Back to resultsPRolaCT - Three Prolactinoma RCTs
Primary Purpose
Prolactinoma, Prolactin-Producing Pituitary Tumor
Status
Recruiting
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Endoscopic trans-sphenoidal adenoma resection
Dopamine Agonists
Sponsored by
About this trial
This is an interventional treatment trial for Prolactinoma focused on measuring prolactinoma, dopamine agonist, endoscopic trans-sphenoidal adenoma resection, remission rate, health-related quality of life
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.
Sites / Locations
- Amsterdam University Medical Center, loc. AMC
- Reinier de Graaf Gasthuis
- Leiden University Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Intervention
Standard care
Arm Description
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.
Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
Short-term remission
Disease remission as defined under the primary outcome for remission, measured at T=27.
Very long-term remission
Disease remission as defined under the primary outcome for remission, measured at T=60
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.
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.
Clinical symptom control
Clinical symptom control is defined as the absence of physical and psychiatric symptoms of prolactinoma.
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%.
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.
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.
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.
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.
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.
Disease burden
Measured with the Leiden Bother and Needs Questionnaire at baseline, T=12, T=36 and T=60.
Healthcare costs
Measured every 6 months until T=36, with the iMTA Medical Consumption Questionnaire.
Non-healthcare costs
Measured every 6 months until T=36, with the iMTA Productivity Cost Questionnaire.
Quality-Adjusted Life Years (QALYs)
Measured at 3-6 month intervals, with the EQ-5D-5L.
Full Information
NCT ID
NCT04107480
First Posted
August 27, 2019
Last Updated
July 17, 2020
Sponsor
Leiden University Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT04107480
Brief Title
PRolaCT - Three Prolactinoma RCTs
Official Title
PRolaCT - Three Multicenter Prolactinoma Randomized Clinical Trials
Study Type
Interventional
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Recruiting
Study Start Date
June 21, 2019 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
March 31, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prolactinoma, Prolactin-Producing Pituitary Tumor
Keywords
prolactinoma, dopamine agonist, endoscopic trans-sphenoidal adenoma resection, remission rate, health-related quality of life
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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)
Allocation
Randomized
Enrollment
880 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Intervention
Arm Type
Experimental
Arm Description
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.
Arm Title
Standard care
Arm Type
Active Comparator
Arm Description
Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society.
Intervention Type
Procedure
Intervention Name(s)
Endoscopic trans-sphenoidal adenoma resection
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Dopamine Agonists
Other Intervention Name(s)
Standard Care
Intervention Description
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.
Primary Outcome Measure Information:
Title
Health-Related Quality of Life
Description
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.
Time Frame
12 months after randomization/baseline
Title
Long-term remission
Description
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.
Time Frame
36 months after randomization/baseline
Secondary Outcome Measure Information:
Title
Short-term remission
Description
Disease remission as defined under the primary outcome for remission, measured at T=27.
Time Frame
27 months after randomization/baseline
Title
Very long-term remission
Description
Disease remission as defined under the primary outcome for remission, measured at T=60
Time Frame
60 months after randomization/baseline
Title
Biochemical disease control
Description
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.
Time Frame
12 months after randomization/baseline
Title
Recurrence rate
Description
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.
Time Frame
36 and 60 months after randomization/baseline
Title
Clinical symptom control
Description
Clinical symptom control is defined as the absence of physical and psychiatric symptoms of prolactinoma.
Time Frame
12, 27, 36 and 60 months after randomization/baseline
Title
Tumor shrinkage on MRI
Description
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%.
Time Frame
12 and 36 months after randomization/baseline
Title
Pituitary functioning
Description
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.
Time Frame
12 and 36 months after randomization/baseline
Title
Complications
Description
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.
Time Frame
Baseline and 12 months after randomization/baseline
Title
Side effects
Description
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.
Time Frame
Baseline and 12, 27 and 36 months after randomization/baseline
Title
Health-Related Quality of Life
Description
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.
Time Frame
Baseline and 12, 27, 36 and 60 months after randomization/baseline
Title
Depression and anxiety scores
Description
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.
Time Frame
baseline and 12 and 36 months after randomization/baseline
Title
Disease burden
Description
Measured with the Leiden Bother and Needs Questionnaire at baseline, T=12, T=36 and T=60.
Time Frame
baseline and 12, 36 and 60 months after randomization/baseline
Title
Healthcare costs
Description
Measured every 6 months until T=36, with the iMTA Medical Consumption Questionnaire.
Time Frame
Every 6 months until 36 months after randomization/baseline
Title
Non-healthcare costs
Description
Measured every 6 months until T=36, with the iMTA Productivity Cost Questionnaire.
Time Frame
Every 6 months until 36 months after randomization/baseline
Title
Quality-Adjusted Life Years (QALYs)
Description
Measured at 3-6 month intervals, with the EQ-5D-5L.
Time Frame
Baseline and 6, 9, 12, 18, 24, 27, 30 and 36 months after randomization/baseline
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ingrid M Zandbergen, MD
Phone
+3171-5296748
Email
i.m.zandbergen@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Coordinating invesitgator
Phone
+3171-5296748
Email
prolactinoom@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nienke R Biermasz, MD, prof.
Organizational Affiliation
Endocrinologist LUMC
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Wouter R van Furth, MD, PhD
Organizational Affiliation
Neurosurgeon LUMC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amsterdam University Medical Center, loc. AMC
City
Amsterdam-Zuidoost
State/Province
Noord-Holland
ZIP/Postal Code
1105 AZ
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Local principal investigator
Phone
+3120-5663542
First Name & Middle Initial & Last Name & Degree
Coordinating investigator
Phone
+3171-5296748
Email
prolactinoom@lumc.nl
Facility Name
Reinier de Graaf Gasthuis
City
Delft
State/Province
Zuid-Holland
ZIP/Postal Code
2625 AD
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Local principal investigator
Phone
+3115-2604207
First Name & Middle Initial & Last Name & Degree
Coordinating investigator
Phone
+3171-5296748
Email
prolactinoom@lumc.nl
Facility Name
Leiden University Medical Center
City
Leiden
State/Province
Zuid-Holland
ZIP/Postal Code
2333 ZA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Coordinating investigator
Phone
+3171 5296748
Email
prolactinoom@lumc.nl
First Name & Middle Initial & Last Name & Degree
Ingrid M Zandbergen
Email
i.m.zandbergen@lumc.nl
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34563236
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.
Results Reference
derived
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PRolaCT - Three Prolactinoma RCTs
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