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Introduction: Many clinical trials terminate early due to safety and efficacy concerns, and less often due to unexpected “positive” findings. However, early termination of post-approval (Phase IV) pragmatic randomized trials for commercial reasons is less frequent, may be more complex, and may require added flexibility in closure methods, including short term follow-up. VOLUME was a randomized, open-label, post-approval pragmatic clinical trial (PCT) or large simple trial that terminated early due to product withdrawal. The aim of this paper is to describe circumstances unique to post-approval PCTs that may require a closure amendment rather than immediate study termination, and our recommendations for operational study closure in these circumstances. We use the VOLUME case study throughout to provide a practical example. Methods: Study closeout considerations at the study level include: notifying external governance bodies, e.g., data monitoring committees (DMC), and scientific steering committees (SSC); executing a study closure amendment; notifying and training of study physicians; and institutional review board (IRB)/ethics committee (EC) approvals. Study closure considerations at the patient level focus on patient safety and include: patient notification, efficient transition to alternative treatments, the need for re-consenting; and drug supply shortages. Conclusions: Early study closeout logistics require careful analysis, detailed planning, and close coordination, and are ideally considered at the study planning phase. Lessons learned from the VOLUME closeout should help other researchers devise contingencies when terminating post approval pragmatic trials that utilize a marketed product.ClinicalTrials.gov: NCT00359801. Keywords: Large simple trial, Closure, Product withdrawal, Commercial withdrawal, Pragmatic