PRolaCT - Three Prolactinoma RCTs

Study Overview
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Brief Summary
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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.

Official Title
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PRolaCT - Three Multicenter Prolactinoma Randomized Clinical Trials

Conditions
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Prolactinoma, Prolactin-Producing Pituitary Tumor

Intervention / Treatment
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* Procedure: Endoscopic trans-sphenoidal adenoma resection
* Drug: Dopamine Agonists


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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<br>* 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.<br>|
| Active Comparator: Standard care<br>Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society. | Drug: Dopamine Agonists<br>* 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.<br>* Other names: Standard Care;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prolactinoma, dopamine agonist, endoscopic trans-sphenoidal adenoma resection, remission rate, health-related quality of life