Balancing Protocol Requirements with Patient Autonomy: A Case Study on Post-Randomization Refusal in an HIV related clinical trial

Balancing Protocol Requirements with Patient Autonomy: A Case Study on Post-Randomization Refusal in an HIV related clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Balancing Protocol Requirements with Patient Autonomy: A Case Study on Post-Randomization Refusal in an HIV related clinical trial Olivie Carolyne Namuju, Provia Ainembabazi, Gila Hale, Sylvia Namanda, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8688903/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Randomization is central to ensuring the scientific validity of clinical trials. However, real-world complexities such as polypharmacy and individual treatment readiness may lead to post-randomization refusal. Post-randomization refusal presents several challenges to both the ethical integrity and methodological rigor trials. This case report explores a unique scenario in a randomized controlled trial where a participant initially refused their allocated arm due to concerns about pill burden but later agreed to proceed after supportive dialogue. Case presentation: This case report describes an instance where a participant initially refused intervention in a randomized controlled, open-label clinical trial involving a tuberculosis preventive treatment, in which patients were randomized to start the product as in-patient (immediate initiation) or outpatients (delayed initiation). Following the provision of written informed consent, the participant was randomized to the inpatient arm. However, he hesitated to start the intervention as per protocol, citing concerns about his already high pill burden. He requested to be re-randomized to the outpatient arm. The research team held a substantive dialogue with the participant, and together with the caretakers’ support, he ultimately agreed to continue in the assigned arm. The participant later encountered adherence challenges, which were successfully addressed through ongoing counseling support. Conclusion This case underscores the importance of responsive communication and participant-centered care in managing post-randomization uncertainty without compromising trial integrity. We reflect on the ethical, methodological, and design implications of managing participant preference in randomized controlled trials. Post-randomization Refusal Clinical Trial Randomization Background Randomization serves as a cornerstone of clinical trials, designed to minimize bias and ensure comparability between study arms ( 1 , 2 ). In a randomized controlled trial (RCT), the process is especially vital for ensuring the internal validity and scientific credibility of trial outcomes ( 2 ). However, the assumption that participants will accept and adhere to their assigned intervention immediately after randomization does not always hold in practice( 3 ). Despite comprehensive informed consent and pre-enrollment screening procedures, some participants may choose to withdraw or refuse to participate in the trial after randomization has occurred. Participants may reconsider their participation due to various reasons, including dissatisfaction with their assigned treatment/arm, anxiety about side effects, or changes in their personal circumstances( 4 – 6 ). This post-randomization refusal presents several challenges to both the ethical integrity and methodological rigor of the trial. Post-randomization withdrawal while respecting the principle of autonomy can introduce attrition bias, compromise statistical power, and affect generalizability of trial findings, especially in trials with small sample sizes or limited resources( 7 ). From an ethical perspective, the situation is further complicated when a participant appears to misunderstand the nature of randomization, highlighting potential gaps in the consent process. Previous studies have shown that randomization and concepts of placebo-controlled trials are sub-optimally understood by participants when obtaining informed consent( 8 ). As clinical research increasingly engages participants with complex health backgrounds often involving polypharmacy and multiple comorbidities, individual post-randomization treatment readiness becomes a critical, though often underestimated, factor. Participants may have strong preferences or logistical barriers that only come to light after randomization has occurred( 9 ). This case report explores a unique scenario in an RCT involving a preventive medicinal product, where a participant initially refused their allocated arm due to concerns about pill burden, but later agreed to proceed after supportive dialogue. The case highlights the importance of managing post-randomization concerns through ethically-grounded, patient-centered communication. Case Presentation The scenario occurred in an open-label randomized controlled trial (IMPROVE, ISRCTN18437550) that aimed to improve clinical outcomes in advanced HIV disease through integrated management of cryptococcal and opportunistic infections. Study participants were hospitalized adults with advanced HIV disease receiving treatment for cryptococcal meningitis. Participants were required to have no evidence of active TB disease and to meet all other eligibility criteria for inclusion. Thereafter, they were approached for consent to take part in the IMPROV Refusal Refusal_OCN Refusal RefusalE trial. The trial design included two parallel arms: 1) the inpatient initiation arm (immediate initiation), in