Primary ObjectiveThe primary objective of this double-blind, randomized, placebo-controlled, Phase 3 study is to assess the efficacy and safety of treatment with Kiacta in adult patients with AA amyloidosis. Efficacy will be assessed by the time…
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Brief title
Condition
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint will be the time from Baseline to the earliest of
a persistent decrease in CrCl of 40% or more, a persistent increase in SCr of
80% or more, or progression to ESRD.
Secondary outcome
The secondary efficacy endpoint will be the rate of change (slope) in CrCl over
time.
The exploratory efficacy endpoints will be the following:
* Time from Baseline to a persistent decrease in CrCl of 40% or more, a
persistent increase in SCr of 80% or more, progression to ESRD, or all-cause
mortality;
* Time from Baseline to a decrease in CrCl of 50% or more, an increase in SCr
of 100% or more, progression to ESRD, or all-cause mortality;
* Times from Baseline to a persistent decrease in CrCl of 40% or more, a
persistent increase in SCr of 80% or more, a decrease in CrCl of 50% or more,
an increase in SCr of 100% or more, progression to ESRD, and all-cause
mortality (each component of the previously mentioned exploratory endpoints);
* Rates of change (slope) in 1/SCr, eGFR (as calculated with the modification
of diet in renal disease formula), and serum cystatin C over time; and
* Absolute changes from Baseline in CrCl, SCr, eGFR, proteinuria, urinary
protein/creatinine ratio, serum cystatin C, and serum amyloid A at each study
visit.
Background summary
In the first Phase 2/3 study (CL-503004), Kiacta showed a consistent,
clinically meaningful, and statistically significant effect in the preservation
of kidney function in patients with AA amyloidosis. In this new study, doses
will be the same as the ones used in the previous studies (CL-503004 and OLE
CL-503009) as Kiacta is safe and was well tolerated following chronic
administration for up to 6 years. The rationale for conducting this second
Phase 3 study is to provide additional evidence for the efficacy and safety of
Kiacta in patients with AA amyloidosis and to confirm the findings of the
CL-503004 study. (zie section 5.2 protocol version 1.1 dd 05 aug10)
Study objective
Primary Objective
The primary objective of this double-blind, randomized, placebo-controlled,
Phase 3 study is to assess the efficacy and safety of treatment with Kiacta in
adult patients with AA amyloidosis. Efficacy will be assessed by the time from
Baseline to the primary endpoint. This primary efficacy endpoint will be the
time from Baseline to the earliest of a persistent decrease in creatinine
clearance (CrCl) of 40% or more, a persistent increase in serum creatinine
(SCr) of 80% or more, or progression to end-stage renal disease (ESRD). Safety
will be assessed by the incidence of nonserious adverse events (AEs) and
serious AEs (SAEs). Neither progression to ESRD nor a clinically significant
change in CrCl or SCr will be considered an AE or SAE.
Secondary Objectives
The secondary objective will be to assess the effect of treatment with Kiacta
on the slope of CrCl over time
Exploratory Objectives
The exploratory objectives will be to assess the effects of treatment with
Kiacta on the time from Baseline to a persistent decrease in CrCl of 40% or
more, a persistent increase in SCr of 80% or more, progression to ESRD, or
all-cause mortality. Assessments will also be made of the effect on time from
Baseline to a decrease in CrCl of 50% or more, an increase in SCr of 100% or
more, progression to ESRD, or all cause mortality. Additionally, time from
Baseline to each component of the previously mentioned exploratory endpoints
will be assessed individually. Other exploratory objectives will include the
slopes of 1/SCr, estimated glomerular filtration rate (eGFR), and serum
cystatin C over time. Absolute changes from Baseline in CrCl, SCr, eGFR,
proteinuria, urinary protein/creatinine ratio, serum cystatin C, and serum
amyloid A will be measured every 3 months throughout the duration of the study,
including the last study visit as applicable.
