Clinical trial NCT04107480: PRolaCT - Three Prolactinoma RCTs
Official title: PRolaCT - Three Multicenter Prolactinoma Randomized Clinical Trials
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Prolactinoma
Prolactin-Producing Pituitary Tumor
Keywords: prolactinoma
dopamine agonist
endoscopic trans-sphenoidal adenoma resection
remission rate
health-related quality of life
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2019-09-27
Enrollment: 880
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This partially randomized, preference trial design, comprises three unblinded randomized controlled trials (RCTs) and an observational study arm (PRolaCT-O) that compare neurosurgical counselling and potentially subsequent endoscopic transsphenoidal adenoma resection with current standard care (DA treatment). Patients with a non-invasive prolactinoma of limited size (\<2.5 cm) will be divided over the three RCTs based on duration of pre-treatment with DA: PRolaCT-1: newly diagnosed, treatment naive 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 randomization or those with a clear treatment preference. After study inclusion and treatment allocation, all study procedures and follow up are equal for the three RCTs and PRolaCT-O and are therefore discussed as one.
Primary purpose: TREATMENT

Brief summary: This study aims to investigate if endoscopic trans-sphenoidal prolactinoma resection as a first line treatment, or as an equally valid second line treatment after a short (4-6 months) or long (\>2 years) period of pretreatment with a dopamine agonist is superior to standard care for several outcome parameters. The main objectives are to investigate this for quality of life and remission rate. The secondary objectives are to investigate this for biochemical disease control, recurrence rates, clinical symptom control, tumor shrinkage on MRI, pituitary functioning, the occurrence of adverse reactions to treatment, disease burden, and cost-effectiveness.


Eligibility criteria: Inclusion Criteria:

* At least 18 years of age.
* A history of signs and symptoms compatible with the diagnosis prolactinoma.
* New, recent (PRolaCT-1) or known diagnosis of hyperprolactinaemia, defined as a prolactin level 2 times the local laboratory maximum. At the time of randomization hyperprolactinaemia is still present, or was present \< 12 months before inclusion (PRolaCT-2 and PRolaCT-3).
* No clear alternative explanation for hyperprolactinaemia, e.g. medication use.
* Presence of a clearly identifiable (persisting) pituitary mass on MRI not invading the cavernous sinus and having an optimal chance to be completely resected (generally adenomas with a maximum diameter nog exceeding 25mm). A representative MRI at the time of randomization is required, this MRI should generally not be older than 12 months in PRolaCT-3 and 2 months in PRolaCT-1 and PRolaCT-2.
* Competent and able to fill in questionnaires.
* One of the following, dividing patients in to our three RCTs:

  * PRolaCT-1: no prior treatment for prolactinoma;
  * PRolaCT-2: treatment with a dopamine agonist for 4-6 months; or
  * PRolaCT-3: treatment with a dopamine agonist for at least 2 years.

Exclusion Criteria:

* Contraindication for one of the treatment modalities, e.g. severe side effect of cabergoline, contraindications to surgery, or a clear indication for surgical resection.
* Pregnancy at the time of randomization.
* Clinical acromegaly.
* Prior pituitary gland surgery or radiotherapy to the pituitary gland area.
* Severe renal failure (eGFR \<30 ml/min).
* Insufficient understanding of the Dutch or English language.
* Other medical conditions that to the opinion of the physician are not compatible with inclusion in a trial.

Patients eligible for participation in one of the RCTs, but do not consent to randomisation or in whom there is a clear patient or physician preference for either DA treatment or surgery, are considered for participation in PRolaCT-O.

Primary outcomes:
measure: Health-Related Quality of Life
timeFrame: 12 months after randomization/baseline
measure: Long-term remission
timeFrame: 36 months after randomization/baseline
Secondary outcomes:
measure: Short-term remission
timeFrame: 27 months after randomization/baseline
measure: Very long-term remission
timeFrame: 60 months after randomization/baseline
measure: Biochemical disease control
timeFrame: 12 months after randomization/baseline
measure: Recurrence rate
timeFrame: 36 and 60 months after randomization/baseline
measure: Clinical symptom control
timeFrame: 12, 27, 36 and 60 months after randomization/baseline
measure: Tumor shrinkage on MRI
timeFrame: 12 and 36 months after randomization/baseline
measure: Pituitary functioning
timeFrame: 12 and 36 months after randomization/baseline
measure: Complications
timeFrame: Baseline and 12 months after randomization/baseline
measure: Side effects
timeFrame: Baseline and 12, 27 and 36 months after randomization/baseline
measure: Health-Related Quality of Life
timeFrame: Baseline and 12, 27, 36 and 60 months after randomization/baseline
measure: Depression and anxiety scores
timeFrame: baseline and 12 and 36 months after randomization/baseline
measure: Disease burden
timeFrame: baseline and 12, 36 and 60 months after randomization/baseline
measure: Healthcare costs
timeFrame: Every 6 months until 36 months after randomization/baseline
measure: Non-healthcare costs
timeFrame: Every 6 months until 36 months after randomization/baseline
measure: Quality-Adjusted Life Years (QALYs)
timeFrame: Baseline and 6, 9, 12, 18, 24, 27, 30 and 36 months after randomization/baseline
Other outcomes:
Locations:
city: Amsterdam-Zuidoost
country: Netherlands
facility: Amsterdam University Medical Center, loc. AMC
state: Noord-Holland
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
state: Zuid-Holland
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid-Holland
Study officials:
affiliation: Endocrinologist LUMC
name: Nienke R Biermasz, MD, prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Neurosurgeon LUMC
name: Wouter R van Furth, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zandbergen IM, Zamanipoor Najafabadi AH, Pelsma ICM, van den Akker-van Marle ME, Bisschop PHLT, Boogaarts HDJ, van Bon AC, Burhani B, le Cessie S, Dekkers OM, Drent ML, Feelders RA, de Graaf JP, Hoogmoed J, Kapiteijn KK, van der Klauw MM, Nieuwlaat WCM, Pereira AM, Stades AME, van de Ven AC, Wakelkamp IMMJ, van Furth WR, Biermasz NR; Dutch Prolactinoma Study Group. The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma. Trials. 2021 Sep 25;22(1):653. doi: 10.1186/s13063-021-05604-y.