which participants started TB preventive therapy (TPT) before hospital discharge, and 2) the outpatient arm, in which TPT was started at week 6 of clinic follow-up for cryptococcal treatment. Participants were informed during the informed consent process that the timing of TPT initiation would vary by assignment. Following the provision of informed consent, participants were randomized to one of the two arms after assessment of understanding. We present a 25-year-old male living with HIV for 5 years who interrupted his HIV antiretroviral therapy (Zidovudine/Lamivudine/Atazanavir/ritonavir; AZT/3TC/ATVr) for a period greater than 3 years due to social reasons. He denied prior opportunistic infections, tuberculosis exposure, or other comorbidities like diabetes or hypertension, but admitted to occasional alcohol use. He was hospitalized at Kiruddu National Referral Hospital, Uganda, with a 2-week history of progressively worsening throbbing frontal headaches, associated with neck pain, blurred vision, photophobia, and odynophagia. No fever, drenching night sweats, weight loss, cough, vomiting, seizures, or altered mentation at presentation, and no focal neurological deficits. Review of other systems was unremarkable. On admission, vital signs showed tachycardia (pulse 110 bpm), mild fever (37.8°C), and normal blood pressure. Physical exam revealed nuchal rigidity, oral thrush, and papilledema. Baseline laboratories included a CD4 count of 45 cells/µL (indicating severe immunosuppression), unknown HIV viral load, hemoglobin 11.6 g/dL, and normal renal/liver function. Lumbar puncture confirmed cryptococcal meningitis with positive serum and CSF cryptococcal antigen tests, normal protein, glucose and white cell count in cerebrospinal fluid, with CSF opening pressure 28cm H 2 O). TB screening (via GeneXpert on CSF, urine Lipoarabinomanan, abdominal ultrasound, chest X-ray) was negative. He was promptly initiated on standard-of-care induction therapy for cryptococcal meningitis: intravenous liposomal amphotericin B (10mg/kg single dose) plus oral fluconazole (1200mg/day), and oral flucytosine (100mg/kg/day in 4 divided doses), alongside therapeutic lumbar punctures to control raised intracranial pressure, cotrimoxazole prophylaxis, and supportive care (e.g., analgesics, oral potassium, oral Magnesium). ART was to be re-initiated after 4 weeks as per guidelines. This regimen resulted in a daily pill burden exceeding 10 tablets. He was subsequently approached to consent and participate in the IMPROVE trial. He provided informed consent after receiving all the information about the study procedures, including the randomization process. The participant was randomized into the inpatient arm (immediate-start). Upon notifying him of the randomization outcome, he expressed a concern that he had assumed that there would be a delay and was uncomfortable adding a new drug to his regimen without time to prepare: “I didn’t think I’d have to start today. I’m already on too many meds, and I need time to get things in order before adding something new.” He requested to re-run the randomization with hopes of landing in the delayed arm, believing that the delayed arm might be more suitable for his current situation. In response, the study team reviewed the informed consent discussion with the participant and reminded him about the rationale for randomization. They also reassured him that monitoring for interactions and side effects would be actively ongoing. After an intensive discussion with the research team together with the caretakers’ support, he ultimately agreed to continue in the assigned arm. Finally, he was enrolled in the IMPROVE trial, started on TPT, and discharged with scheduled follow-up clinic visits. During these visits, the participant reported intermittent adherence to TPT due to difficulty managing his full regimen. He expressed feelings of being “overwhelmed” by the number of medications. The study team provided ongoing counseling support, including medication organization strategies, weekly phone check-ins, and motivational interviewing to support adherence. Over time, his inconsistency improved, and he remained engaged in the trial. With intensive adherence counseling, he tried to take the drugs well, and by termination at week 18 he had successfully taken > 90% of the 1HP study medications, Discussion This case report highlights the complex relationships between participants' autonomy, comprehension of randomization during the informed consent process, and treatment readiness in a randomized clinical trial, especially those with already existing challenges such as high pill burden. The participant was a 25-year-old male with HIV-associated cryptococcal meningitis who demonstrated an initial willingness to participate in the trial, including the agreement to randomization. However, upon learning that he had been allocated to the immediate-initiation arm of the study drug, he expressed discomfort and preference for the delayed-start group. The participant's initial refusal after randomization to the immediate-initiation arm highlights a potential disconnect between procedural informed consent and true personal readiness. Post-randomization refusals raise important ethical and operational considerations. While the participant had been informed about the randomization process and its implications during the informed consent process, including translation into Luganda and assessment of understanding, his reaction suggested that the information