Safety and Potency of a High Cabergoline Dosage in Microprolactinomas

Overview

This will be a multicenter, prospective, randomized, open-label trial with women harboring microprolactinomas and treatment naïve. The sample will be added consecutively and randomized into 2 unblinded groups: the high dosage group will receive a high cabergoline (CAB) dose for a period of \~6 months vs the standard dosage group, which will use the lowest needed dose of CAB to achieve normoprolactinemia for 2 years. The primary outcome will be remission rate.

Detailed description

Prolactinoma is the most common subtype of pituitary adenoma, and dopamine agonists are the gold standard for treatment, primarily CAB. The SPARAGMOS trial will be an interventional, randomized, open-label, multicenter study utilizing a high dose of CAB for \~6 months to suppress prolactin levels, with the hypothetical goal of achieving greater tumor apoptosis and remission rates. The control group will receive CAB for two years at the lowest dose necessary to achieve normoprolactinemia, as per current guidelines. Of note, for both groups, the final cumulative dose will be similar. The findings from this trial have the potential to inform and redefine future therapeutic strategies for microprolactinoma.

Interventions

• Drug Cabergoline
  Patients eligible for the study and randomized to the HIGH CAB arm will start oral CAB, 1 pill of 0.5mg, once a week. The dose will be increased by 0.5mg every week until the target dose of 3.5 mg/w. This initial low-dose-escalating regimen of 7 weeks will be used to prevent symptoms of intolerance. When 3.5 mg/w (1 pill every day) is reached, the patient must maintain this dose for 6 months. After this period, a 1-month de-escalation regime is implemented, reducing the dose by 1 mg/w (2 pills p
• Drug Cabergoline
  The standard dosage group will receive conventional treatment as recommended by current guidelines: a low dose of CAB enough to achieve normoPRL for 2 years. All patients will start CAB with 1 pill (0.5mg) once a week. The CAB dose can be adjusted during visits if hyperPRL is not resolved (maximum dose 2mg/w to prevent inclusion of resistant cases). The expected dose used for this arm during follow-up is between 0.5 and 1 mg/w. After completion of 2 years of treatment, all patients will have CAB

Primary outcome measures

• Remission [Time frame: 3, 6 and 12 months after treatment]

Eligibility criteria

Inclusion criteria

• 1\. Willing and able to provide written informed consent prior to any study-related procedures
• 2\. Adults >18 years old
• 3\. Pre-menopausal women
• 4\. Presence of signs and symptoms matching prolactinoma
• 5\. Hyperprolactinemia, defined as a prolactin (PRL) level ≥2 times the local laboratory maximum level of normality, present at the time of enrolment
• 6\. Presence of an identifiable pituitary mass on MRI with a maximum diameter of less than 1cm, independently of Knosp/invasiveness of the cavernous sinus
• 7\. Treatment naïve
• 8\. Females who engage in heterosexual intercourse must agree to use either a highly effective or a clinically acceptable method of contraception from the beginning of screening to the last study visit, which will include:
• Hysterectomy or bilateral salpingectomy
• Bilateral tubal occlusion or ligation
• Vasectomized partner
• Intrauterine device (copper or hormonal)
• Progestogen-only contraception (oral, injectable or implantable)
• Male or female condom with or without spermicide
• Sexual abstinence (only when it is the usual and preferred lifestyle of the subject)

Exclusion criteria

• 1\. History of primary hyperparathyroidism
• 2\. Use of combined hormonal contraceptive within the past 4 weeks
• 3\. Pregnancy or current pregnancy desire
• 4\. Prolactinoma associated with a known genetic syndrome
• 5\. Familial history of pituitary adenoma
• 6\. Renal failure (estimated glomerular filtration rate <30 mL/min /1.73m2)
• 7\. IGF-1 level above the age-adjusted normal range of the local laboratory (IGF 1 >1x ULNR)
• 8\. Idiopathic hyperprolactinemia (normal MRI) or presence of macroprolactinemia
• 9\. Concomitant mental condition rendering her unable to understand the nature, scope, and possible consequences of the study, and/or decompensated psychiatric disease (i.e. gambling or severe obsessive-compulsive disorder), as judged by the Investigator
• 10\. Chronic use of drugs related to hyperprolactinemia (such as metoclopramide, methyldopa, ranitidine, and opioid-related analgesics)
• 11\. Resistant prolactinoma, defined as non-normalization of PRL levels with 2mg/w of CAB
• 12\. Patients in the high dosage group who did not use 3.5mg/w of CAB for an entire 6 months (due to intolerance or non-compliance) or failed to achieve the target dose for any other reason
• 13\. Active malignant disease within the last 5 years, except basal and squamous cell carcinoma of the skin with complete local excision
• 14\. Any decompensated chronic condition (i.e. heart failure NYHA 3-4, diabetes with HbA1c >8.5%, hypothyroidism with TSH >10 mIU/L) that, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes
• 15\. Male sex
• 16\. Cushing stigmas (moon face, muscle weakness, red striation) or suspicious
• 17\. Prior radiotherapy of the pituitary gland area for any reason
• 18\. Additional pituitary tumor-directed therapy, including temozolomide, everolimus, lapatinib, or cytotoxic chemotherapy
• 19\. Hepatopathy with AST/TGO or ALT/TGP >3x the upper limit of normality

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 16 centers

• UFMG — Belo Horizonte
• Unesp — Botucatu
• UNB — Brasília
• Unicamp — Campinas
• UFPR — Curitiba
• UFG — Goiânia
• CPC — Ponta Grossa
• HCPA — Porto Alegre
• … and 8 more centers

Identifiers

NCT: NCT07463235 · 94925726.0.1001.0068 · 94925726.0.1001.0068

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