Main objective:To assess the efficacy of Orelvo (voclosporin) compared with placebo in achieving renal response after 52 weeks of therapy in subjects with active lupus nephritis (LN)Secondary objective:To assess the safety and tolerability of Orelvo…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Renal response at Week 52 will be adjudicated by the Clinical Endpoints
Committee based on the following parameters:
* UPCR of *0.5 mg/mg, and
* eGFR *60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of
>20%, and
* Received no rescue medication for LN (see protocol Section 7.8, Prohibited
Therapy and Concomitant Treatment), and
* Did not receive more than 10 mg prednisone for *3 consecutive days or for *7
days in total during Weeks 44 through 52, just prior to the renal response
assessment.
Subjects who withdraw from the study prior to the Week 52 assessment will be
defined as non responders.
Secondary outcome
* Time to UPCR of *0.5 mg/mg
* Partial renal response as defined by 50% reduction from baseline in UPCR at
Weeks 24 and 52
* Time to 50% reduction in UPCR from baseline
* Renal response at Week 52 (based on definition of primary endpoint)
* Duration of UPCR <0.5 mg/mg
*Proportion of subjects experiencing a confirmed >30% decrease from baseline in
eGFR at each timepoint.
*Change from baseline in UPCR at each time point.
*Change from baseline in serum creatinine, urine protein, and eGFR.
*Change from screening in immunology parameters (complement 3 (C3), C4, and
anti double-stranded DNA).
*Renal response with low-dose steroids (defined as renal response in the
presence of corticosteroids of *2.5 mg between Weeks 16 to 24 and Weeks 44 to
52).
*Change from baseline in health-related quality of life at Weeks 12, 24, and 52.
*Health Resource Utilization at Weeks 24 and 52.
*Change from baseline in the Safety of Estrogens in Lupus Erythematosus
National Assessment - Systemic Lupus Erythematosus Disease Activity
(SELENA-SLEDAI) Index score at Weeks 24 and 52.
Background summary
The trial AUR-VCS-2016-01 proposed indication is active lupus nephritis (LN).
LN is the most common serious manifestation of systemic lupus erythematosus
(SLE). LN is divided into different classes according to the level of treatment
required, using a classification system for renal biopsy pathology originally
developed by the World Health Organization (WHO).
LN manifests as diverse patterns of immune complex-mediated renal disease
affecting glomerular, tubulointerstitial, and vascular compartments. It can
lead to permanent and irreversible tissue damage within the kidney, resulting
in end-stage renal disease (ESRD), and thus making LN a serious and potentially
life-threatening condition.
The current treatment paradigm for LN includes two goals, based on the severity
of disease. The first goal of treatment in subjects with active LN is intended
to bring the disease under control as quickly as possible to limit the
potential for extensive renal scarring or loss of life.
The second goal of treatment, after the patient successfully responds to
treatment, is to maintain remission by preventing renal flares and any
resulting deterioration in renal function. In this second phase of treatment,
lower doses of both corticosteroids and immunosuppressant are used.
However, the treatment of SLE remains unsatisfactory. No therapy has been
specifically approved for the treatment of LN in either the USA or Europe. In
many patients, the disease is inadequately controlled, resulting in the
progression to end-stage organ failure.
Current therapies, such as corticosteroids (CS) and other immunosuppressive
drugs, which must be administered at high doses, can also lead to serious side
effects.
In this trial, Investigational medicinal product Orelvo (voclosporin) is a
Calcineurin inhibitor (CNI). CNIs are a class of immunosuppressants which
reversibly inhibit immunocompetent lymphocytes, particularly T-lymphocytes in
the G0 and G1 phase of the cell cycle, and also reversibly inhibit the
production and release of lymphokines. CNIs mediates its suppressive effects by
binding to an ubiquitous intracellular protein cyclophilin. This complex, in
turn, inhibits the calcium- and calmodulin-dependent serine/threonine
phosphatase activity of the enzyme calcineurin. Calcineurin inhibition then
prevents the activation of various transcription factors necessary for the
induction of cytokine genes during T-cell activation, such as interleukin-2,
interleukin-4, tumor necrosis factor-*, granulocyte macrophage colony
stimulating factor, and interferon-*.