may not have been fully internalized or clearly understood. This may be attributed to assumptions and misunderstanding of what randomization is during the informed consent process, which has been reported in previous studies ( 8 , 10 ). Additionally, his initial reaction and adherence challenges revealed an unmet need: a more comprehensive assessment of treatment readiness. In populations with high pill burden concerns, it is important to anticipate practical barriers to intervention uptake. In other instances, application of assisted consenting techniques like video consenting could be helpful including brief tools or conversations about regimen fatigue, scheduling capacity, or health literacy may allow teams to better tailor support before and after randomization ( 11 ). The participants' expectations of delayed initiation, despite consenting to randomization suggests a gap between procedural consent and personal readiness, underscoring the need for iterative, comprehension-based consent strategies in complex trials as suggested in several literature( 12 , 13 ). Perhaps a question needs to be added to the assessment of understanding about willingness to continue the study regardless of what arm one is assigned to before randomization is performed. Post-randomization refusal introduces the risk of protocol deviations, poses risks to trial validity, including attrition bias, especially if participants request re-randomization. However, through ethical engagement and patient-centered communication, the research team was able to uphold the trial integrity without overriding the participant's autonomy. The participant must still be allowed to withdraw if they prefer to as per the ethical principles for conduct of research( 14 ). The decision to revisit the consent process and provide psychosocial support allowed the participant to re-engage with the trial voluntarily and with a clear understanding of its demands. This denotes the importance of trial team training to understand Good Clinical Practice principles trial design concepts, and implications ( 15 ). While the research team’s refusal to re-randomize was consistent with good clinical practice, the ethical handling of the participant’s concerns, through open dialogue and support, helped maintain trust, and he chose to continue with the allocated arm. The request for re-randomization, if accommodated, would have introduced selection bias and compromised the purpose of randomization to minimize confounding. The team's firm but supportive refusal aligned with methodological rigor yet highlights the tension between strict protocol adherence and real-world participant needs. In some trial designs, such as patient-preference trials or adaptive designs, participant preferences can be formally integrated, particularly when equipoise exists or where non-adherence might otherwise threaten trial validity ( 16 ). His subsequent challenges with adherence further demonstrate how psychosocial burdens and pill burden may affect participant capacity to maintain trial requirements, even after consent and enrollment. These realities underscore the importance of proactive, continuous support mechanisms, particularly in trials that introduce additional pill burden to an already complex regimen. The use of phone follow-ups contributes meaningfully to the improved adherence and trial completion. Conclusion In conclusion, post-randomization refusal will infrequently represent a critical challenge in trial conduct. In this case report, re-enforcement of informed consent principles and a patient-centered approach enabled continued participation without compromising trial integrity. This experience highlights the need for enhanced pre-randomization assessments in populations prone to polypharmacy, emphasis on randomization implications during the consent process, and assessment of understanding and willingness to comply with procedures. Incorporating brief screening for treatment readiness, such as questions on regimen fatigue, scheduling capacity, health literacy, or explicit willingness to accept the assigned treatment arm, could identify at-risk participants earlier. Innovative consenting strategies, including video-assisted consent or iterative teach-back methods, may improve comprehension of randomization. The ongoing psychosocial support, tailored adherence strategies, and responsive communication are essential for promoting participant retention and ensuring the ethical conduct of clinical trials in a complex real-world setting. Future studies should consider integrating readiness screening, clearer intervention timelines, and adherence support into trial workflows among other forms of assisted consenting. Declarations Ethics approval and consent to participate This is a write-up based on a case study with no patient identifier, and no ethical approval is required. Consent for publication The patient provided verbal and written consent for publication of his information. Competing interests No competing interests. Funding No funding for this work was given. Author Contribution OCN, PA, GH, SN, FAS, SN, JE, and DBM all contributed to the conceptualisation and drafting of the manuscript, and provided critical revisions. OCN made the initial draft of the manuscript. All authors reviewed and contributed to the final draft of the paper, and all authors are responsible for the decision to submit the publication. Acknowledgement We sincerely express our gratitude to the patient and their family, and we gratefully acknowledge the support of the clinical trial staff and the administration at Kirruddu National Referral Hospital. Availability of data and materials Data sharing does not apply to this article as no datasets were generated. All data analyzed and relevant to this case report (excluding the Patient Identifying Information) are included in this published article. References European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials - Step 5. 