Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT00921609 |
| Other study ID # |
8997 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 2006 |
| Est. completion date |
April 2025 |
Study information
| Verified date |
April 2024 |
| Source |
Cedars-Sinai Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Acromegaly is a rare disorder characterized by excessive production of growth hormone most
often by a pituitary adenoma. A pituitary adenoma is a tumor, almost always benign or
non-cancerous, that grows on the pituitary, a small gland located at the base of the brain.
Treatment of acromegaly usually involves surgery, medication, or radiation, but can involve a
combination of these three treatments.
Subjects for this study will be recruited if they are:
1. Adults, male or female, between the ages of 18-90.
2. Have been diagnosed with acromegaly, based on elevated levels of growth hormone, IGF-I
(a hormone made in response to growth hormone), and a pituitary adenoma visualized on an
MRI.
3. Patients would have already agreed to have their acromegaly treated with surgery prior
to study entry.
Subjects will have measurements of growth hormone using an oral glucose tolerance test
(OGTT), IGF-I, free IGF-I and levels of IGF binding proteins at four time points after their
pituitary surgery: Day 1, Day 42 (6 weeks), Day 84 (12 weeks), and day 365 (1 year). Subjects
will also have an MRI of the pituitary done at 12 weeks and 1 year. OGTT and IGF-I are
routinely measured to assess whether or not a person is cured of their acromegaly. An MRI of
the pituitary is routinely done at 12 weeks and 1 year after surgery to assess the results of
surgery. Free IGF-I and IGF binding proteins are not routinely measured after surgery, but
are being done to see if they relate more strongly to disease activity than IGF-I and growth
hormone.
OGTT and the IGF-I binding proteins are not routinely measured on the day after surgery, but
are being done to examine the predictive ability of these tests at a very early time after
surgery. Data obtained from these tests will be compared to the data gathered at the 1 year
time point.
IGF-I and growth hormone will be measured by a commercial clinical lab, Quest Diagnostics,
for clinical decision-making at the time of service. IGF-I and growth hormone will also be
measured using other methods to attempt to investigate the variability of these hormones when
different assays are used.
Description:
Acromegaly Overview
Acromegaly is a rare, insidious disorder characterized by excessive secretion of growth
hormone (GH) almost always from a pituitary adenoma. (Melmed NEJM 1990) Excess GH secretion
in turn leads to increased levels of insulin-like growth factor-I (IGF-I), which is primarily
responsible for the clinical manifestations of the disease. Features of acromegaly are
numerous and include acral and soft tissue growth, arthropathy, excessive sweating, glucose
intolerance, and carpal tunnel syndrome. Many patients have cardiomyopathy and hypertension
and the diagnosis of acromegaly carries with it an excessive morbidity and mortality related
to cardiovascular disease.
Therapy
The goals of therapy include management of the pituitary mass, control of symptoms of GH
excess, improvement in long term morbidity and mortality associated with GH excess, and
biochemical normalization of IGF-I and GH secretion without disruption of normal anterior
pituitary function. Treatment for acromegaly has generally included one or a combination of
three modalities, surgery, radiation and medication.
Classically, surgery has been the primary treatment modality with surgical cure being
dependent upon pituitary tumor size and the surgical expertise of the surgeon. In experienced
hands, transsphenoidal surgical resection of pituitary adenomas is a low risk procedure with
few peri-operative or long term complications. Published cure rates for microadenomas and
macroadenomas range from 39-91% and 12-71%, respectively. (Melmed S, Kleinberg DL, Williams
Textbook of Endocrinology.) Subjects who are not controlled with surgery alone require
additional therapy in the form of radiation or medication.
Medical therapy is the preferred choice of second line therapies and is available in multiple
forms including short and long acting somatostatin analog therapy aimed at reducing GH
secretion via the SSTR2 receptor, dopamine agonist therapy (effective in only about 10% of
patients) and pegvisomant, a GH receptor antagonist which lowers IGF-I levels but does not
decrease GH secretion or control tumor size.
Radiation therapy is available in multiple modalities and is an effective form of controlling
excessive GH secretion and tumor size. One drawback to radiation therapy is the length of
time needed for the therapy to take effect. GH secretion gradually declines over several
years and medical therapy is often needed to control GH secretion until radiation therapy has
taken effect. The major side effect of all forms of radiation therapy is hypopituitarism,
with approximately 50% of all subjects experiencing some form of hypopituitarism at 10 years.
Assessing Control
Since there is no well-defined clinical outcome to help establish if a patient is cured, the
assessment of disease activity has generally relied on arbitrary biochemical parameters.