Study design
This will be a multicenter, international, randomized, double-blind,
placebo-controlled study with 1 unblinded interim analysis (IA). Patients
diagnosed with AA amyloidosis will be randomly assigned at a 1:1 ratio to
receive either Kiacta or placebo. Randomization will be stratified by averaged
screening proteinuria (<3 or *3 g/day) and averaged screening eGFR (<60 or *60
mL/min/1.73 m2). Patients will be assessed as follows:
* Twice during the screening period (Month *3 to Week *1);
* At Baseline;
* Every 3 months until one of the following has occurred:
o ESRD has been confirmed by adjudication,
o The CrCl or SCr component of the primary endpoint has been reached and a
minimum of 24 months of treatment has been completed,
o The end of the study is reached;
* At an early-termination, treatment-completion, or end-of-study (EOS) visit,
as applicable.
Patients who experience a persistent decrease in CrCl or persistent increase in
SCr and who have not completed a minimum of 24 months of treatment will remain
in the study Investigational product for a total treatment period of 24 months,
until they reach ESRD, or until the end of the study. Patients who do not
experience a persistent decrease in CrCl or persistent increase in SCr within
24 months will remain on the study and on treatment until they reach ESRD or
until the end of the study.
Patients will discontinue treatment when they reach ESRD but will remain in the
study until ESRD is adjudicated by the clinical endpoint committee (CEC).
If the CEC adjudicates the ESRD as absent, the patient will have the option to
resume treatment. If the CEC adjudicates the ESRD as present, the patient will
undergo an early-termination visit. All efforts will be made to ensure that
patients who discontinue the study prior to adjudicated ESRD attend an
early-termination visit.
Patient who discontinue treatment prematurely, will be asked to participate in
a long-term follow-up study. These patients will be contacted by phone monthly
and every 12 weeks a blood sample will be drawn. The follow-up study is
conducted in parallel with the main study, meaning that the follow-up study
will also end when the main study is ended. It is expected that both studies
will be ongoing untl March 2014.
The patients can participate in the follow-up study until their kidney function
decreases to end stage kidney disease, until the start of permanent renal
replacement therapy or kidney transplant or until the end of the main study.
All patients who remain on treatment at the end of the study will attend an
end-of-study visit. Telephone or e-mail contact will be made monthly from
Baseline until the end of the study, and survival and renal function status
(ESRD or not) of all patients will be assessed at the end of the study.
The study will end when approximately 104 adjudicated events are reached. The
number of events and enrollment target for the study will be refined at the IA.
Following the IA, the protocol will be amended to reflect the exact number of
events required. At the end-of-study visit, patients who complete the study
will be offered the option to continue treatment in an expanded access program
or follow-up study.
Safety data from this study will be reviewed by an independent data monitoring
committee. A CEC will be appointed to adjudicate potential endpoint events on
an ongoing basis throughout the study.
Intervention
Study Drug Administration
Patients will receive either Kiacta or placebo, administered orally as 1 to 3
capsules (Kiacta 400 mg or placebo) twice a day from Baseline, depending on the
CrCl. Eligible patients must have a CrCl of 25 mL/min/1.73 m2 or more during
the screening period.
The dosage will be based on CrCl as determined with no correction for body
surface area (in order to maintain consistency with previous studies) and the
mean value of the 2 screening CrCl measurements. The dosage will be as follows:
Creatinine (mL/min) Kiacta(400 mg capsules twice daily) Placebo(twice daily)
>80 3 capsules (1200 mg) 3
capsules
30 to 80 2 capsules (800
mg) 2 capsules
<30 1 capsule (400 mg)
1 capsule
If the CrCl level increases or decreases to the next range level at a given
visit, the dose regimen has to be adjusted as per the above table.
Study burden and risks
See section 'Which side-effects can you expect' and 'Risks of the Biopsy
Procedures' from the PIF mentioned below..
The most common and expected side effects and discomforts reported for KIACTA
are diarrhea, headache, nausea and vomiting.
Other events less frequently described with this medication were: sore nose
(like the common cold), cough, sore joints, back pain, dizziness, high blood
pressure, fluid retention, sore stomach, itching, and indigestion.
When, despite every precaution, you or your partner becomes pregnant during the
study this may have effects for your unborn child.