2020. Hariton E, Locascio JJ. Randomised controlled trials - the gold standard for effectiveness research: Study design: randomised controlled trials. BJOG. 2018;125(13):1716. Adewuyi TE, MacLennan G, Cook JA. Non-compliance with randomised allocation and missing outcome data in randomised controlled trials evaluating surgical interventions: a systematic review. BMC Res Notes. 2015;8:403. Dwyer CP, Moses A, Rogers FM, Casey D, Joyce R, Hynes SM. A qualitative investigation of reasoning behind decisions to decline participation in a research intervention: A study-within-a-trial. J Health Psychol. 2023;28(4):374–87. Jenkins V, Farewell V, Farewell D, Darmanin J, Wagstaff J, Langridge C, et al. Drivers and barriers to patient participation in RCTs. Br J Cancer. 2013;108(7):1402–7. Kim J, Kim MG, Lim KM. Participation in and withdrawal from cancer clinical trials: A survey of clinical research coordinators. Asia Pac J Oncol Nurs. 2022;9(4):197–201. Siddiqi AE, Sikorskii A, Given CW, Given B. Early participant attrition from clinical trials: role of trial design and logistics. Clin Trials. 2008;5(4):328–35. Wu C, Wang N, Wang Q, Wang C, Wei Z, Wu Z, et al. Participants' understanding of informed consent in clinical trials: A systematic review and updated meta-analysis. PLoS ONE. 2024;19(1):e0295784. Robiner WN. Enhancing adherence in clinical research. Contemp Clin Trials. 2005;26(1):59–77. Featherstone K, Donovan JL. Why don't they just tell me straight, why allocate it? The struggle to make sense of participating in a randomised controlled trial. Soc Sci Med. 2002;55(5):709–19. Mantica G, Esperto F, Malinaric R, Ambrosini F, Cacciatore L, Papalia R, et al. Video-Assisted Informed Consent in Endoscopic Urology: A Randomized Trial on Ureteroscopy. J Endourol. 2024;38(9):916–20. Kadam RA. Informed consent process: A step further towards making it meaningful! Perspect Clin Res. 2017;8(3):107–12. Fons-Martinez J, Ferrer-Albero C, Diez-Domingo J. Keys to improving the informed consent process in research: Highlights of the i-CONSENT project. Health Expect. 2022;25(4):1183–5. Miteu GD. Ethics in scientific research: a lens into its importance, history, and future. Ann Med Surg (Lond). 2024;86(5):2395–8. Arango J, Chuck T, Ellenberg SS, Foltz B, Gorman C, Hinrichs H, et al. Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency. Ther Innov Regul Sci. 2016;50(4):480–6. Food and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics. Guidance for. Industry. 2019. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8688903","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":580550549,"identity":"c5019665-ee11-49e9-b597-dc82dc5425f4","order_by":0,"name":"Olivie Carolyne Namuju","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYNACHgY5NobEBtK0GJOqhQGkPoFIpfyzm59u5pE5nN7HntzA8KOCIXG+AwEtEneOmd3m4Tmc28bzsIGx5wxD4sYDBLQYSCRAtUgkNjAztgG1NBDUkv4NpCWdjQQtOWBbEuBa5hPQwSBxI6fs5hyedEOQXw72nJEw3kBIC/+M9G033vZYy8u3pz988KPCRnY+IYeBAWMPhD4AtJXB4AAxWhh+ILHlibJlFIyCUTAKRhIAAAYDPu624YXeAAAAAElFTkSuQmCC","orcid":"","institution":"Makerere University","correspondingAuthor":true,"prefix":"","firstName":"Olivie","middleName":"Carolyne","lastName":"Namuju","suffix":""},{"id":580550550,"identity":"ef7b6366-21ec-458c-ac6a-832971049205","order_by":1,"name":"Provia Ainembabazi","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Provia","middleName":"","lastName":"Ainembabazi","suffix":""},{"id":580550551,"identity":"dbee16e2-f763-47ee-ac0b-be4d9fabf5e5","order_by":2,"name":"Gila Hale","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Gila","middleName":"","lastName":"Hale","suffix":""},{"id":580550552,"identity":"67f948fd-4a8d-4c79-b16a-f82523ec8846","order_by":3,"name":"Sylvia Namanda","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Sylvia","middleName":"","lastName":"Namanda","suffix":""},{"id":580550553,"identity":"a763ca0f-a646-41da-96f0-a0b6f413b5c4","order_by":4,"name":"Faizo Ssenkindi","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Faizo","middleName":"","lastName":"Ssenkindi","suffix":""},{"id":580550554,"identity":"ab4d2050-0a45-4fb5-9095-8b1c7bcfaddf","order_by":5,"name":"Suzan Namombwe","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Suzan","middleName":"","lastName":"Namombwe","suffix":""},{"id":580550555,"identity":"5ea85e11-6442-4cd6-95d0-2120e4f341c8","order_by":6,"name":"Jayne Ellis","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Jayne","middleName":"","lastName":"Ellis","suffix":""},{"id":580550556,"identity":"ff6d03d1-c9bc-48d1-b4bb-c05cf9f20368","order_by":7,"name":"David B Meya","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"B","lastName":"Meya","suffix":""}],"badges":[],"createdAt":"2026-01-24 19:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8688903/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8688903/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101487721,"identity":"f9532bca-fdd6-4f80-895f-d3cc428818e6","added_by":"auto","created_at":"2026-01-30 09:28:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":387038,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8688903/v1/481488bb-1fd7-4e8c-866b-286ba654b4ff.