Orelvo (voclosporin) is a next-generation CNI developed for the treatment of
autoimmune diseases and for use in the prevention of organ graft rejection.
Voclosporin is structurally similar to cyclosporine A (CsA) except for a
modification of a functional group on the amino acid 1 residue of the molecule.
This alteration has changed the binding of voclosporin to calcineurin leading
to a 3- to 5-fold increase in potency when compared to CsA. This modification
has also shifted metabolism away from amino acid 1, the major site of
metabolism for CsA, thus altering the metabolic profile. This in turn has led
to faster elimination of metabolites resulting in lower measured metabolite
exposure as compared to CsA. The combination of increased potency and decreased
measured metabolite exposure, for voclosporin as compared to CsA, has led to
better pharmacokinetic (PK)/ pharmacodynamic predictability.
In the proposed AUR-VCS-2016-01 clinical study, it is planned to randomize
approximately 324 subjects. One arm shall receive treatment with Orelvo softgel
capsules containing 7.9 mg drug (23.7 mg twice daily (BID)) and the other arm
shall receive matching placebo (162 subjects per arm). All subjects will
receive an initial treatment of intravenous (IV) methylprednisolone, followed
by a reducing taper of oral corticosteroid. Additionally, all subjects will
receive background therapy with mycophenolate mofetil (MMF).
Study objective
Main objective:
To assess the efficacy of Orelvo (voclosporin) compared with placebo in
achieving renal response after 52 weeks of therapy in subjects with active
lupus nephritis (LN)
Secondary objective:To assess the safety and tolerability of Orelvo over 52
weeks compared with placebo in subjects with active LN
Study design
Prospective, randomized, placebo-controlled, double-blind, parallel-group,
52-week, international, multicenter, 2-arm comparison study of Orelvo versus
matching placebo.
Intervention
NA
Study burden and risks
Because Orelvo is investigational, there is a risk of your lupus nephritis
getting worse or not changing if the drug does not work for you. Signs of lupus
activity will be closely monitored and patients will be managed according to
medical practice if this occurs.
Use of immunosuppressants in general can increase risk of developing a serious
infection which may lead to death, or may reduce body's ability to fight
serious infections. Use of immunosuppressants in general can increase your risk
of certain cancers.
Side effects reported by subjects and considered by the Study Doctor to be
related to Orelvo treatment are described below.
Common side effects, those reported by >10% of subjects receiving Orelvo
include high blood pressure and changes in kidney function. Less common side
effects (>5% of subjects) include upper respiratory infections and headache.
Other side effects reported by between 1 and 5% of subjects include sore
joints, nausea, abdominal pain/discomfort, weakness, abnormal hair growth, and
pain in your limbs extremities.
It is not known if you will experience any of these side effects. Since Orelvo
is investigational, there may be other risks that are currently unknown or
unforeseen. Any drug has the potential risk of an allergic reaction which, if
serious and not treated promptly, can become life-threatening.
The side effects and discomforts reported for MMF include, but are not limited
to mild to moderate stomach pain, nausea, vomiting, diarrhea, fever, anemia,
headache, infection (including tuberculosis, opportunistic infections and
Progressive Multifocal Leukoencephalopathy * a neurological disorder caused by
a virus that can lead to brain damage), fluid retention, swelling, weakness,
shakiness, pain, high blood pressure and a low amount of white blood cells.
The most frequent side effects of corticosteroids are increased appetite,
weight gain, high blood pressure, indigestion and nervousness or restlessness.
There may also be side effects and discomforts from the treatments that are not
yet known. In addition, when treated with intravenous (IV) methylprednisolone,
you might experience some discomfort that includes bruising or infection at the
IV site.
Some people have discomfort or pain when blood is collected. The insertion of
needles into the arm can cause pain, swelling, bruising and occasionally
fainting reactions; in rare occasions nerve damage can occur. Fainting
reactions are usually harmless, of short duration, and typically produce
feelings of weakness accompanied by sweating, slowing of the heart rate and an
abnormal decrease in blood pressure. There is also a risk of infection and
small blood clots in blood vessels.
