Primary:*To identify the maximum tolerated dose (MTD) and to investigate the pharmacokinetics (PK) of a single dose of lanreotide PRF in subjects with acromegalySecondary:*To investigate the safety and tolerability of a single dose of lanreotide PRF…
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety variables:
* AEs, throughout the study.
* Vital signs (supine and standing blood pressure and heart rate, and body
temperature) at Screening, Baseline (predose on Day 1), 6 and 24 hours
postdose, and at Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the treatment period.
* Physical examination at Screening, Baseline (predose on Day 1), 6 and 24
hours postdose, and at Weeks 2, 3, 4, 5, 7, 9, 11 and 13 of the treatment
period.
* 12 lead ECG, QTc interval will be calculated using Fridericia methodology in
all subjects at Screening, Baseline (predose on Day 1), 6 hours postdose on Day
1, 24 hours postdose, and at Weeks 2, 5 and 13.
* Clinical laboratory assessments: haematology, coagulation, clinical
biochemistry, urinalysis at Screening, Baseline (predose on Day 1), 6 hours
postdose on Day 1, Day 3, and Weeks 2, 3, 4, 5, 9 and 13 of the treatment
period.
* HbA1c at Screening and Week 13.
* Estimated glomerular filtration rate (eGFR) estimated by the Modification of
Diet in Renal Disease (MDRD) formula [1], at Screening, Baseline (predose on
Day 1), and Weeks 2, 5, 9 and 13 of the treatment period.
* Gallbladder echography at Screening, Week 5 and Week 13 of the treatment
period.
* Putative antibodies to lanreotide at Baseline (predose on Day 1) and Week 13.
* Evaluation of injection site reactions (appearance, local symptoms). These
will be evaluated on a specific form in the electronic case report form (eCRF)
at 1 and 6 hours postdose on Day 1, 24 hours postdose and at Weeks 2, 3, 4, 5,
7, 9, 11 and 13 of the treatment period.
Pharmacokinetic variables:
Lanreotide serum concentration at the following timepoints after administration
of lanreotide PRF:
* Baseline (predose on Day 1 of lanreotide PRF administration).
* At 1, 2, 4, 6, 8 and 12 hours postdose on the day of dosing (Day 1).
* At 24 hours postdose (Day 2).
* On Days 3 and 5, and at Weeks 2, 3, 5, 9 and 13 after lanreotide PRF
administration (the Week 13 sample will be on Day 85 and will correspond to the
concentration at the end of the dosing interval (Ctrough)).
* Noncompartmental analysis will be performed and the following PK parameters
will be computed: Ctrough, maximum serum concentration (Cmax), time to maximum
serum concentration (Tmax), area under the serum concentration time curve from
time 0 to 85 days (AUC0 85), area under the concentration time curve
extrapolated to infinity (AUC0 *), apparent terminal half life (t1/2), mean
residence time (MRT), apparent clearance (CL/F) and apparent volume of
distribution (V/F).
Excipient serum concentration at the following timepoints:
* Baseline (predose on Day 1 of lanreotide PRF administration).
* At 1, 2, 4, 6, 8 and 12 hours postdose on the day of dosing (Day 1), at 24
hours postdose (Day 2), and on Days 3 and 5 after lanreotide PRF administration.
* Noncompartmental analysis of the excipient time concentration data will be
performed and the following PK parameters will be computed: Cmax, Tmax, area
under the serum concentration time curve from time 0 to last quantifiable
timepoint (AUCt), AUC0 *, t1/2, MRT, CL/F and V/F.
Secondary outcome
Pharmacodynamic variables:
The following PD variables will be assessed in all subjects:
* IGF 1 at Screening, Baseline (predose on Day 1), at 6 hours postdose on the
day of dosing (Day 1) and at Weeks 5, 9 and 13.
* GH cycle (five sampling times with a sample every 30 minutes for 2 hours in
the morning) at Screening, Baseline (predose on Day 1) and at Weeks 5 and 13.
* Random GH sample at 6 hours postdose on the day of dosing (Day 1) and at Week
9.
* Free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating
hormone (TSH) and prolactin (PRL) at Screening, Baseline (predose on Day 1),
and at Weeks 2, 5 and 13 of the treatment period.
Background summary
Acromegaly is a rare (incidence approximately 3 cases per million persons per
year; prevalence approximately 60 per million), chronic disease caused by
excessive secretion of growth hormone (GH) from a pituitary tumour. Increased
plasma levels of GH cause the symptoms and pathology of the disease, either
directly through actions on target tissues, or indirectly by stimulating
excessive secretion of insulin like growth factor 1 (IGF 1).
Disease control of acromegaly consists of different components: biochemical
control, tumour volume reduction and improvement of clinical symptoms. GH and
IGF 1 concentrations are the main biochemical markers used to measure the
response to treatment and represent the most frequent primary endpoints in
clinical trials that evaluate efficacy. Both GH and IGF 1 responses have been
associated with improved prognosis and mortality decrease.
The treatment of choice is trans sphenoidal surgery, sometimes in association
with radiotherapy. However, despite these measures acromegaly remains active in
many patients, as defined by increased systemic levels of GH and IGF 1, the
persistence of clinical symptoms, and increased morbidity and mortality. For
example, between 40% and 60% of macroadenomas are unlikely to be controlled
with surgery alone. Primary medical therapy or surgical debulking followed by
medical therapy and/or radiation therapy are options for treatment of such
tumours.
Somatostatin analogues (SSTa) successfully reduce GH and IGF 1 secretion in
approximately 70% of patients. They alleviate many symptoms of acromegaly,
improve related comorbid complications, and may reduce or stabilise tumour size
in a subset of patients.