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Balancing Protocol Requirements with Patient Autonomy: A Case Study on Post-Randomization Refusal in an HIV related clinical trial","fulltext":[{"header":"Background","content":"\u003cp\u003eRandomization serves as a cornerstone of clinical trials, designed to minimize bias and ensure comparability between study arms (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In a randomized controlled trial (RCT), the process is especially vital for ensuring the internal validity and scientific credibility of trial outcomes (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, the assumption that participants will accept and adhere to their assigned intervention immediately after randomization does not always hold in practice(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite comprehensive informed consent and pre-enrollment screening procedures, some participants may choose to withdraw or refuse to participate in the trial after randomization has occurred. Participants may reconsider their participation due to various reasons, including dissatisfaction with their assigned treatment/arm, anxiety about side effects, or changes in their personal circumstances(\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This post-randomization refusal presents several challenges to both the ethical integrity and methodological rigor of the trial. Post-randomization withdrawal while respecting the principle of autonomy can introduce attrition bias, compromise statistical power, and affect generalizability of trial findings, especially in trials with small sample sizes or limited resources(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFrom an ethical perspective, the situation is further complicated when a participant appears to misunderstand the nature of randomization, highlighting potential gaps in the consent process. Previous studies have shown that randomization and concepts of placebo-controlled trials are sub-optimally understood by participants when obtaining informed consent(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). As clinical research increasingly engages participants with complex health backgrounds often involving polypharmacy and multiple comorbidities, individual post-randomization treatment readiness becomes a critical, though often underestimated, factor. Participants may have strong preferences or logistical barriers that only come to light after randomization has occurred(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis case report explores a unique scenario in an RCT involving a preventive medicinal product, where a participant initially refused their allocated arm due to concerns about pill burden, but later agreed to proceed after supportive dialogue. The case highlights the importance of managing post-randomization concerns through ethically-grounded, patient-centered communication.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe scenario occurred in an open-label randomized controlled trial (IMPROVE, ISRCTN18437550) that aimed to improve clinical outcomes in advanced HIV disease through integrated management of cryptococcal and opportunistic infections.\u003c/p\u003e \u003cp\u003eStudy participants were hospitalized adults with advanced HIV disease receiving treatment for cryptococcal meningitis. Participants were required to have no evidence of active TB disease and to meet all other eligibility criteria for inclusion. Thereafter, they were approached for consent to take part in the IMPROV Refusal Refusal_OCN Refusal RefusalE trial. The trial design included two parallel arms: 1) the inpatient initiation arm (immediate initiation), in which participants started TB preventive therapy (TPT) before hospital discharge, and 2) the outpatient arm, in which TPT was started at week 6 of clinic follow-up for cryptococcal treatment. Participants were informed during the informed consent process that the timing of TPT initiation would vary by assignment. Following the provision of informed consent, participants were randomized to one of the two arms after assessment of understanding.\u003c/p\u003e \u003cp\u003eWe present a 25-year-old male living with HIV for 5 years who interrupted his HIV antiretroviral therapy (Zidovudine/Lamivudine/Atazanavir/ritonavir; AZT/3TC/ATVr) for a period greater than 3 years due to social reasons. He denied prior opportunistic infections, tuberculosis exposure, or other comorbidities like diabetes or hypertension, but admitted to occasional alcohol use. He was hospitalized at Kiruddu National Referral Hospital, Uganda, with a 2-week history of progressively worsening throbbing frontal headaches, associated with neck pain, blurred vision, photophobia, and odynophagia. No fever, drenching night sweats, weight loss, cough, vomiting, seizures, or altered mentation at presentation, and no focal neurological deficits. Review of other systems was unremarkable.