This study aims to investigate if endoscopic trans-sphenoidal prolactinoma resection as a first line treatment (PRolaCT-1), or as an equally valid second line treatment after a short (2-12 months) or long (>12 months) period of pretreatment with…
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Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
- Endocrine neoplasms benign
- Endocrine gland therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This study has two main outcomes, including the health-related quality of life
after 12 months as measured on the mental health sub scale of the Short-Form 36
questionnaire; and the percentage of patients in remission after 36 months,
where remission is defined as normoprolactinaemia (a prolactin below the upper
limit of normal as defined by the laboratory where it is measured) in the
absence of dopamine agonist treatment or an actual pregnancy that was
established in the absence of dopamine agonist treatment.
Secondary outcome
The secondary outcomes of this study are:
- Remission rate, according to the above mentioned definition, 27 and 60 months
after randomization.
- Biochemical disease control, defined as normoprolactinaemia (a prolactin
below the upper limit of normal as defined by the laboratory where it is
measured), or an actual pregnancy, with or without dopamine agonist treatment,
measured 12 months after randomisation.
- Disease recurrence, 36 and 60 months after randomisation, defined as
recurrence of hyperprolactinaemia in the absence of dopamine agonist treatment
in patients who achieved disease remission at T=27.
- Clinical symptom control 12, 27, 36 and 60 months after randomization,
defined as:
> the absence of psychiatric symptoms measured with the Hospital Anxiety and
Depression Scale; and
> the absence of physical symptoms that are associated with prolactinoma,
i.e. galactorrhea, hypogonadism, loss of libido, subfertility, emotional
complaints, headache and visual complaints.
- Tumor shrinkage after 12 and 36 months, defined as a reduction in maximal
diameter or tumor volume of at least 20% on pituitary MRI.
- Normal(ized) pituitary functioning 12, 36 and 60 months after randomisation,
defined as normal funtioning of the following pituitary axes:
> gonadal axis, assessed with measurement of FSH, LH and estrogen or
testosterone
> thyroidal axis, assessed with measurement of TSH and free T4
> corticoid axis, assessed with measurement of morning cortisol and if
suppressed an additional CRH- or synacthen-test
> growth hormone axis, assessed with measurement of IGF-1 and additional
GH-suppression test or insulin-tolerance test, when indicated
> ADH secretion, assessed with measurement of serum sodium
- The occurrence of adverse reactions to treatment after 12 and 36 months,
defined as the occurrence of side effects to dopamine agonist treatment
documented with the use of the National Cancer Institute Patient-Reported
Outcomes version of the Common Terminology Criteria for Adverse Events
(PRO-CTCAE*) and a modified Impulse Control Disorder Questionnaire (ICD-Q); and
the occurrence of complications to surgery.
- HRQoL after 36 and 60 months, defined by the scores on all sub scales of the
SF-36.
- Disease burden after 12, 36 and 60 months, defined by the bother score on the
Leiden Bother and Needs Questionnaire.
- Cost-effectiveness after 12 andd 36 months, calculated from:
> Quality-of-Life adjusted life-years (QALY's), based on the EQ-5D-5L,
measured at baseline and 6, 9, 12, 18, 24, 27, 30 and 36 months after
randomisation.
> Healthcare costs, calculated from inventory with the iMTA Medical
Consumption Questionnaire (iMCQ), measured at baseline and every 6
months thereafter, until 36 months after randomisation.
> Productivity loss in the work field, measured with the iMTA Productivity
Costs Questionnaire (iPCQ) at baseline and every 6 months thereafter
until 36 months after randomisation.
From amendment 7 dated 19-11-2024 onwards, the cost-effectiveness
questionnaires will no longer be filled out.
Background summary
Current guidelines describe dopamine agonists, e.g. cabergoline, as first line
of treatment for prolactinoma patients. Only a selection of patients with a
prolactinoma undergoes surgical resection. Although most patients are under
good clinical control, the majority needs prolonged treatment with a dopamine
agonist, because 2-year remission rates remain low. While up to 40% of patients
experience side-effects. In contrast, endoscopic trans-sphenoidal prolactinoma
resection results in immediate remission in more than 80-90% of patients with a
low rate of long term morbidity from complications (< 3%). Thus, our hypothesis
is that early or upfront endoscopic trans-sphenoidal surgery in patients with a
non-invasive prolactinoma of limited size, will increase the health-related
quality of life and the remission rate.
