PRolaCT - Three Prolactinoma RCTs

PRolaCT - Three Multicenter Prolactinoma Randomized Clinical Trials

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.

Study Overview

• Status: Recruiting
• Conditions: Prolactinoma; Prolactin-Producing Pituitary Tumor
• Intervention / Treatment: Procedure: Endoscopic trans-sphenoidal adenoma resection; Drug: Dopamine Agonists

• Study Type: Interventional
• Enrollment (Anticipated): 880
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ingrid M Zandbergen, MD; Phone Number: +3171-5296748; Email: i.m.zandbergen@lumc.nl
• Study Contact Backup: Name: Coordinating invesitgator; Phone Number: +3171-5296748; Email: prolactinoom@lumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam-Zuidoost, Noord-Holland, Netherlands, 1105 AZ
      • Not yet recruiting
      • Amsterdam University Medical Center, loc. AMC
      • Contact: Local principal investigator; Phone Number: +3120-5663542
      • Contact: Coordinating investigator; Phone Number: +3171-5296748; Email: prolactinoom@lumc.nl
  • Zuid-Holland
    • Delft, Zuid-Holland, Netherlands, 2625 AD
      • Not yet recruiting
      • Reinier de Graaf Gasthuis
      • Contact: Coordinating investigator; Phone Number: +3171-5296748; Email: prolactinoom@lumc.nl
      • Contact: Local principal investigator; Phone Number: +3115-2604207
    • Leiden, Zuid-Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: Coordinating investigator; Phone Number: +3171 5296748; Email: prolactinoom@lumc.nl
      • Contact: Ingrid M Zandbergen; Email: i.m.zandbergen@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention; Patients in the intervention groups will be referred to one of the participating neurosurgical centers, for surgical consultation. After this consultation, the patient may choose to continue with surgery or not.	Procedure: Endoscopic trans-sphenoidal adenoma resection; Neurosurgical consultation consists of at least one consult with a neurosurgeon and at least one consult with an endocrinologist with relevant experience. If the multidisciplinary team (MDT) agrees the patient is a good surgical candidate, the patient is asked consent for surgery, as is a custom part of preoperative requirements. When the patient decides not to have the surgery, (s)he will receive standard medical treatment, but will continue study follow up in the intervention group. Surgery only takes place if both the MDT and the patient agree to it and should then be planned within three months after randomization. Surgery is performed by one or two trained neurosurgeons in the hospital where the counseling took place. A standard, semi-protocolled, endoscopic trans-sphenoidal surgical resection of the prolactinoma is performed according to standard practice.
ACTIVE_COMPARATOR: Standard care; Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society.	Drug: Dopamine Agonists; The treating physician adheres to the treatment protocol in general, but has freedom to choose treatment to his/her ideas how to deliver best care. Current first line treatment consists of a dopamine agonists: cabergoline (currently the most used), bromocriptine or quinagolide. All dopamine agonists are taken orally, and the dosage may be raised based on its effect. It is usually titrated to achieve a normal or suppressed prolactin level and restoration of the gonadal axis. Dopamine agonist treatment is discontinued after 2 years of treatment, unless a normal prolactin level cannot be achieved. The dopamine agonist is restarted when prolactin levels rise after the medication is discontinued. In standard care, surgical treatment is reserved for patients who don't tolerate medication, or whose adenoma fails to show a sufficient response. Patients in the control group with an intolerance for dopamine agonists or an insufficient response may be offered surgery as part of standard care.; Other Names: Standard Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health-Related Quality of Life	Health-Related Quality of Life is defined as the score on the mental health scale of the Medical Outcomes Study (MOS) Short-Form Health Survey (SF-36), measured at T=12.	12 months after randomization/baseline
Long-term remission	Disease remission is defined as normoprolactinaemia (a prolactin level below the upper limit of normal as defined by the laboratory site where it is measured), in the absence of dopamine agonist treatment for at least 3 months or an actual pregnancy that was established during at least 3 months absence of dopamine agonist treatment, measured at T=36.	36 months after randomization/baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short-term remission	Disease remission as defined under the primary outcome for remission, measured at T=27.	27 months after randomization/baseline
Very long-term remission	Disease remission as defined under the primary outcome for remission, measured at T=60	60 months after randomization/baseline
Biochemical disease control	Biochemical disease control is defined as normoprolactinaemia (a prolactin level below the upper limit of normal as defined by the laboratory site where it is measured), or an actual pregnancy, with or without the use of a dopamine agonist, measured at T=12.	12 months after randomization/baseline