\u003c/p\u003e \u003cp\u003eOn admission, vital signs showed tachycardia (pulse 110 bpm), mild fever (37.8°C), and normal blood pressure. Physical exam revealed nuchal rigidity, oral thrush, and papilledema. Baseline laboratories included a CD4 count of 45 cells/µL (indicating severe immunosuppression), unknown HIV viral load, hemoglobin 11.6 g/dL, and normal renal/liver function. Lumbar puncture confirmed cryptococcal meningitis with positive serum and CSF cryptococcal antigen tests, normal protein, glucose and white cell count in cerebrospinal fluid, with CSF opening pressure 28cm H\u003csub\u003e2\u003c/sub\u003eO). TB screening (via GeneXpert on CSF, urine Lipoarabinomanan, abdominal ultrasound, chest X-ray) was negative. He was promptly initiated on standard-of-care induction therapy for cryptococcal meningitis: intravenous liposomal amphotericin B (10mg/kg single dose) plus oral fluconazole (1200mg/day), and oral flucytosine (100mg/kg/day in 4 divided doses), alongside therapeutic lumbar punctures to control raised intracranial pressure, cotrimoxazole prophylaxis, and supportive care (e.g., analgesics, oral potassium, oral Magnesium). ART was to be re-initiated after 4 weeks as per guidelines. This regimen resulted in a daily pill burden exceeding 10 tablets.\u003c/p\u003e \u003cp\u003eHe was subsequently approached to consent and participate in the IMPROVE trial. He provided informed consent after receiving all the information about the study procedures, including the randomization process. The participant was randomized into the inpatient arm (immediate-start). Upon notifying him of the randomization outcome, he expressed a concern that he had assumed that there would be a delay and was uncomfortable adding a new drug to his regimen without time to prepare:\u003c/p\u003e \u003cp\u003e \u003cem\u003e“I didn’t think I’d have to start today. I’m already on too many meds, and I need time to get things in order before adding something new.”\u003c/em\u003e He requested to re-run the randomization with hopes of landing in the delayed arm, believing that the delayed arm might be more suitable for his current situation.\u003c/p\u003e \u003cp\u003eIn response, the study team reviewed the informed consent discussion with the participant and reminded him about the rationale for randomization. They also reassured him that monitoring for interactions and side effects would be actively ongoing. After an intensive discussion with the research team together with the caretakers’ support, he ultimately agreed to continue in the assigned arm.\u003c/p\u003e \u003cp\u003eFinally, he was enrolled in the IMPROVE trial, started on TPT, and discharged with scheduled follow-up clinic visits. During these visits, the participant reported intermittent adherence to TPT due to difficulty managing his full regimen. He expressed feelings of being “overwhelmed” by the number of medications. The study team provided ongoing counseling support, including medication organization strategies, weekly phone check-ins, and motivational interviewing to support adherence. Over time, his inconsistency improved, and he remained engaged in the trial. With intensive adherence counseling, he tried to take the drugs well, and by termination at week 18 he had successfully taken \u0026gt; 90% of the 1HP study medications,\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eThis case report highlights the complex relationships between participants' autonomy, comprehension of randomization during the informed consent process, and treatment readiness in a randomized clinical trial, especially those with already existing challenges such as high pill burden. The participant was a 25-year-old male with HIV-associated cryptococcal meningitis who demonstrated an initial willingness to participate in the trial, including the agreement to randomization. However, upon learning that he had been allocated to the immediate-initiation arm of the study drug, he expressed discomfort and preference for the delayed-start group.\u003c/p\u003e\u003cp\u003eThe participant's initial refusal after randomization to the immediate-initiation arm highlights a potential disconnect between procedural informed consent and true personal readiness. Post-randomization refusals raise important ethical and operational considerations. While the participant had been informed about the randomization process and its implications during the informed consent process, including translation into Luganda and assessment of understanding, his reaction suggested that the information may not have been fully internalized or clearly understood. This may be attributed to assumptions and misunderstanding of what randomization is during the informed consent process, which has been reported in previous studies (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Additionally, his initial reaction and adherence challenges revealed an unmet need: a more comprehensive assessment of treatment readiness. In populations with high pill burden concerns, it is important to anticipate practical barriers to intervention uptake. In other instances, application of assisted consenting techniques like video consenting could be helpful including brief tools or conversations about regimen fatigue, scheduling capacity, or health literacy may allow teams to better tailor support before and after randomization (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe participants' expectations of delayed initiation, despite consenting to randomization suggests a gap between procedural consent and personal readiness, underscoring the need for iterative, comprehension-based consent strategies in complex trials as suggested in several literature(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Perhaps a question needs to be added to the assessment of understanding about willingness to continue the study regardless of what arm one is assigned to before randomization is performed.