PRolaCT - Three Prolactinoma RCTs

Prolactinoma Clinical Trial

Official title:

PRolaCT - Three Multicenter Prolactinoma Randomized Clinical Trials

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04107480
• Other study ID #: PRolaCT
• Secondary ID: 843002806NL63919
• Status: Recruiting
• Phase: Phase 4
• Start date: June 21, 2019
• Est. completion date: March 31, 2026

Study information

• Verified date: July 2020
• Source: Leiden University Medical Center
• Contact: Ingrid M Zandbergen, MD
• Phone: +3171-5296748
• Email: i.m.zandbergen[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 880
• Est. completion date: March 31, 2026
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Pituitary Neoplasms
• Prolactin-Producing Pituitary Tumor
• Prolactinoma

Intervention

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.

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.

Locations

Country	Name	City	State
Netherlands	Amsterdam University Medical Center, loc. AMC	Amsterdam-Zuidoost	Noord-Holland
Netherlands	Reinier de Graaf Gasthuis	Delft	Zuid-Holland
Netherlands	Leiden University Medical Center	Leiden	Zuid-Holland

Sponsors (1)

Lead Sponsor	Collaborator
Leiden University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Short-term remission	Disease remission as defined under the primary outcome for remission, measured at T=27.	27 months after randomization/baseline
Secondary	Very long-term remission	Disease remission as defined under the primary outcome for remission, measured at T=60	60 months after randomization/baseline
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Healthcare costs	Measured every 6 months until T=36, with the iMTA Medical Consumption Questionnaire.	Every 6 months until 36 months after randomization/baseline
Secondary	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
Secondary	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