Primary Study Objective:To assess the efficacy and safety of the co-administration of low-dose pegvisomant (40 mg, administered via subcutaneous injection given once a week) and long-acting somatostatin analogs (administered once monthly) on the…
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
change in the AcroQol-physical score at the end of the treatment period
Secondary outcome
Secondary Study Objectives:
To assess the effect of low-dose pegvisomant co-administration on:
* Total body water / body weight.
* Blood pressure
* HbA1c
* BNP levels
* Ring-size
* IGF-I levels
* Safety based on:
* Adverse events, clinical examination, vital signs
* Glucose tolerance
* Standard hematology and biochemistry, including liver function tests
Background summary
Recent improvements in the medical treatment of acromegaly has resulted in
better biochemical disease control in virtually every acromegaly patient. The
current consensus on the goals of treatment of acromegaly has focused on
normalization of IGF1 and GH and thereby a reduction in long-term morbidity and
mortality [1-2]. However, normalization of levels of total serum IGF1 and GH do
not necessarily reflect optimal quality of life (QoL) nor relief of symptoms,
in acromegalic patients [3-7]. From the patient*s perspective an important
parameter of disease control is QoL. To quantify the symptoms and QoL in
patients with acromegaly, the Patient-Assessed Acromegaly Symptom Questionnaire
(PASQ) [8-9] and the Acromegaly Quality of Life Questionnaire (AcroQoL) have
been developed [10]. In a prospective, double-blind, placebo-controlled,
crossover trial QoL was assessed by AcroQoL and PASQ to assess the effects of
the addition of a weekly low dose of pegvisomant in patients with acromegaly
whose levels of IGF1 were within the age-adjusted normal limits during
long-term SRIF analog therapy [11]. After 16 weeks of treatment with 40 mg
pegvisomant weekly, the patients' quality of life improved, as indicated by
increases in the AcroQoL total score and the AcroQoL score's physical
dimension. These improvements were accompanied by a reduction in the total PASQ
score and in improvement of perspiration, soft-tissue swelling and overall
health status. Moreover, these symptoms; perspiration and soft-tissue swelling
can also be provoked during overdosing GH treatment in patients with GH
deficiency.
The improvements in patients' quality of life, and signs and symptoms of
acromegaly were not accompanied by a significant decrease in IGF1 level. Only
change in body weight correlated with the improvement in the AcroQoL score's
physical dimension, but the treatment-related decrease in body weight was not
significant. The pegvisomant-related improvement in patients' quality of life
might be also explained by the mode of action of somatostatin analogs.
Somatostatin analogs reduce portal insulin concentration and the number of
available growth hormone receptors in the liver, and can directly inhibit IGF1
production by hepatocytes. These mechanisms suggest that whereas the liver
becomes relatively resistant to growth hormone during somatostatin analog
treatment, acromegalic symptoms still persist in other parts of the body. One
might expect that treatment of this 'extrahepatic acromegaly' with low-dose,
weekly pegvisomant could improve the growth-hormone-dependent signs and
symptoms and the patient's quality of life. The observed improvement in quality
of life with combination therapy calls into question the widely used step-up
approach, according to which patients are only treated with pegvisomant if
somatostatin analog monotherapy is not able to normalize IGF1 levels.
Although in some individuals IGF1 levels clearly decreased during PEG-V
co-treatment, for the whole group, IGF1 did not decrease significantly. This
observation might be explained by an observation by Segev et al. [12], who
reported that a GH receptor antagonist in rodents was able to block (in this
case, renal) GH actions at lower concentrations than were necessary to decrease
serum IGF1 and somatic growth. However, our study was powered to detect a
difference in PASQ score and not designed to detect a difference in IGF1.
Therefore, it is possible that studies in larger populations will observe a
significant decrease.
The improvement in QoL can not be explained by a recall phenomenon of the
questions. Our study assessed QoL over a 4-month period and it is
internationally accepted that in
most studies, a 2-wk period between test and retest is enough to circumvent the
memory effect [13-14].
Therefore we would like to conduct a study in a large group of patients. To
assess the efficacy and safety of the co-administration of low-dose pegvisomant
(40 mg, administered via subcutaneous injection given once a week) and
long-acting somatostatin analogs (administered once monthly) on the Quality of
Life over 16 weeks in 40 acromegalic patients.
The primary endpoint will be the change in the AcroQol-physical score at the
end of the treatment period.
Secondary Study Objectives:
To assess the effect of low-dose pegvisomant co-administration on:
Total body water / body weight, Blood pressure, HbA1c, BNP levels, Ring-size
and IGF-I levels.
Safety based on: Adverse events, clinical examination, vital signs, Glucose
tolerance, Standard hematology and biochemistry and including liver function
tests.