\u003c/p\u003e\u003cp\u003ePost-randomization refusal introduces the risk of protocol deviations, poses risks to trial validity, including attrition bias, especially if participants request re-randomization. However, through ethical engagement and patient-centered communication, the research team was able to uphold the trial integrity without overriding the participant's autonomy. The participant must still be allowed to withdraw if they prefer to as per the ethical principles for conduct of research(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The decision to revisit the consent process and provide psychosocial support allowed the participant to re-engage with the trial voluntarily and with a clear understanding of its demands. This denotes the importance of trial team training to understand Good Clinical Practice principles trial design concepts, and implications (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhile the research team’s refusal to re-randomize was consistent with good clinical practice, the ethical handling of the participant’s concerns, through open dialogue and support, helped maintain trust, and he chose to continue with the allocated arm. The request for re-randomization, if accommodated, would have introduced selection bias and compromised the purpose of randomization to minimize confounding. The team's firm but supportive refusal aligned with methodological rigor yet highlights the tension between strict protocol adherence and real-world participant needs. In some trial designs, such as patient-preference trials or adaptive designs, participant preferences can be formally integrated, particularly when equipoise exists or where non-adherence might otherwise threaten trial validity (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHis subsequent challenges with adherence further demonstrate how psychosocial burdens and pill burden may affect participant capacity to maintain trial requirements, even after consent and enrollment. These realities underscore the importance of proactive, continuous support mechanisms, particularly in trials that introduce additional pill burden to an already complex regimen. The use of phone follow-ups contributes meaningfully to the improved adherence and trial completion.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, post-randomization refusal will infrequently represent a critical challenge in trial conduct. In this case report, re-enforcement of informed consent principles and a patient-centered approach enabled continued participation without compromising trial integrity. This experience highlights the need for enhanced pre-randomization assessments in populations prone to polypharmacy, emphasis on randomization implications during the consent process, and assessment of understanding and willingness to comply with procedures. Incorporating brief screening for treatment readiness, such as questions on regimen fatigue, scheduling capacity, health literacy, or explicit willingness to accept the assigned treatment arm, could identify at-risk participants earlier.\u003c/p\u003e \u003cp\u003eInnovative consenting strategies, including video-assisted consent or iterative teach-back methods, may improve comprehension of randomization. The ongoing psychosocial support, tailored adherence strategies, and responsive communication are essential for promoting participant retention and ensuring the ethical conduct of clinical trials in a complex real-world setting. Future studies should consider integrating readiness screening, clearer intervention timelines, and adherence support into trial workflows among other forms of assisted consenting.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThis is a write-up based on a case study with no patient identifier, and no ethical approval is required.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e The patient provided verbal and written consent for publication of his information.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eNo competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding for this work was given.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eOCN, PA, GH, SN, FAS, SN, JE, and DBM all contributed to the conceptualisation and drafting of the manuscript, and provided critical revisions. OCN made the initial draft of the manuscript. All authors reviewed and contributed to the final draft of the paper, and all authors are responsible for the decision to submit the publication.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe sincerely express our gratitude to the patient and their family, and we gratefully acknowledge the support of the clinical trial staff and the administration at Kirruddu National Referral Hospital.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eData sharing does not apply to this article as no datasets were generated. All data analyzed and relevant to this case report (excluding the Patient Identifying Information) are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEuropean Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials - Step 5. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHariton E, Locascio JJ. Randomised controlled trials - the gold standard for effectiveness research: Study design: randomised controlled trials. BJOG. 2018;125(13):1716.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdewuyi TE, MacLennan G, Cook JA. Non-compliance with randomised allocation and missing outcome data in randomised controlled trials evaluating surgical interventions: a systematic review. BMC Res Notes. 2015;8:403.