Peri- and Post-operative Dynamics of the Growth Hormone Axis in Subjects With Acromegaly During the First Year After Surgical Resection

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Brief Title

Peri-operative Dynamics of the Growth Hormone Axis in Subjects With Acromegaly

Official Title

A Study Examining the Peri- and Post-operative Dynamics of the GH-IGF-1 Axis in Subjects With Acromegaly During the First Year After Surgical Resection

Brief 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.
    

Detailed 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.
    


Study Type

Observational


Primary Outcome

Correlation of normalization of Growth hormone postoperatively with 1 year remission rates

Secondary Outcome

 Predictor of remission

Condition

Acromegaly

Intervention

Oral glucose tolerance test

Study Arms / Comparison Groups

 Acromegaly patients
Description:  All patients will undergo oral glucose tolerance test at postoperative day 1, 6 weeks, 3 months, and 1 year

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

20

Start Date

June 2006

Completion Date

December 2021

Primary Completion Date

December 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Male or Female age 18-90

          -  Diagnosed with acromegaly from a pituitary adenoma visualized by MRI, and with
             elevated IGF-1 levels compared to age and gender matched control values and nadir GH
             response to OGTT>1mg/L

          -  Having already agreed to undergo surgical resection of their pituitary adenoma prior
             to study entry

          -  Must provide informed consent

        Exclusion Criteria:

          -  Inability to complete the protocol due to intercurrent medical or psychiatric illness

          -  Pregnant or breastfeeding

          -  Use of insulin

          -  Use of estrogen, progesterone, testosterone or thyroid hormone will be allowed as long
             as the dose is stable during the study
      

Gender

All

Ages

18 Years - 90 Years

Accepts Healthy Volunteers

No

Contacts

Odelia Cooper, MD, 424-315-4489, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00921609

Organization ID

8997


Responsible Party

Principal Investigator

Study Sponsor

Cedars-Sinai Medical Center


Study Sponsor

Odelia Cooper, MD, Principal Investigator, Cedars-Sinai Medical Center


Verification Date

July 2020