PRolaCT - Three Prolactinoma RCTs

NCT ID: NCT04107480

Last Updated: 2020-07-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 880 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-21
• Study Completion Date: 2026-03-31

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.

Conditions

Prolactinoma; Prolactin-Producing Pituitary Tumor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Endoscopic trans-sphenoidal adenoma resection

Intervention Type: PROCEDURE

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.

Standard care

Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society.

Group Type: ACTIVE_COMPARATOR

Dopamine Agonists

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: PROCEDURE

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.

Intervention Type: DRUG

Other Intervention Names

Standard Care

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

I.M. Zandbergen, MD

Coordinating Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nienke R Biermasz, MD, prof.

Role: PRINCIPAL_INVESTIGATOR

Endocrinologist LUMC

Wouter R van Furth, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Neurosurgeon LUMC

Locations

Amsterdam University Medical Center, loc. AMC

Amsterdam-Zuidoost, North Holland, Netherlands

Site Status: NOT_YET_RECRUITING

Reinier de Graaf Gasthuis

Delft, South Holland, Netherlands

Site Status: NOT_YET_RECRUITING

Leiden University Medical Center

Leiden, South Holland, Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Ingrid M Zandbergen, MD

Role: CONTACT

i.m.zandbergen@lumc.nl

+3171-5296748

Coordinating invesitgator

Role: CONTACT

prolactinoom@lumc.nl

+3171-5296748

Facility Contacts

Local principal investigator

Role: primary

+3120-5663542

Coordinating investigator

Role: backup

prolactinoom@lumc.nl

+3171-5296748

Local principal investigator

Role: primary

+3115-2604207

Coordinating investigator

Role: backup

prolactinoom@lumc.nl

+3171-5296748

Coordinating investigator

Role: primary

prolactinoom@lumc.nl

+3171 5296748

Ingrid M Zandbergen

Role: backup

i.m.zandbergen@lumc.nl

References

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.

Reference Type: DERIVED

PMID: 34563236 (View on PubMed)

Other Identifiers

843002806

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

NL63919.058.18

Identifier Type: REGISTRY

Identifier Source: secondary_id

PRolaCT

Identifier Type: -

Identifier Source: org_study_id