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDwyer CP, Moses A, Rogers FM, Casey D, Joyce R, Hynes SM. A qualitative investigation of reasoning behind decisions to decline participation in a research intervention: A study-within-a-trial. J Health Psychol. 2023;28(4):374\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJenkins V, Farewell V, Farewell D, Darmanin J, Wagstaff J, Langridge C, et al. Drivers and barriers to patient participation in RCTs. Br J Cancer. 2013;108(7):1402\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim J, Kim MG, Lim KM. Participation in and withdrawal from cancer clinical trials: A survey of clinical research coordinators. Asia Pac J Oncol Nurs. 2022;9(4):197\u0026ndash;201.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiddiqi AE, Sikorskii A, Given CW, Given B. Early participant attrition from clinical trials: role of trial design and logistics. Clin Trials. 2008;5(4):328\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu C, Wang N, Wang Q, Wang C, Wei Z, Wu Z, et al. Participants' understanding of informed consent in clinical trials: A systematic review and updated meta-analysis. PLoS ONE. 2024;19(1):e0295784.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobiner WN. Enhancing adherence in clinical research. Contemp Clin Trials. 2005;26(1):59\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeatherstone K, Donovan JL. Why don't they just tell me straight, why allocate it? The struggle to make sense of participating in a randomised controlled trial. Soc Sci Med. 2002;55(5):709\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMantica G, Esperto F, Malinaric R, Ambrosini F, Cacciatore L, Papalia R, et al. Video-Assisted Informed Consent in Endoscopic Urology: A Randomized Trial on Ureteroscopy. J Endourol. 2024;38(9):916\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKadam RA. Informed consent process: A step further towards making it meaningful! Perspect Clin Res. 2017;8(3):107\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFons-Martinez J, Ferrer-Albero C, Diez-Domingo J. Keys to improving the informed consent process in research: Highlights of the i-CONSENT project. Health Expect. 2022;25(4):1183\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiteu GD. Ethics in scientific research: a lens into its importance, history, and future. Ann Med Surg (Lond). 2024;86(5):2395\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArango J, Chuck T, Ellenberg SS, Foltz B, Gorman C, Hinrichs H, et al. Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency. Ther Innov Regul Sci. 2016;50(4):480\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFood and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuidance for. Industry. 2019.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Post-randomization Refusal, Clinical Trial, Randomization","lastPublishedDoi":"10.21203/rs.3.rs-8688903/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8688903/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRandomization is central to ensuring the scientific validity of clinical trials. However, real-world complexities such as polypharmacy and individual treatment readiness may lead to post-randomization refusal. Post-randomization refusal presents several challenges to both the ethical integrity and methodological rigor trials. This case report explores a unique scenario in a randomized controlled trial where a participant initially refused their allocated arm due to concerns about pill burden but later agreed to proceed after supportive dialogue.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eThis case report describes an instance where a participant initially refused intervention in a randomized controlled, open-label clinical trial involving a tuberculosis preventive treatment, in which patients were randomized to start the product as in-patient (immediate initiation) or outpatients (delayed initiation). Following the provision of written informed consent, the participant was randomized to the inpatient arm. However, he hesitated to start the intervention as per protocol, citing concerns about his already high pill burden. He requested to be re-randomized to the outpatient arm. The research team held a substantive dialogue with the participant, and together with the caretakers\u0026rsquo; support, he ultimately agreed to continue in the assigned arm. The participant later encountered adherence challenges, which were successfully addressed through ongoing counseling support.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case underscores the importance of responsive communication and participant-centered care in managing post-randomization uncertainty without compromising trial integrity. We reflect on the ethical, methodological, and design implications of managing participant preference in randomized controlled trials.\u003c/p\u003e","manuscriptTitle":"Balancing Protocol Requirements with Patient Autonomy: A Case Study on Post-Randomization Refusal in an HIV related clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-27 14:35:14","doi":"10.21203/rs.3.rs-8688903/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d346fc8b-e74a-48d4-b2f6-8ea0771072e8","owner":[],"postedDate":"January 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-30T09:27:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-27 14:35:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8688903","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8688903","identity":"rs-8688903","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}