The primary study objective is to assess the proportion of patients who remain within the IGF-I age adjusted normal limits with pasireotide LAR (60 mg) monotherapy, after 24 weeks of treatment.Secondary study objectives are assessment of the…
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients who remain within the IGF-I age adjusted normal
limits with pasireotide LAR (60 mg) monotherapy, after 24 weeks of treatment
(V4).
Secondary outcome
To assess the proportion of patients who remain within the IGF-I age adjusted
normal limits with pasireotide LAR (60 mg) monotherapy, after 48 weeks of
treatment (V8). Also the proportion of patients and the necessary dose of PEG-V
in patients with an IGF-I level within the age adjusted normal limits with
pasireotide LAR (60 mg) combined with PEG-V, after 48 weeks of treatment (V8).
Safety will be assessed based on: adverse events, clinical examination, vital
signs, glucose tolerance, EKG, standard hematology, biochemistry, endocrine
function tests, GH, PEG-V levels and liver function tests.
Background summary
Recent improvements in the medical treatment of acromegaly have 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 IGF-I and GH and thereby a reduction in long-term morbidity
and mortality [1]. PEG-V is currently considered to be the most effective
treatment of acromegaly, as monotherapy and in combination with long-acting
somatostatin analogs (LA-SRIF) for normalizing IGF-1 levels in acromegaly. In
our cohort the long-term efficacy of acromegaly patients using the combination
PEG-V and LA-SRIF was over 90% in terms of normalization of IGF-I, but it is
costly.
Pasireotide LAR (SOM230) is a novel multireceptor ligand somatostatin analog
with affinity for somatostatin receptor subtypes SSTR1-3 and SSTR5. Because
most GH-secreting pituitary adenomas express SST2 and SST5, pasireotide LAR is
potentially more effective than SSTR2-preferential somatostatin analogs like
octreotide LAR and lanreotide Autogel. A recent prospective, randomized, double
blind head-to-head superiority study in medically naïve acromegaly patients,
showed that after one year of treatment pasireotide LAR was about 60% more
effective in normalizing IGF-I levels than octreotide LAR (Colao 2014).
The combination pegvisomant with pasireotide LAR has not been studied yet. An
important advantage of this combination is the PEG-V sparing effect of
somatostatin analogues. PEG-V is an expensive drug; at a median dose of 80 mg
weekly it costs around ¤35.000 per year in Netherlands. Combining PEG-V with
pasireotide could result in a lower dose of pegvisomant needed and ultimately
in a more cost-effective treatment. However, the costs of pasireotide LAR are
not known yet. A secondary objective is to assess the effect of pegvisomant
addition on reducing the incidence of hyperglycemia in pasireotide LAR. Due to
its anti-insulin resistances effects PEG-V may be an attractive option.
References
1. Colao, A., et al., Pasireotide versus octreotide in acromegaly: a
head-to-head superiority study. J Clin Endocrinol Metab, 2014: p. jc20132480.
Study objective
The primary study objective is to assess the proportion of patients who remain
within the IGF-I age adjusted normal limits with pasireotide LAR (60 mg)
monotherapy, after 24 weeks of treatment.
Secondary study objectives are assessment of the proportion of patients who
remain within the IGF-I age adjusted normal limits with pasireotide LAR (60 mg)
monotherapy, after 48 weeks of treatment. Also the proportion of patients and
the necessary dose of PEG-V in patients with an IGF-I level within the age
adjusted normal limits with pasireotide LAR (60 mg) combined with PEG-V, after
48 weeks of treatment.
To assess the other efficacy parameters and safety of pasireotide LAR 60 mg
administration during combination and monotherapy.
Study design
Single-centre prospective open-label intervention study
Intervention
The interventions include reduction of the weekly pegvisomant dose by 50% for
12 weeks. When IGF*I remains within the age adjusted normal limits after 12
weeks, PEG-V and the LA-SRIF are discontinued and patients are switched to
pasireotide LAR 60 mg for 12 weeks.
When IGF-I rises above the adjusted normal limits after 12 weeks, these
subjects will switch their LA-SRIF to pasireotide LAR 60 mg every 4 weeks and
continue with the reduced PEG-V dose of the run in phase, for the remaining 12
weeks. Between week 12 and 24 no dose adaptations of PEG-V are permitted for
efficacy reasons.
From week 24 patients will continue with pasireotide LAR 60 mg monotherapy, or
pasireotide will be combined with 50% of the original dose of PEG-V, or with an
increasing dose of PEG-V every 8 weeks depending on the treatment arm.
Study burden and risks
Pasireotide LAR (SOM230 LAR) has a similar safety profile as currently used
long-acting somatostatin analogs (Lanreotide Autogel and Sandostatin LAR), i.e.
the most commonly reported adverse events are transient gastrointestinal
disturbances and local injection site reactions. Although at the start of
treatment, hyperglycemia-related events seem to occur more frequently in the
subcutaneous (short-acting) formulation of pasireotide, this does not seem to
be case with pasireotide LAR.
Furthermore, it is known that if patients who already are treated with
somatostatine analogues switch to a different somatostatin analogue that they
generally experience fewer side effects due to desensitization.
There is no information in the literature on the safety of the combination of
pasireotide with pegvisomant. It is possible that the same side effects occur
as in monotherapy with a possible reduced risk of hyperglycemia due to the
anti-insulin resistance effects of pegvisomant.
The possible benefits entail a treatment with Pasireotide LAR alone or
reduction of the pegvisomant dose during combination with pasireotide LAR. This
will lead to an improvement in the quality of life of patients because they
need fewer number of injections and they have a lower risk of developing
hyperglycemia.
's Gravendijkwal 230
Rotterdam 3000CA
NL
's Gravendijkwal 230
Rotterdam 3000CA
NL
Listed location countries
Age
Inclusion criteria
• Written informed consent male or female aged >= 18 years
• Documentation supporting the diagnosis of acromegaly based on elevated GH and/or IGF-I levels due to a pituitary tumor
• The patient is treated with lanreotide Autogel or octreotide LAR and PEG-V (twice) weekly for at least 6 months and has a serum IGF-I level within 120 % of the age adjusted normal limits. These patients were previously not controlled by somatostatin analogs alone.
• Female of no childbearing potential or male. No childbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired) or using two acceptable contraceptive measures, except for oral contraceptives.
• Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use a medically accepted, effective method of contraception (i.e. use a condom) for the duration of the study
• Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.
Exclusion criteria
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 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 3 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 < 50 ml/min.
Poorly controlled Diabetes Mellitus with an HbA1c & ggt; 9.0%.
Patients with a QTc > 500 ms on the EKG.
Participation in a clinical trial in the last 6 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 |
|---|---|
| EudraCT | EUCTR2014-002219-41-NL |
| CCMO | NL49517.078.14 |
| OMON | NL-OMON26386 |