* To assess maintenance of biochemical control of octreotide capsules compared to parenteral SRLs in patients with acromegaly, who previouslydemonstrated biochemical control on both treatments.* To assess symptomatic response to octreotide capsules…
ID
Source
Brief title
Condition
- Hypothalamus and pituitary gland disorders
- Endocrine neoplasms benign
- Nervous system neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients who are biochemically controlled throughout the RCT
phase. A patient will be considered biochemically controlled if their IGF-1
Time Weighted Average (TWA), during the RCT phase is < 1.3 x ULN.
Secondary outcome
* Proportion of patients with clinical and biochemical response at the end of
the RCT phase (week 62/End of Treatment; EOT). Patients will be considered
controlled if they meet both of the following criteria:
- Biochemically controlled if their IGF-1 TWA during the RCT phase is < 1.3 x
ULN;
- Clinical control defined as maintained or reduced Acromegaly Symptoms - Index
of Severity (AIS) score at week 62/EOT as compared to week 26 (start of RCT).
* Proportion of patients who maintain or reduce the overall number of active
acromegaly symptoms, at the end of the RCT phase (week 62/EOT), compared to
week 26 (start of RCT).
* Proportion of patients who maintain or improve their overall AIS score at the
end of the RCT phase (improvement defined as a reduction of at least one point
in the AIS score), compared to week 26 (start of RCT)
* Acromegaly treatment satisfaction questionnaire (ACRO-TSQ) at the end of the
RCT phase.
* Proportion of patients of those completing the RCT phase (at a time
octreotide capsules were not commercially available at the specific country),
who enter the Study Extension phase, overall and by treatment group.
* Change from the start of the randomized phase of the study (week 26) through
the end of the RCT (week 62) for IGF-1.
* Change from the start of the randomized phase of the study (week 26) to end
of the RCT (week 62) in mean integrated GH.
Background summary
Acromegaly is a rare disorder of disproportionate skeletal, tissue, and organ
growth arising from hypersecretion of growth hormone (GH) and insulin-like
growth factor 1 (IGF-1). The elevated GH and IGF-1 levels lead also to a wide
range of cardiovascular, respiratory, endocrine, and
metabolic co-morbidities. In over 95% of cases the etiology is attributed to
GH-producing benign pituitary adenoma (Ben-Shlomo and Melmed, 2008; Melmed,
2009; Melmed et al., 2009).
Treatment options for acromegaly include surgical resection of the pituitary
adenoma, radiotherapy, and drug therapy to reduce GH and IGF-1 levels to normal
values. Currently, there are three drug classes available for the treatment of
acromegaly: somatostatin receptor ligands
(SRLs) or somatostatin analogs (octreotide, lanreotide and pasireotide),
dopamine agonists (bromocriptine and cabergoline), and a GH receptor antagonist
(pegvisomant) (Melmed et al., 2009; Melmed et al., 2014). SRLs are, at present,
the most widely used drugs to control acromegaly.
Chiasma has developed octreotide capsules, a new formulation of octreotide for
oral delivery. It is an enteric coated capsule filled with an oily suspension
of unmodified octreotide formulated with transient permeability enhancer
(TPE®)1 excipients. The enteric coating allows the intact
capsule to pass through the stomach and disintegrate when it reaches the higher
pH of the small intestine to discharge octreotide capsules suspension.
Study objective
* To assess maintenance of biochemical control of octreotide capsules compared
to parenteral SRLs in patients with acromegaly, who previously
demonstrated biochemical control on both treatments.
* To assess symptomatic response to octreotide capsules compared to parenteral
SRLs.
* To assess patient reported outcome (PRO) in patients treated with octreotide
capsules compared to parenteral SRLs.
* To evaluate the safety profile of octreotide capsules compared to parenteral
SRLs.
Combination phase sub-study (in selected sites) objective:
* To assess the efficacy of octreotide capsules co-administered with
cabergoline in the treatment of acromegaly patients with modestly elevated
IGF-1 levels (defined as 1.3 * IGF-1 <2 × ULN).
Study design
This will be a phase 3, randomized, open-label, active controlled, multicenter
study to evaluate maintenance of response, safety and patient reported outcomes
(PROs) in acromegaly patients treated with octreotide capsules and in patients
treated with SOC parenteral SRLs, who previously tolerated and demonstrated
biochemical control on both treatments.
The core study will consist of three phases: a Screening phase, Run-in phase
and an RCT phase.
Suitable patients enter the Study Extension treatment phase which will continue
until the date when the study medication becomes commercially available in the
applicable region or country or when the Sponsor decides to terminate the study.