Compared to short acting SSTa, long acting formulations have been shown to
provide equivalent or better control of acromegaly. The main adverse events
(AEs) associated with SSTa are gastrointestinal disorders, including abdominal
cramps and an increased incidence of gallbladder sludge and/or stones.
Study objective
Primary:
*To identify the maximum tolerated dose (MTD) and to investigate the
pharmacokinetics (PK) of a single dose of lanreotide PRF in subjects with
acromegaly
Secondary:
*To investigate the safety and tolerability of a single dose of lanreotide PRF
*To investigate the pharmacodynamics (PD) of a single dose of lanreotide PRF
*To investigate the PK of the excipient
Exploratory:
Biobanking of blood samples for further biomarkers analysis in subjects who
consent to the exploratory part of the study
Study design
This is an open label, dose ascending study to assess the PK, PD, safety and
tolerability of a single dose of lanreotide PRF. Doses of 180 mg, 270 mg and
360 mg will be investigated in adults with acromegaly previously treated and
controlled with a stable dose of either octreotide LAR or lanreotide Autogel.
The study consists of a 4 week run in period, followed by a 12 week treatment
period, and then a 12 week follow up period.
Intervention
Eligible subjects will enter a 4 week screening period, during which they will
receive the same single dose of either octreotide LAR or lanreotide Autogel as
their previous treatment (Day *28). A 12 week treatment period will then
commence, during which subjects will receive one deep subcutaneous injection of
lanreotide PRF on Day 1 (4 weeks after the last octreotide LAR administration).
It is planned to include three cohorts of subjects; Cohort 1 will receive
lanreotide PRF 180 mg, Cohort 2 will receive 270 mg and Cohort 3 will receive
360 mg.
Study burden and risks
The study overall has more frequent clinic visits and more comprehensive
monitoring compared with normal clinical practice. Screening (Visit 1) involves
patient interview, a physical exam, a 12 lead ECG, venepuncture (fasting),
urine collection and Gallbladder echography The main burden falls on the day
of study drug administration (Visit 2) where hospitalization for 24 hours and
serial venepuncture is required. Procedures at subsequent clinic visits
(treatment and follow-up) will be of less burden for the patients. The side
effects associated with the study medication are well characterized, and
patients will be monitored carefully for injection site reactions. The study
burden and risks are balanced by the potential for extended (up to 12 weeks)
relief from or lessening of the signs and symptoms of acromegaly.
quai George Gorse 65
Boulogne Billancourt 92650
FR
quai George Gorse 65
Boulogne Billancourt 92650
FR
Listed location countries
Age
Inclusion criteria
All subjects must fulfil all of the following criteria to be included in the study:
- Documented diagnosis of acromegaly.
- Provided written informed consent prior to any study related procedures.
- Between 18 and 75 years of age inclusive.
- Female of nonchildbearing potential or male. Nonchildbearing potential is defined as being postmenopausal for at least 1 year, or women with documented infertility (natural or acquired).
- 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. condom) for the duration of the study (up to 7.5 months).
- Treatment with a stable dose of either octreotide LAR or lanreotide Autogel for at least 3 months immediately prior to study entry, with confirmation of disease control during this treatment period (documentation of age adjusted IGF-1 < 1.3 x upper limit of normal (ULN), based on local lab results, during Screening period).
- If the subject is receiving treatment for hypertension, the dose has been stable for at least 1 month prior to study entry.
- 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
Subjects will not be included in the study if the subject:
- Has undergone radiotherapy within 2 years prior to study entry.
- Has been treated with a dopamine agonist and/or GH receptor antagonist or has undergone pituitary surgery within 3 months prior to study entry.
- Is anticipated to require pituitary surgery or radiotherapy during the study.
- Has clinically significant hepatic abnormalities and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) *3 x ULN and/or alkaline phosphatase (AP) *2.5 x ULN and/or total bilirubin *1.5 x ULN and/or gamma-glutamyl transpeptidase (GGT) *2.5 x ULN during the Screening period (central laboratory results) or a history of these findings when on somatostatin analogue (SSTa) treatment.
- Has clinically significant pancreatic abnormalities and/or amylase and/or lipase *1.5 x ULN during the Screening period (central laboratory results).
- Has any significant renal abnormalities and/or creatinine *1.5 x ULN during the Screening period (central lab results).
- Has uncontrolled diabetes (glycosylated haemoglobin (HbA1c) *9%, centrally assessed during the Screening period), or has diabetes treated with insulin for less than 6 months prior to study entry.
- Has any known uncontrolled cardiovascular disease or had any of the following within 6 months of Screening: ventricular or atrial dysrhythmia *grade 2, bradycardia *grade 2, electrocardiogram (ECG) QT interval corrected (QTc) prolonged *grade 2, myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, hypertension not adequately controlled by current medications.
- Use of any hormone replacement therapy (HRT) with oestrogens.
- Has symptomatic gallstones/sludge at the Screening Visit echography (local assessment) OR is asymptomatic but has echography showing clear evidence of impending inflammation such as localized mucosal thickening suggesting the subject is at high risk of developing acute disease. Subjects with asymptomatic gallstones/sludge and otherwise normal echography may be entered at the discretion of the investigator.
- Has abnormal findings during the Screening period, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject*s safety.
- Has been treated with any other investigational medicinal product (IMP) prior to the first study visit without undergoing a washout period of seven times the elimination half life of the investigational compound.
- Has a known hypersensitivity to any of the test materials or related compounds.
- Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
- Has a history of, or known current, problems with alcohol or drug abuse.
- Has any mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002389-62-NL |
| CCMO | NL51243.078.14 |