Recurrence rate	Disease recurrence is defined as recurrence of hyperprolactinaemia (a prolactin level >2 times the upper limit of normal as defined by the laboratory site where it is measured) in the absence of dopamine agonist treatment, after a period of normoprolactinaemia (without dopamine agonist treatment). This is measured only in patients who have achieved disease remission at T=27, and is measured at T=36 and T=60.	36 and 60 months after randomization/baseline
Clinical symptom control	Clinical symptom control is defined as the absence of physical and psychiatric symptoms of prolactinoma.	12, 27, 36 and 60 months after randomization/baseline
Tumor shrinkage on MRI	Tumor growth or shrinkage will be calculated as the percentage difference from baseline in tumor size (defined as the maximal diameter measured in mm) and tumor volume (calculated using Cavalieri's principle: tumor volume = 4/3 × pi (a/2 × b/2 × c/2) where a, b and c represent the diameters (in mm) in the 3 dimensions), measured at T=12 and T=36. It will be considered as a relevant shrinkage if tumor diameter or volume decreases at least 20%.	12 and 36 months after randomization/baseline
Pituitary functioning	The functioning of the pituitary axes other than prolactin (i.e. gonadal, thyroidal, corticoid, growth hormone and ADH axes), measured when indicated upon judgement by the treating physician (e.g. when an axis was deviant at baseline of as part of routine follow up after surgery) at T=12 and T=36. A pituitary axis will be considered normal when the associated measurement is within its normal range specific to the laboratory where it was measured in the absence of supplement treatment.	12 and 36 months after randomization/baseline
Complications	Treatment specific adverse effects: - The occurrence of known complications to surgery (i.e. cerebrospinal fluid leakage, diabetes insipidus, syndrome of inappropriate ADH-secretion, nasal complaints, decreased sense of smell/taste, intradural hemorrhage, meningitis, visual loss or a new pituitary deficit), as documented in patients' medical records by the treating physician, measured at T=12.	Baseline and 12 months after randomization/baseline
Side effects	Treatment specific adverse effects: - Occurrence of known side effects to dopamine agonist treatment as documented with the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) and a combined Impulse Control Disorder questionnaire at baseline, T=12, T=27 and T=36.	Baseline and 12, 27 and 36 months after randomization/baseline
Health-Related Quality of Life	Described by the scores on all sub-scales of the SF-36, in addition to the primary outcome on health-related quality of life. Measured at baseline, T=12, T=27, T=36 and T=60.	Baseline and 12, 27, 36 and 60 months after randomization/baseline
Depression and anxiety scores	Measured with the Hospital Anxiety and Depression Scale (HADS). This questionnaire uses 14 items; seven related to anxiety and seven to depression, to calculate anxiety and depression scores, ranging from 0 to 21.	baseline and 12 and 36 months after randomization/baseline
Disease burden	Measured with the Leiden Bother and Needs Questionnaire at baseline, T=12, T=36 and T=60.	baseline and 12, 36 and 60 months after randomization/baseline
Healthcare costs	Measured every 6 months until T=36, with the iMTA Medical Consumption Questionnaire.	Every 6 months until 36 months after randomization/baseline
Non-healthcare costs	Measured every 6 months until T=36, with the iMTA Productivity Cost Questionnaire.	Every 6 months until 36 months after randomization/baseline
Quality-Adjusted Life Years (QALYs)	Measured at 3-6 month intervals, with the EQ-5D-5L.	Baseline and 6, 9, 12, 18, 24, 27, 30 and 36 months after randomization/baseline

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Nienke R Biermasz, MD, prof., Endocrinologist LUMC; Principal Investigator: Wouter R van Furth, MD, PhD, Neurosurgeon LUMC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 21, 2019
• Primary Completion (ANTICIPATED): March 31, 2024
• Study Completion (ANTICIPATED): March 31, 2026

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: September 26, 2019
• First Posted (ACTUAL): September 27, 2019

Study Record Updates

• Last Update Posted (ACTUAL): July 20, 2020
• Last Update Submitted That Met QC Criteria: July 17, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: health-related quality of life; dopamine agonist; prolactinoma; endoscopic trans-sphenoidal adenoma resection; remission rate
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Hypothalamic Diseases; Hypothalamic Neoplasms; Supratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Pituitary Diseases; Adenoma; Pituitary Neoplasms; Prolactinoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Cardiotonic Agents; Dopamine Agents; Sympathomimetics; Dopamine; Dopamine Agonists
• Other Study ID Numbers: PRolaCT; 843002806 (OTHER_GRANT: ZonMw); NL63919.058.18 (REGISTRY: CCMO-registry)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No