Primary Objective: To characterize the long-term safety and tolerability of AMG 416 in the treatment of SHPT in subjects with CKD on hemodialysisSecondary Objective: To characterize the long-term efficacy of AMG 416 on intact parathyroid hormone (…
ID
Source
Brief title
Condition
- Parathyroid gland disorders
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* nature, frequency, severity, and relationship to treatment of all adverse
events reported throughout the study
* vital signs and changes in laboratory parameters, including clinical chemistry
* evaluation of antibody formation to AMG 416
Secondary outcome
* proportion of subjects with > 30% reduction from baseline in predialysis iPTH
during the efficacy assessment phase (EAP) and the EAP at 12 months (EAP12) (as
defined in Section 10.4)
* proportion of subjects with predialysis iPTH * 300 pg/mL during the EAP and
EAP12
* percent change from baseline in predialysis iPTH during the EAP and EAP12
* percent change from baseline in predialysis serum cCa during the EAP and EAP12
* percent change from baseline in predialysis cCa x P during the EAP and EAP12
* percent change from baseline in predialysis serum phosphorus during the EAP
and EAP12
Background summary
Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a complex
disorder associated with CKD and end-stage renal disease (ESRD) in which the
impairment of blood and bone mineral homeostasis (calcium and phosphorus) and
vitamin D metabolism [1,25(OH)2D] lead to excessive parathyroid hormone (PTH)
levels and secondary hyperparathyroidism (SHPT). These changes begin early in
CKD in conjunction with the significant loss of renal function that occurs in
Stage 3 and Stage 4 CKD patients, and gradually worsens as CKD progresses to
ESRD. Elevated PTH levels further exacerbate the mineral imbalances
(particularly calcium and phosphorus), and are linked to pathological effects
in a variety of organ systems including osteodystrophy, vascular calcification,
left ventricular hypertrophy and increased risk for cardiovascular events,
which are the leading cause of morbidity and mortality in these patients
(approximately 66% 5-year mortality).
The importance of the appropriate management of SHPT is underscored by the
clinical practice guidelines promulgated by the National Kidney Foundation
Kidney Disease Outcomes Quality Initiative (NKF KDOQI*) and International
Society of Nephrology Kidney Disease Improving Global Outcomes (KDIGO*).
Several approaches have been used to control SHPT in patients with renal
failure. One approach, based on the demonstration that PTH secretion by the
parathyroid gland is primarily controlled by the action of a cell surface
calcium-sensing receptor (CaSR) residing on parathyroid cells, involves the use
of CaSR agonist to mimic the effects of ionized calcium to activate the CaSR
and thus reduce PTH synthesis and secretion. This has been shown to be the
mechanism of action of AMG 416.
Furthermore, patients on hemodialysis in general have shown poor compliance
with oral dosing regimens, due to a high daily pill burden, and the time
commitment required to manage their condition. AMG 416 provides the opportunity
for hemodialysis patients with SHPT to increase compliance over an oral
calcimimetic and have one less oral regimen to manage as AMG 416 is dosed 3
times a week, concurrent with hemodialysis and administered by the dialysis
site staff.
The AMG 416 phase 3 program is designed to demonstrate the safety and efficacy
of AMG 416 for the treatment of SHPT in CKD patients on hemodialysis. It is
comprised of two 26-week, randomized, double-blind, placebo-controlled pivotal
studies in CKD patients on hemodialysis with SHPT (iPTH > 400 pg/mL). Safety
will be evaluated in the 2 pivotal trials (20120229 also known as KAI-4169-006,
and 20120230 also known as KAI-4169-007), and long-term safety of AMG 416 will
be evaluated in this single-arm extension study (20120231 also known as
KAI-4169-008).
The clinical hypothesis is as follows:
A formal hypothesis does not apply for the study. The long-term safety and
efficacy of AMG 416 will be characterized in this study.
Study objective
Primary Objective: To characterize the long-term safety and tolerability of AMG
416 in the treatment of SHPT in subjects with CKD on hemodialysis
Secondary Objective: To characterize the long-term efficacy of AMG 416 on
intact parathyroid hormone (iPTH), corrected calcium (cCa), corrected
calcium-phosphorus product (cCa x P), and phosphorus
Study design
This is a 52-week multicenter, single-arm, extension study designed to
characterize long-term tolerability, safety, and efficacy of AMG 416. Eligible
subjects will have completed the treatment and follow-up period or have been
discontinued for rising iPTH in one of the AMG 416 phase 3 parent studies
(protocol 20120229 also known as KAI-4169-006, or protocol 20120230 also known
as KAI-4169-007).