Study objective
This study aims to investigate if endoscopic trans-sphenoidal prolactinoma
resection as a first line treatment (PRolaCT-1), or as an equally valid second
line treatment after a short (2-12 months) or long (>12 months) period of
pretreatment with a dopamine agonist is superior to standard care for several
outcome parameters of treatment. 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.
Study design
This protocol covers three similar but individual, unblinded Randomized
Clinical Trials (RCTs), that will run simultaneously; (1) PRolaCT-1, an RCT
that compares endoscopic trans-sphenoidal surgery as a first line treatment to
standard care in newly diagnosed, treatment naïve patients; (2) PRolaCT-2, an
RCT that compares endoscopic trans-sphenoidal surgery as an early treatment to
standard care in patients that have had short term treatment (2-12 months) with
medication; and (3) PRolaCT-3, an RCT that compares endoscopic trans-sphenoidal
surgery as an equal second line treatment to standard care in patients who
have persisting prolactinoma and had treatment with medication for a long
period of time (>12 months).
As mentioned in Amendment 6 dated 19-01-2024, all randomized arms
(PRolaCT-1,2,3) will be closed because of low willingness to randomize. All
eligible patients will therefore be inclded in the observational arm
(PRolaCT-O).
Intervention
The intervention groups of the three RCTs are referred to a participating
neurosurgical expertise center for extensive neurosurgical counseling with the
intention to perform the endoscopic trans-sphenoidal adenoma resection, when
the patients consents to this. The control groups receive standard care (thus
primary treatment with a dopamine agonist) by their own endocrinologist or
gynecologist, in the local hospital.
Study burden and risks
A risk of participation in this study is that endoscopic trans-sphenoidal
prolactinoma resection is performed in patients who in standard care would not
have underwent this surgery or would have at a later moment. The risk of
complications from the endoscopic surgery is low, with long-term morbidity
occurring in less than 3% and a mortality rate of <0.4-1%. The potential
benefit is a high chance of remission, relieving the patient from the need for
prolonged dopamine agonist treatment. As these treatments have not yet been
compared in a randomized clinical trial, it is the aim of this study to further
assess the extent of this benefit and its effect on the quality of life in a
randomized clinical trial design. The only way to adequately perform such a
study is with participation of the patients who suffer from the condition that
is aimed to be investigated.
As study follow up is designed to reflect routine clinical follow up, in both
the intervention as the control group, the burden of participation is kept to a
minimum. In addition to the documentation of clinical follow up, all
participants are asked to fill in a number of questionnaires on several moments
during the course of this study. The time this should cost a patient varies
from 30-60 minutes at the 5 time points connected to study visits (T=0, T=12,
T=27, T=36 and T=60), to 10-30 minutes at 5 additional time points spread over
the first three years of the study.
There is no direct therapeutic effect expected for the patients participating
in the control groups of this study. However, it is thought that the burden of
their participation in this study is outweighed by the potential benefit for
all patients with a relatively small, non-invasive prolactinoma, if our
hypothesis is thought to be right.
From amendment 6 dated 19-01-2024 onwards, participants are no longer subject
to increased risk due to the closing of the randomization arms of the study.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
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 with a
diameter smaller than 25mm, and more importantly not invading the cavernous
sinus and having an optimal chance to achieve surgical remission. A
representative MRI at the time of randomization is required, this MRI should
generally not be older than 12 months for all PRolaCT arms.
- Competent, or having proxy who can sign on their behalf.
- 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 2-12 months; or
* PRolaCT-3: treatment with a dopamine agonist for >12 months
As mentioned in Amendment 6 dated 19-01-2024, all randomized arms
(PRolaCT-1,2,3) will be closed because of low willingness to randomize. All
eligible patients will therefore be inclded in the observational arm
(PRolaCT-O).
As mentioned in Amendment 7 dated 19-11-2024, participants of all pretreatment
duration groups (PRolaCT-1,2,3) will be recruited for the observational arm,
resulting in a total of 3x220 participants = 660 participants.
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 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.
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL63919.058.18 |