These parameters include normalization of IGF-I when compared to age and gender matched
normal values and reducing the GH response to glucose suppression to less than 1mcg/L. The
level of GH suppression has evolved to the current level due to advances in the sensitivity
of the growth hormone assay. Previous values of greater than 1mcg/L were based on the use of
a less sensitive polyclonal radio-immunoassay (RIA) and have become obsolete with the
widespread use of far more sensitive monoclonal assays (chemiluminescent, immunoradiometric,
or immunoflourometric). Future improvements in GH assay sensitivity may alter the currently
held cutoff point of 1mcg/L to even lower levels, but the clinical significance of these
lower levels has yet to be established.
The amount of glucose used for the suppression of GH during an oral glucose tolerance test
(OGTT) has been either 75g or 100g, and there has been no data establishing the superiority
of one dose compared to the other. Recent consensus guidelines suggest the use of 75g of oral
glucose for the purposes of standardization (Giustina et al, 2000, JCEM, Vol 85: p526-9).
Long-Term Management
Long-term follow-up of subjects treated for their acromegaly has shown an improvement in
morbidity and mortality. Swearingen et al. (JCEM 1998 Vol. 83: p 3419-3426) showed that
patient-years with persistence of disease, as defined by normalization of IGF-I, carried with
it a 3.5 fold relative mortality risk compared to patient-years in remission using a Cox
proportional hazards model. They were also able to demonstrate that subjects who had achieved
control of their acromegaly showed similar survival rates to those in the general U.S.
population. These data underscore the benefits of achieving control of acromegaly and draws
attention to the need for accurate criteria for defining control and standardized methodology
of observation following treatment of acromegaly.
GH-IGF-I Discordance and the Risk For Recurrence
Other investigators (Freda et al, 2004, JCEM 89: 495-500) have found that some post-operative
subjects with acromegaly with normal IGF-I levels (age and gender matched) have persistently
abnormal nadir GH responses to OGTT (100g dextrose; nadir GH >0.14 mcg/L). These subjects had
an increased rate of disease recurrence when followed longitudinally as compared to
post-operative subjects with normal IGF-I and normal nadir GH responses to OGTT (GH < 0.14
mcg/L).
Abnormal GH responses to OGTT in the setting of normal IGF-I levels may not be reflective of
a "lack of cure" in subjects status-post surgical treatment for acromegaly. These subjects
may be secreting elevated amounts of GH due to a lack of inhibition by lower levels of IGF-I.
IGF-I levels may be considered normal in comparison to control data for the age and gender
matched populations; but may be either low for that particular individual, or lower than
IGF-I levels seen prior to treatment for acromegaly. In this setting, the IGF-I level is
considered low and the normal pituitary tissue responds by secreting excessive amounts of GH
in the absence of IGF-I suppression.
Recent data regarding the feedback mechanism responsible for GH release from pituitary
somatotroph cells supports what has long been theorized: that circulating levels of free
IGF-I, and not IGF-I bound to the IGF binding protein complex, suppress secretion of GH (Chen
JW et al., 2005, JCEM 90: 366-371.) Generally, measuring levels of free IGF-I has not added
any significant clinical data to the assessment of GH secretion in the diagnosis or
management of acromegaly. However, it has been suggested that in situations where there is
discordant information regarding the GH suppression in response to oral glucose and the
measurement of total IGF-I, that free IGF-I levels may be a better indicator of GH secretion
and bioactivity (Frystyk J, 2004, GH and IGF-I Research, 14: 337-75 and Feelders RA, 2005,
JCEM 90: 6480-6489.)
Hypothesis: Assessment of post-operative subjects with low-normal IGF-I but non-suppressed
nadir GH levels will show normalization over time with lower, normal nadir levels of GH in
response to OGTT. IGF-I levels could increase over time, but would still be considered normal
as compared to age and gender matched normal levels in subjects who are considered
"controlled." Rather than consider subjects with abnormal responses to OGTT in the setting of
low-normal IGF-I as "not cured" and at a higher risk for recurrence, these subjects may be
exhibiting compensatory elevation of GH in the absence of IGF-I suppression. Over time,
subjects with non-suppressed GH responses to OGTT and low-normal IGF-I would have lower GH
nadirs in response to OGTT and persistently normal (although possibly higher than the
post-operative initial assessment) IGF-I levels. This setting would be contrary to the
expected elevation of IGF-I above normal limits in the setting of excess GH secretion.
Objectives: The primary objective of this study will be to determine the natural course of
acromegaly treated with surgery in subjects with non-suppressed GH nadir values and normal
total IGF-I values. A second objective of the study will be to determine the reliability of
GH nadir to OGTT, free IGF-I, total IGF-I, and IGF binding proteins on post-operative day 1
in predicting long-term cure outcomes in acromegaly. A third objective will be to determine
inter-assay variability in the measurement of GH and IGF-I levels.