In addition, you might feel uncomfortable during some of the tests and may also
have risks, such as:
Blood draws: Possible side effects of blood draws are pain, bruising, bleeding
or infection at the site of the needle puncture. Blood draws may also cause
temporary headache, nausea, and lightheadedness.
ECG: Skin irritation is rare but could occur during an ECG from the electrodes
or gel that is used.
If a biopsy has to be performed to diagnose AA Amyloidosis, you may experience
some additional side effects. You might feel uncomfortable during some of the
tests and may also have risks, such as:
Abdominal wall fat pad biopsy: Although your health care provider may have
numbed the skin, there can be some mild discomfort or pressure during the
needle insertion. Afterward, the area may feel tender or bruised for several
days.
Kidney biopsy: The amount of pain during and after the procedure depends on the
patient. Because a local anesthetic is used, discomfort during the procedure is
usually minimal. The anesthetic may burn or sting when first injected. After
the procedure, the area may feel tender or sore for a few days. You may see
bright, red blood in the urine the first 24 hours after the test. If the
bleeding lasts longer, tell your health care provider.
Gum biopsy: The topical anesthetic should numb the area during the procedure,
although some tugging or pressure may be felt. If there is bleeding, the blood
vessels may be sealed off with an electric current or laser. This is called
electrocauterization. After the numbness wears off, the area may be sore for a
few days.
Rectal biopsy: There will be some discomfort during the procedure, and you may
feel an urge to have a bowel movement. Cramping sometimes occurs as the
instrument is placed into the rectal area.
A.T. Development Switzerland SARL, Route de la Corniche 3B
Epalinges 1066
CH
A.T. Development Switzerland SARL, Route de la Corniche 3B
Epalinges 1066
CH
Listed location countries
Age
Inclusion criteria
*Patients must be at least 18 years of age and no more than 80 years of age.
*Patients are males or nonpregnant, nonlactating females.
* Women must be of nonchildbearing potential (ie, more than 1 year postmenopausal or use effective contraception for at least 2 months prior to the baseline visit and through 30 days after the last dose of study medication
* Patients must have a confirmed diagnosis of AA amyloidosis during the screening period.
* Patients must have persistent proteinuria defined as urinary protein excretion *1 g/24 h at 2 distinct 24-hour urine collections at least 1 week apart during the screening period.
* Patients must have CrCl *25 mL/min/1.73 m² at 2 distinct 24-hour urine collections at least 1 week apart during the screening period.
Exclusion criteria
*Evidence or suspicion of chronic kidney disease secondary to a disease process other than renal AA amyloidosis (eg, diabetes, long-standing uncontrolled hypertension, polycystic kidney disease, recurring polynephritis, or systemic lupus erythematosus).
*History of kidney transplantation.
*Evidence or suspicion of a cause of potentially reversible acute renal failure, such as uncontrolled hypertension, urinary tract infection, or drug nephrotoxicity within 3 months prior to the baseline visit.
*Presence of concomitant diseases or concomitant medication that could interfere with the interpretation of study results or compromise patient safety.
*Presence of conditions that could reduce life expectancy to less than 2 years.
*Presence of type 1 or type 2 diabetes mellitus.
*Presence of significant hepatic enzyme elevation or cirrhosis.
*Presence of unstable angina, myocardial infarction, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty within 6 months prior to the baseline visit.
*Presence of, or history of, stroke or transient ischemic attack within 6 months prior to the baseline visit.
*Presence of New York Heart Association class III or IV heart failure (Section 1).
*Use of any investigational drug within 30 days prior to the first screening visit.
*Initiation of, or any changes in, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist therapy, or renin inhibitor within 3 months prior to the baseline visit.
* Initiation of, or any changes in, cytotoxic agents, anti-tumor necrosis factor agents, anti-interleukin-1 or anti-interleukin-6 agents, or colchicine therapy within 3 months prior to the baseline visit.
*History of malignancy within 5 years prior to study entry, except for cervical carcinoma in situ, nonmelanomatous carcinoma of the skin, or ductal carcinoma in situ of the breast that has been surgically cured.
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 | EUCTR2010-022313-25-NL |
| ClinicalTrials.gov | NCT01215747 |
| CCMO | NL33777.068.10 |