References:
1. Biochemical assessment and long-term monitoring in patients with acromegaly:
statement from a joint consensus conference of the Growth Hormone Research
Society and the Pituitary Society (2004). The Journal of clinical
endocrinology and metabolism 89 (7):3099-3102
2. Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis
J, Wass J, Von Werder K, Melmed S (2000) Criteria for cure of acromegaly: a
consensus statement. The Journal of clinical endocrinology and metabolism 85
(2):526-529
3. Biermasz NR, Dekker FW, Pereira AM, van Thiel SW, Schutte PJ, van Dulken H,
Romijn JA, Roelfsema F (2004) Determinants of survival in treated acromegaly in
a single center: predictive value of serial insulin-like growth factor I
measurements. The Journal of clinical endocrinology and metabolism 89
(6):2789-2796
4. Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F (2005) Morbidity
after long-term remission for acromegaly: persisting joint-related complaints
cause reduced quality of life. The Journal of clinical endocrinology and
metabolism 90 (5):2731-2739
5. Bonapart IE, van Domburg R, ten Have SM, de Herder WW, Erdman RA, Janssen
JA, van der Lely AJ (2005) The 'bio-assay' quality of life might be a better
marker of disease activity in acromegalic patients than serum total IGF-I
concentrations. European journal of endocrinology / European Federation of
Endocrine Societies 152 (2):217-224
6. Hua SC, Yan YH, Chang TC (2006) Associations of remission status and
lanreotide treatment with quality of life in patients with treated acromegaly.
European journal of endocrinology / European Federation of Endocrine Societies
155 (6):831-837
7. Rowles SV, Prieto L, Badia X, Shalet SM, Webb SM, Trainer PJ (2005) Quality
of life (QOL) in patients with acromegaly is severely impaired: use of a novel
measure of QOL: acromegaly quality of life questionnaire. The Journal of
clinical endocrinology and metabolism 90 (6):3337-3341
8. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely
AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA,
Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC,
Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S,
Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S,
Zib K, Bennett WF, Davis RJ (2000) Treatment of acromegaly with the growth
hormone-receptor antagonist pegvisomant. The New England journal of medicine
342 (16):1171-1177
9. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L,
Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend
KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ,
Hackett S, Zib KA, Davis RJ, Scarlett JA, Thorner MO (2001) Long-term treatment
of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet
358 (9295):1754-1759
10. Webb SM, Prieto L, Badia X, Albareda M, Catala M, Gaztambide S, Lucas T,
Paramo C, Pico A, Lucas A, Halperin I, Obiols G, Astorga R (2002) Acromegaly
Quality of Life Questionnaire (ACROQOL) a new health-related quality of life
questionnaire for patients with acromegaly: development and psychometric
properties. Clinical endocrinology 57 (2):251-258
11
Study objective
Primary Study Objective:
To assess the efficacy and safety of the co-administration of low-dose
pegvisomant (40 mg, administered via subcutaneous injection given once a week)
and long-acting somatostatin analogs (administered once monthly) on the Quality
of Life over 16 weeks in 40 acromegalic patients.
The primary endpoint will be the change in the AcroQol-physical score at the
end of the treatment period.
Secondary Study Objectives:
To assess the effect of low-dose pegvisomant co-administration on:
* Total body water / body weight.
* Blood pressure
* HbA1c
* BNP levels
* Ring-size
* IGF-I levels
* Safety based on:
* Adverse events, clinical examination, vital signs
* Glucose tolerance
* Standard hematology and biochemistry, including liver function tests
Study design
This will be a multicentre, randomized double blind parallel study
Intervention
Treatment with Pegvisomant 40 mg weekly or placebo
Study burden and risks
there are little to no site effect with the administration of pegvisomant.
Other procedures are the same for every acromegaly patient, who visits the out
patients clinic
's-Gravendijkwal 230
rotterdam 3015CE
NL
's-Gravendijkwal 230
rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
Acromegalic patients will be recruited in order to ensure 40 evaluable patients will enter the co-treatment period. All subjects should previously be treated with somatostatin analogues during which treatments their IGF-I levels should have normalized.
Inclusion criteria:
All patients must fulfill the following:
At the screening visit,
* Provision of written informed consent prior to any study related procedures.
* Male or female aged between 18 and 75 years inclusive
* The patient must have had documentation supporting the diagnosis of acromegaly based on elevated GH and/or IGF-1 levels.
* The patient is treated with lanreotide Autogel or octreotide LAR for at least 6 months and has a serum IGF-1 level above the 60th percentile and below ULN, 28 days after the last injection.
Exclusion criteria
Patients will not be included in the study if he/she:
* Has undergone pituitary surgery or radiotherapy within 6 months prior to study entry.
* It is anticipated that the patient will receive pituitary surgery or radiotherapy during the study.
* Has a history of hypersensitivity to lanreotide, octreotide or pegvisomant or drugs with a similar chemical structure.
* Has already been treated with a somatostatin analogue associated with pegvisomant.
* Has received a dopamine agonist within 6 weeks prior to study entry.
* Has been treated with any unlicensed drug within the last 30 days before study entry.
* Has abnormal hepatic function at study entry (defined as AST, ALT, gGT, alkaline phosphatase, or total bilirubin above 2 ULN).
* Is at risk of pregnancy or is lactating. Females of childbearing potential must provide a negative pregnancy test within 5 days before the start of the study and must be using contraception. Non-childbearing potential is defined as post-menopause for at least one year, surgical sterilization or hysterectomy at least three months before the start of the study.
* Has a history of, or known current, problems with alcohol or drug abuse.
* Has a mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
* Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject*s safety or decrease the chance of obtaining satisfactory data needed to achieve the objective(s) of the study.
* Renal insufficiency, clearance < 60 ml/min
* Participation in a clinical trail in the last 12 months
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| Other | 3032 |
| EudraCT | EUCTR2011-004231-31-NL |
| CCMO | NL37992.078.11 |
| OMON | NL-OMON24622 |