A Steering Committee (SC) will act in an advisory capacity to the Sponsor to
provide oversight to the trial conduct and to support its successful completion.
An Independent Data Monitoring Committee (IDMC) will act in an advisory
capacity to the Sponsor to monitor patient safety during the study.
For a more explicit explanation of the study design see 'Intervention' section.
Intervention
Following up to 4-weeks Screening phase, eligible patients who are
biochemically controlled (defined as IGF-1 < 1.3 × ULN and mean integrated GH
<2.5 ng/mL), on parenteral SRLs will be switched to octreotide capsules for a
26-week Run-in phase. During this phase the effective dose for each patient
will be determined through dose titration (see Run-in phase below).
Patients whose acromegaly is been controlled biochemically on octreotide
capsules at the end of the Run-in Phase will enter a 36-week open-label RCT
phase where they will be randomized to continue on octreotide capsules or
switch back to their injectable SRL treatment (as received prior to Screening)
or other treatment as determined by their physician. Following the completion
of the core study (Screening, Run-in and RCT phases), eligible patients will be
offered to enter the Study Extension phase and receive octreotide capsules
until product marketing or study termination.
Patients who fail to respond to octreotide capsules 80 mg for at least two
weeks therapy during the course of the Run-in phase, or patients ineligible to
enter the RCT phase on octreotide capsules 80 mg, due to in-adequate
biochemical control, with IGF-1 * 1.3 × ULN to IGF-1 <2 × ULN), will be
eligible to enter the Combination phase sub-study (in selected sites). These
patients will receive co-administration of octreotide capsules (80 mg/day) with
cabergoline (up to 3.5 mg/week) for a total of 24 weeks. At the end of the
Combination phase sub-study eligible patients will be offered to enter the
Study Extension phase and continue the same combined treatment regimen.
Patients discontinuing early from the Combination phase sub-study (not executed
in NL) or all other patients not meeting the criteria for randomization into
the RCT phase or Combination phase sub-study will revert to their prior
injectable SRL treatment (prior to Screening) or other treatment as determined
by their physician, and be followed for 12 weeks after last dose.
Patients who early terminate the Run-in phase for any reason in sites who do
not participate in the Combination phase sub-study (in selected sites) will
revert back to their injectable SRL treatment (prior to Screening) or other
treatment as determined by their physician and will be followed up for 12 weeks
after last dose of study medication.
Study burden and risks
Side effects with octreotide capsules are consistent with the known safety
profile of octreotide but with no injection site reactions. No new AEs related
to the new formulation or change in route of administration were identified in
the clinical (and non-clinical) development program.
The most common body systems (system organ class) associated with the reported
AEs were gastrointestinal disorders, nervous system disorders, and
musculoskeletal and connective tissue disorders, consistent with the known
safety profile of octreotide.
The following side effects, according to how common or rare they are, may be
caused by oral octreotide in this study:
Common (occurs in more than 10 out of 100 patients): nausea, diarrhea,
headache, pain in your joints, weakness, swollen feet and ankles, excessive
sweating.
Less Common (occurs in 1-10 out of 100 patients): iIndigestion, excessive gases
in your stomach, abdominal pain, abdominal distension, vomiting, feeling
faint,* fatigue, common cold, influenza, upper respiratory tract infection.
In completed studies, side effects related to the digestive system usually
started within 8 weeks of start of treatment, and lasted for a short time.
Four patients had serious side effects (requiring hospitalization) that were
assessed as possibly related to octreotide capsules. 3 had bile stones and one
patient had jaundice (yellowing of the skin) and increased liver enzymes
(indicative of damage to liver cells). These side effects have also been
reported with octreotide injections. It is not known if these side effects are
more or less frequent with octreotide capsules compared to octreotide
injections.
The risk/side effects that have been observed with the use of cabergoline
include:
Occurs in more than 1 out of 100 patients: nausea, headache, dizziness,
constipation, weakness/lack of energy, fatigue, abdominal pain,
drowsiness/sleepiness, head rush/dizzy spell, depression, intense or unusual
urges.
POSSIBLE RISKS AND DISCOMFORT ASSOCIATED WITH DRAWING BLOOD
During this study, small amounts of blood will be drawn from a vein and used
for tests that allow study doctors to see how patients are doing. Drawing
blood may cause pain where the needle is inserted, and there is a small risk of
bruising or infection at the place where the needle is inserted. Some people
experience dizziness, upset stomach, or fainting when their blood is drawn.
REPRODUCTIVE (ABILITY TO HAVE CHILDREN) RISKS
Men able to father a child must agree to use birth control methods.
