The PRolaCT studies — a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma
Authors: Zandbergen Ingrid M. , Zamanipoor Najafabadi Amir H. , Pelsma Iris C. M. , van den Akker-van Marle M. Elske , Bisschop Peter H. L. T. , Boogaarts H. D. Jeroen , van Bon Arianne C. , Burhani Bakhtyar , le Cessie Saskia , Dekkers Olaf M. , Drent Madeleine L. , Feelders Richard A. , de Graaf Johan P. , Hoogmoed J. , Kapiteijn Kitty K. , van der Klauw Melanie M. , Nieuwlaat Willy-Anne C. M. , Pereira Alberto M. , Stades Aline M. E. , van de Ven Annenienke C. , Wakelkamp Iris M. M. J. , van Furth Wouter R. , Biermasz Nienke R. ,   on behalf of the Dutch Prolactinoma Study Group
Published: September 2021

Abstract
Background
First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size.

Methods
We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4–6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months.

Discussion
Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine.

Trial registration
US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480. Registered on 27 September 2019, registered retrospectively (by 2 months).