PRolaCT - Three Prolactinoma RCTs

Phase 4

Recruiting

• Conditions: Prolactinoma; Prolactin-Producing Pituitary Tumor
• Interventions: Procedure: Endoscopic trans-sphenoidal adenoma resection; Drug: Dopamine Agonists

• Registration Number: NCT04107480
• Lead Sponsor: Leiden University Medical Center

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-06-21
• Study First Submitted: 2019-08-27
• Study First Submitted QC: 2019-09-26
• Study First Posted: 2019-09-27
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-17
• Last Update Posted: 2020-07-20
• Primary Completion: 2024-03-31
• Study Completion: 2026-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 880

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention	Endoscopic trans-sphenoidal adenoma resection	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.
Standard care	Dopamine Agonists	Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society.

Primary Outcome Measures

Name	Time	Method
Health-Related Quality of Life	12 months after randomization/baseline	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.
Long-term remission	36 months after randomization/baseline	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.

Secondary Outcome Measures

Name	Time	Method
Biochemical disease control	12 months after randomization/baseline	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.
Short-term remission	27 months after randomization/baseline	Disease remission as defined under the primary outcome for remission, measured at T=27.
Very long-term remission	60 months after randomization/baseline	Disease remission as defined under the primary outcome for remission, measured at T=60
Recurrence rate	36 and 60 months after randomization/baseline	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.
Side effects	Baseline and 12, 27 and 36 months after randomization/baseline	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.
Clinical symptom control	12, 27, 36 and 60 months after randomization/baseline	Clinical symptom control is defined as the absence of physical and psychiatric symptoms of prolactinoma.
Tumor shrinkage on MRI	12 and 36 months after randomization/baseline	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%.
Pituitary functioning	12 and 36 months after randomization/baseline	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.
Complications	Baseline and 12 months after randomization/baseline	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.
Depression and anxiety scores	baseline and 12 and 36 months after randomization/baseline	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.
Healthcare costs	Every 6 months until 36 months after randomization/baseline	Measured every 6 months until T=36, with the iMTA Medical Consumption Questionnaire.
Health-Related Quality of Life	Baseline and 12, 27, 36 and 60 months after randomization/baseline	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.
Disease burden	baseline and 12, 36 and 60 months after randomization/baseline	Measured with the Leiden Bother and Needs Questionnaire at baseline, T=12, T=36 and T=60.
Non-healthcare costs	Every 6 months until 36 months after randomization/baseline	Measured every 6 months until T=36, with the iMTA Productivity Cost Questionnaire.
Quality-Adjusted Life Years (QALYs)	Baseline and 6, 9, 12, 18, 24, 27, 30 and 36 months after randomization/baseline	Measured at 3-6 month intervals, with the EQ-5D-5L.

Trial Locations

Locations (3)

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, Netherlands