E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Renal Function Decline in Patients With AA Amyloidosis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002024 |
E.1.2 | Term | Amyloidosis NOS |
E.1.2 | System Organ Class | 100000004870 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 a persistent decrease in CrCl of 40% or more, a persistent increase in SCr of 80% or more, or progression to ESRD. Safety will be assessed by the incidence of nonserious AEs and SAEs. Neither progression to ESRD nor a clinically significant change in CrCl or SCr will be considered an AE or SAE. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives will be to assess the effect 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 secondary endpoints will be assessed individually. Other secondary objectives will include the slopes of CrCl, 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a) Patients must be at least 18 years of age and no more than 80 years of age.
b) 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 as follows:
i. Oral contraception with an additional barrier method (since the investigational product may impair effectiveness of oral contraception)
ii. Double-barrier method (diaphragm with spermicidal gel or condom with contraceptive foam)
iii. Transdermal or long-acting injected contraceptive (eg, depot medroxyprogesterone acetate [Depo-Provera®])
iv. Intrauterine device or implantable contraceptive
v. Partner who is surgically sterile (vasectomy)
vi. Total abstinence.
- A woman of childbearing potential must have a negative serum pregnancy test at the first screening visit. Urine pregnancy tests will also be performed at every subsequent visit. Should a patient become pregnant during the study, study medication will be discontinued and the patient will be withdrawn from the study and followed-up by research personnel until delivery. Pregnant women will be contacted by telephone every 3 months until delivery.
- Male patients with partners of childbearing potential must be surgically sterile or use a contraceptive method as previously described.
c) Patients must have a confirmed diagnosis of AA amyloidosis demonstrated by positive biopsy using Congo red staining and immunohistochemistry or immunoelectron microscopy during the screening period. Mass spectroscopy may be used at expert centers for the identification of the protein present IF Congo red staining is positive but immunochemistry/immunoelectron microscopy is unrevealing. The mass spectroscopy method will be used upon approval of the Sponsor on a case by case basis. The ELISA assay using monoclonal antihuman serum amyloid A antibodies as described by Hazenberg et al. (Hazenberg 1999) will also be allowed in sites that can demonstrate proficiency in its use. Tissue from previous biopsy or written pathology report confirmation of a previous biopsy can be used for confirmation of diagnosis, provided Congo red staining, immunohistochemistry immunoelectron microscopy, mass spectroscopy, or the Hazenberg method were used as methods of confirmation.
d) 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.
e) 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.
f) Patients must have the ability and willingness to provide informed consent and to comply with all study procedures. |
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E.4 | Principal exclusion criteria |
a) 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).
b) History of kidney transplantation.
c) 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.
d) Presence of concomitant diseases or concomitant medication that could interfere with the interpretation of study results or compromise patient safety. To be reconfirmed at the baseline visit.
e) Presence of conditions that could reduce life expectancy to less than 2 years. To be reconfirmed at the baseline visit.
f) Presence of type 1 or type 2 diabetes mellitus.
g) Presence of significant hepatic enzyme elevation (as defined by aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase more than 5 times the upper limit of normal and/or total bilirubin 50% above the upper limit of normal) or presence of cirrhosis.
h) Presence of unstable angina, myocardial infarction, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty within 6 months prior to the baseline visit.
i) Presence of, or history of, stroke or transient ischemic attack within 6 months prior to the baseline visit.
j) Presence of New York Heart Association class III or IV heart failure (Section 1).
k) Use of any investigational drug within 30 days prior to the first screening visit. To be reconfirmed at the baseline visit.
l) Active alcohol and/or drug abuse.
m) 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.
n) 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.
o) Previous use of Kiacta.
p) 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the time from Baseline to a persistent decrease in CrCl of 40% or more, a persistent increase in SCr of 80% or more, or progression to ESRD. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Development of a diagnostic test for AA amyloidosis and a biomarker for assessment of Kiacta efficacy in a subset of patients. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Armenia |
Belgium |
Bulgaria |
Chile |
Czech Republic |
Egypt |
Estonia |
Finland |
France |
Georgia |
Germany |
India |
Israel |
Italy |
Japan |
Latvia |
Lithuania |
Mexico |
Netherlands |
Peru |
Poland |
Portugal |
Russian Federation |
Spain |
Sweden |
Tunisia |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
This is an event driven clinical trial. When the pre-defined adjudicated total events are reached the study will not continue. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |