The other performsdata entry, plausibility checks and data extraction, anddelivers the data set for data evaluation.MonitoringData monitoring {21a}Data monitoring is carried out by members of theresearch team, which consists of healthcare researchers,physicians and a statistician. The monitoring isperformed completely independently of the fundinginstitution. None of the members of the data monitoringcommittee has competing interests. No independentdata monitoring committee has been installed, as it isnot expected that any adverse events or interim analyseswill lead to a recommendation to terminate the studyprematurely.Plans for collecting adverse events {22}The use of the DAs is not expected to have significantundesired effects on participants. Therefore, no specificplan for the collection, assessment, reporting andmanaging of possible spontaneous unintended effects isprovided and no formal guideline for termination of usewill be established.Auditing {23}Trial conduct will be audited every 6 months by thescientific staff members working within the project. Asemi-annual reporting will be sent to the funding institu-tion (LZG.NRW). Further data monitoring is carried outby another scientist who can conduct quality assuranceaudits at any time. The competent supervisory institu-tions, e.g. the responsible ethics committee, have theright to inspect the study documents and reports or thedata management processes at any time, while maintain-ing confidentiality.Kautz-Freimuth et al. Trials (2022) 23:157 Page 10 of 14Protocol amendments {25}The Ethics Committee of the Medical Faculty of theUniversity of Cologne will be notified of amendments tothe protocol with the application for approval. Thechanges will also be communicated to the fundinginstitution. Amendments will not be implementedbefore the final ethical approval is given.Dissemination policy {31a}The trial results are intended to be published inscientific journals.DiscussionThis study is the first evaluation trial in which two DAsare examined that were specifically developed for femaleBRCA1/2 mutation carriers in Germany. The study willbe conducted within an RCT design. The overallobjective is to further enhance the current specialisedcare and counselling concept for these women byproviding quality and effectiveness tested decisionsupport tools that potentially aid the decision-makingprocess and thus may help to reduce decisional conflict.Secondary outcomes address the questions of whetherboth DAs can also improve the level of knowledge, posi-tively affect psychological strain symptoms, are well ac-cepted by the addressees, and may help to reduce regretregarding the final decision.Both DAs target BRCA1/2 mutation carriers have thesame structure, contain the same elements and areidentical in many aspects of content, but additionally,DA-A addresses specific needs of previvors, while DA-Baddresses specific needs of survivors. Nevertheless, bothDAs can be evaluated in a single RCT, because the re-search question refers to DAs’ impact on the decision-making process rather than to the options the womeneventually will choose.The procedures in the study have some limitationswhich, however, cannot be avoided due to the nature ofthis type of intervention chosen. One limitation is thatthere is no guarantee that all IG participants willactually use the DAs which they will receive per regularmail and are invited to use at home. In order to complywith the voluntary nature of the study participation andto avoid exerting any pressure on study participants, thefollow-up questionnaire at t1 which collects data afterreceipt of the DA does not ask whether the DA was ac-tually used. Therefore, the research team will receive nofeedback as to whether and if so, to what extent thewomen have worked with the DA. On the other hand,discussions with the members of the BRCA network andwith medical specialists who provide genetic counsellingindicated that many women with BRCA1/2 muta-tions hope for a device in which all aspects of theirdecision-making process are explained and broughttogether. A further limitation refers to the possibilitythat study participants might get in contact with eachother. For example, due to the hereditary nature of thegene mutation, multiple family members may take partin the study. In this case, women assigned to the CG orwomen at baseline could unintentionally have access tothe DA. It will also remain unclear, to what extent thestudy participants will use other sources of informationor support. Such interferences may contaminate the col-lected data to a certain extent. Yet, there is no way toprevent this and accessing additional information is as-sumed to happen equally in the IG and CG. Anotherlimitation refers to the blinding of participants, which isnot possible throughout the entire course of the presenttrial. Since all participants will be informed in detailabout the course of the study before inclusion into thestudy, they all are aware that they may or may not re-ceive the intervention. Blinding of the participants cantherefore only be guaranteed at baseline (t0). For IG par-ticipants, unblinding occurs at the moment they receivethe DAs. CG participants are unblinded at the latestwhen they receive the follow-up questionnaire at t1 andhave not yet received the DAs. It seems most appropri-ate to examine the impact of both DAs in a setting thatreflects the current concept of standard care. This im-plies that the CG participants do not receive other infor-mation than that provided by the current concept.Finally, it cannot be excluded that there may be a biasdue to non-response by not returning questionnaires, es-pecially if non-response rates should differ between IGand CG.This real life-based comparison of IG versus CG is,therefore, also a strength of this study. Another convin-cing strength is the study design. An RCT offers a highdegree of quality control for both DAs and enables re-sults of high significance for clinical care. Comparingstandard care with standard care plus, DA allows formore clarity on what kind of support BRCA1/2 mutationcarriers seeking advice can expect from the use of DAsin clinical practice. Furthermore, valuable informationfor revisions of both DAs may be provided by studyparticipants.Following the evaluation described in the presentstudy protocol, the DAs both for previvors and survivorswill be integrated into the care and counselling conceptof the GC-HBOC centres and their affiliated breast cen-tres. This is intended to make an important contributionto strengthening the decision-making competence andautonomy of women with BRCA1/2 mutations.Trial statusStudy protocol version No. 1.0 [23/12/2020]. Therecruitment of the study participants started in January2019. The recruitment closed on 30 September 2021.Kautz-Freimuth et al. Trials (2022) 23:157 Page 11 of 14AbbreviationsBC: Breast cancer; BRCA1/2: BReast CAncer genes 1 and 2; CG: Control group;DA-A: Decision aid A (designed for previvors); DA-B: Decision aid B (designedfor survivors); DAs: Decision aids; DCS: Decisional Conflict Scale;DRS: Decision Regret Scale; GC-HBOC: German Consortium of HereditaryBreast and Ovarian Cancer; HADS: Hospital Anxiety and Depression Scale;ID: Identity number; IES-R: Impact of Event Scale-Revised; IG: Interventiongroup; MRI: Magnetic resonance imaging; RCT: Randomised controlled study;OC: Ovarian cancer; PrepDMS: Preparation for Decision Making Scale; SDM-S: Status of Decision Making ScaleAcknowledgementsWe would like to express our special thanks to the German self-help organ-isation BRCA network for their constant committed support and helpful ad-vice. Our sincere thanks also go to the clinically active physicians and thestudy nurse of the recruiting institution, whose active cooperation and com-mitment make the implementation of the study possible in the first place.Authorship eligibility and use of professional writersThe authors will be members of the research team at the data evaluationinstitution in cooperation with leading specialists responsible for patientcounselling and recruitment at the recruiting institution, both located at theUniversity Hospital of Cologne. No external professional writers will beinvolved.Access to data {29}Only the members of the research team including the statistician whoanalyses the data will have access to the final trial dataset. It will not beopen to the public, but may be available from the corresponding author onreasonable request.Authors’ contributions {31b}SKF manages the entire project and prepared the first draft of thismanuscript. SST designed the study, raised the funding and is the principalinvestigator. SKF, MR, AV, KR and RS contributed to the study design. SKFand MR worked out the detailed procedures of the study. AI provided helpin the psychometric evaluation and selection of instruments and contributedto the draft of the manuscript. AS reviewed the statistical specifications forthe study and helped to harmonise the study questionnaires for datacollection. AV contributed to the planning and preparation of studymaterials. KR and RS contributed substantially to the planning of therecruitment procedure and lead the implementation of participantenrolment in the recruitment institution. All authors critically read, revisedand approved the final manuscript.Funding {4}This trial is funded by the Landeszentrum Gesundheit Nordrhein-Westfalen(LZG.NRW). The funding institution is not involved in the study design, datacollection, data management, data analyses and interpretation, report writ-ing, decision to submit this report for publication or the writing of this publi-cation. Open Access funding enabled and organized by Projekt DEAL.DeclarationsEthics approval and consent to participate {24}Before starting this trial, this project was approved by the Ethics Committeeof the Faculty of Medicine of the University of Cologne [ethical approvalgiven 26 April 2017, reference number 17-128].Consent for publication {32}Not applicable.Competing interests {28}The authors declare that they have no competing interests.Author details1Institute of Health Economics and Clinical Epidemiology, The UniversityHospital of Cologne, Gleueler Straße 176-178, 50935 Cologne, Germany.2School of Population and Public Health, The University of British Columbia,2206 East Mall, Vancouver, BC C6T 1Z3, Canada. 3Centre for Familial Breastand Ovarian Cancer, Centre for Integrated Oncology (CIO), Faculty ofMedicine and The University Hospital of Cologne, University of Cologne,Kerpener Straße 62, 50937 Cologne, Germany.Received: 26 February 2021 Accepted: 3 February 2022References1. 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eng
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Vancouver : University of British Columbia Library
BioMed Central
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BRCA1 mutation
BRCA2 mutation
Decision aid
Decision-making
Evaluation study
Familial breast and ovarian cancer
Hereditary breast and ovarian cancer (HBOC)
Preventive measures
Preference-sensitive decisions
Patient-centred care
Evaluation of two evidence-based decision aids for female BRCA1/2 mutation carriers in Germany: study protocol for a randomised controlled parallel-group trial
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