Women who can become pregnant must have a blood test that shows they are not
pregnant before they can be enrolled in this study. They will also have
pregnancy blood tests when they come to the clinic for their study visit at the
end of each study part. If they can become pregnant, they must agree to use
birth control methods.
Wells Avenue, Suite 102 60
Newton 02459
US
Wells Avenue, Suite 102 60
Newton 02459
US
Listed location countries
Age
Inclusion criteria
1. Adult subjects, aged 18 to 75 years old, inclusive, at the Screening visit.;2. Patients with acromegaly, defined as documented evidence of GH-secreting pituitary tumor that is abnormally responsive to an oral glucose tolerance test or abnormal IGF-1 levels (>1 x ULN), any time in the past, who are currently receiving parenteral SRLs (octreotide or lanreotide but not pasireotide) for at least 6 months with a stable dose for at least the last four months.;3. Documented biochemical control of their acromegaly on the current dose of SRL (IGF 1 < 1.3 x ULN and mean integrated GH < 2.5 ng/mL over two hours) based on Screening assessment.;4. Patients able and willing to comply with the requirements of the protocol at the time of Screening.;5. Women who are of childbearing potential should use an acceptable method for birth control. Acceptable methods include hormonal contraception (oral contraceptives, patch, implant, and injection), intrauterine devices, or double barrier methods (e.g. vaginal diaphragm/ vaginal sponge plus condom, or condom plus spermicidal jelly), sexual abstinence or a vasectomized partner. Women may be surgically sterile or at least 1 year post-last menstrual period. Women taking oral contraception containing levonorgestrel should either change treatment (at least one month prior to first study medication dose) or use a mechanical barrier method.;6.Patients able to understand and sign written informed consent to participate in the study.
Exclusion criteria
1. Patients taking injections of long-acting SRLs less frequently than once every eight weeks (dosing interval > 8 weeks).;2. Patients who previously participated in CH-ACM-01.;3.Symptomatic cholelithiasis.;4. Received pituitary radiotherapy within five years prior to screening (including total body, head and neck or stereotactic radiotherapy).;5. Undergone pituitary surgery within six months prior to screening or have elected surgery planned within the course of the core study.;6. High-risk pattern of pituitary tumor location on pituitary magnetic resonance imaging (MRI)/Computed tomography (CT) as per medical history or most recent MRI.;7.History of unstable angina or acute myocardial infarction within the 12 weeks preceding the screening visit or other clinically significant cardiac disease at the time of screening as judged by the Principal Investigator.;8. Any clinically significant uncontrolled nervous system, gastrointestinal (GI), renal, pulmonary, or hepatic concomitant disease that in the Investigator*s opinion would preclude patient participation.;9.Evidence of active malignant disease or malignancies diagnosed within the previous one year (except for basal cell carcinoma and uncomplicated * up to stage 1 squamous cell carcinoma that has been excised and cured). ;10.Known allergy or hypersensitivity to any of the test compounds or materials.;11.Known uncontrolled diabetes defined as having a fasting glucose >150 mg/dL (8.3 mmol/L) or glycosylated hemoglobin (HbA1c)> = 8% (patients can be rescreened after diabetes is brought under adequate control, or in case HbA1c < 8%).;12.Known defects in visual fields due to optic chiasmal compression or other neurological signs, related to the pituitary tumor mass. Patients with long standing (>12 months), fixed, minor defects may be considered on a case-by-case basis after consultation with the medical monitor.;13.Female patients who are pregnant or lactating or intending to become pregnant during the study.;14.Known history of immunodeficiency (e.g., HIV positive).;15.ALT, AST, ALP or GGT > 3 * ULN or Total Bilirubin >1.5 x ULN.;16.Undergone major surgery/surgical therapy for any cause within four weeks prior to enrollment or planned procedure during the study.;17.Known hypothyroidism or hypocortisolism not adequately treated with a stable dose of thyroid or steroid hormone replacement therapy for > =12 weeks.;18.Any condition that may jeopardize study participation (e.g., clinically significant abnormal screening clinical or laboratory finding during screening), the interpretation of study results or may impede the ability to obtain informed consent (e.g., mental condition).;19.History of illicit drug or alcohol abuse within five years.;20.Intake of an investigational drug within 30 days prior to initiation of study treatment.;21.Treatment with pegvisomant within 12 weeks before the screening visit.;22.Treatment with dopamine agonists within 6 weeks before the screening visit.;23.Treatment with pasireotide within 12 weeks before the screening visit.
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 | EUCTR2015-002854-11-NL |
| CCMO | NL55250.058.16 |