Intervention
AMG 416 will be administered thrice weekly with each hemodialysis treatment for
52 weeks. The starting dose of AMG 416 is 5 mg. The dose of AMG 416 may be
increased in 2.5 mg or 5 mg increments at Weeks 5, 9, 13, 17 and then by 2.5 mg
every 8 weeks up to a maximum dose of
15 mg, to achieve iPTH * 300 pg/mL. AMG 416 dose titration will be based on the
prior week*s iPTH and cCa results. The minimum dose is 2.5mg, ant the maximum
dose is 15mg.
AMG 416 will be administered by bolus injection into the venous line of the
dialysis circuit at the end of hemodialysis and prior to or during the rinse
back procedure.
All patients will receive open label AMG 416.
Study burden and risks
A treatment regimen for SHPT that includes standard of care and AMG 416 will
increase the proportion of subjects who will have a reduction in iPTH. Elevated
PTH levels further exacerbate the mineral imbalances (particularly calcium and
phosphorus), and are linked to pathological effects in a variety of organ
systems including osteodystrophy, vascular calcification, left ventricular
hypertrophy and increased risk for cardiovascular events, which are the leading
cause of morbidity and mortality in these patients (approximately 66% 5-year
mortality).
Four clinical studies have been completed to date. Most adverse events (AE)
were mild or moderate in severity. The most frequent AE was low calcium levels
with or without symptoms following reductions in iPTH levels. The incidence of
nausea, vomiting and diarrhea, common AEs associated with the oral
calcimimetics, were similar in the AMG 416- and placebo-treated subjects.
Serious adverse events (SAEs) have been reported; none were considered related
to study drug.
Administration of foreign proteins poses a small risk of developing
antibody-mediated hypersensitivity reactions, including anaphylaxis. Such
reactions are often related to release of cytokines or vasoactive amines.
Symptoms may include fever, chills, rigor/shakes, hypotension, respiratory
distress, rash/urticaria, and arthralgias and myalgias. However, AMG 416 is a
small peptide produced by chemical synthesis that is unlikely to be immunogenic.
The overall clinical safety findings to date suggest that AMG 416 is
well-tolerated. Furthermore, the burden for the patient is relatively low as
they do not have to have extra visits during the treatment phase. AMG 416
provides the opportunity for hemodialysis patients with SHPT to increase
compliance over an oral calcimimetic and have one less oral regimen to manage
as AMG 416 is dosed 3 times a week, concurrent with hemodialysis and
administered by the dialysis site staff.
For patients the long term safety of AMG 416 is important information.
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US
Listed location countries
Age
Inclusion criteria
- Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
- Subject must complete the treatment and follow-up period, or have been discontinued for rising iPTH, from an AMG 416 phase 3 parent study prior to the start of dosing in this study.
- Subject agrees to not participate in another study of an investigational agent during the study.
- Dialysis prescription dialysate calcium concentration must be * 2.25 mEq/L.
- Female subject who is post menopausal (post menopausal is defined as no menses for the previous 1 year and over the age of 50 years), surgically sterilized, has a medical condition that prevents pregnancy, remains abstinent, or is willing to use highly effective contraception during the study and for 3 months after the last dose. Women of child-bearing potential must have a negative serum pregnancy test within 2 weeks prior to the first dose of AMG 416.
- Male subject is willing to use highly effective contraception when sexually active and will not donate sperm during the treatment phase.
- Subject*s legally acceptable representative has provided informed consent when the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent.
Exclusion criteria
- Currently receiving treatment in another investigational device or drug study.
- Currently receiving other investigational procedures while participating in this study.
- Subject has known sensitivity to any of the products or components to be administered during dosing.
- Subject has received cinacalcet between the last dose of investigational product in the parent study (20120229 or 20120230) and the start of dosing with AMG 416 in the current study.
- Subject has an unstable medical condition based on medical history, physical examination, and routine laboratory tests, or is otherwise unstable in the judgment of the Investigator.
- Subject has a history of any illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject.
- Subject has a serious concurrent medical condition (eg, malignancy) likely to result in death during the next 12 months.
- Subject is pregnant or nursing.
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
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 | EUCTR2012-002808-41-NL |
| ClinicalTrials.gov | NCT01785875 |
| CCMO | NL42549.056.13 |