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Age
Inclusion criteria
Written informed consent before any study specific procedures are performed.
* Male or female subjects with a minimum age of 18 (or legal age of consent if >18 years) to 75 years of age, inclusive, at the time of screening (Visit 1).
* Previous diagnosis of SLE according to the American College of Rheumatology criteria
* Subjects with evidence of active nephritis, defined as follows:
- Kidney biopsy result within 2 years prior to screening indicating Class III, IV S, IV-G (alone or in combination with Class V), or Class V LN (see Appendix 3) with a doubling or greater increase of urine protein creatinine ratio (UPCR) within the last 6 months to a minimum of *1.5mg/mg for Class III/IV or to a minimum of *2 mg/mg for Class V at screening. Biopsy results over 6 months prior to screening must be reviewed with a medical monitor to confirm eligibility.
OR
- Kidney biopsy result within 6 months prior to screening indicating Class III, IV S or IV-G (alone or in combination with Class V) LN with a UPCR of *1.5 mg/mg at screening.
OR
- Kidney biopsy result within 6 months prior to screening indicating Class V LN and a UPCR of *2 mg/mg at screening.
A biopsy can be performed during screening, if not available. The above criteria must be fulfilled at baseline.
* In the opinion of the Investigator, subject requires high-dose corticosteroids and immunosuppressive therapy.
* Subject is willing to take oral MMF for the duration of the study, either by continuing current MMF therapy or by initiating it on or before the Baseline Visit.
* Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline. Two effective forms of contraception must be used
simultaneously unless abstinence is the chosen method. Subjects must use effective contraception during the study
Exclusion criteria
1. Subjects unable or unwilling to give written informed consent and/or to comply with study procedures.
2. Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation of *45 mL/minute/1.73 m2 at screening confirmed before randomization.
3. Currently taking or known need for any of the medications listed in Section 7.8, Prohibited Therapy and Concomitant Treatment at screening or during the study. This includes prohibited medications prior to screening as specified in Section 7.8.1, Prohibited Medications.
4. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to require dialysis during the study period.
5. A previous kidney transplant or planned transplant within study treatment period.
6. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, cyclosporine, corticosteroids or any components of these drug products.
7. Current or medical history of:
* Congenital or acquired immunodeficiency.
* In the opinion of the Investigator, clinically significant drug or alcohol abuse within 2 years prior to screening.
* Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Subjects with cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been treated with conization or loop electrosurgical excision procedure and have had a normal repeat Papanicolaou test are allowed.
* Lymphoproliferative disease or previous total lymphoid irradiation.
* Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C virus) within 3 months of screening; or known HIV infection. Severe viral infection is defined as active disease requiring antiviral therapy.
* Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid (see Section 9.2.1, Screening Visit Procedures).
8. Other known clinically significant active medical conditions, such as:
* Severe cardiovascular disease including congestive heart failure, history of cardiac dysrhythmia or congenital long QT syndrome. QT interval duration corrected for heart rate using method of Fridericia exceeding 480 msec in the presence of a normal QRS interval (<110 msec) at time of screening will result in exclusion.
* Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin *2.5 times the upper limit of normal) at screening and, if abnormal at screening, then confirmed that the levels have returned to <2.5 times upper limit of normal before randomization.
* Chronic obstructive pulmonary disease or asthma requiring oral steroids.
* Bone marrow insufficiency unrelated to active SLE (according to Investigator judgment) with white blood cell count <2,500/mm3; absolute neutrophil count <1.3 × 103/*L; thrombocytopenia (platelet count <50,000/mm3).
* Active bleeding disorders.
* Current infection requiring IV antibiotics.
9. Any overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes (e.g., scleroderma with significant pulmonary hypertension; any condition for which additional immunosuppression is indicated). Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes (e.g., Sjögren*s syndrome) are not excluded.
10. No vaccines using live organisms, virus or bacterial, are allowed during screening and while taking the study treatment.
11. Other major physical or psychiatric illness or major traumatic injury within 6 months prior to screening that may affect study conduct or interfere with study assessments or outcome.
12. Any other medical condition which, in the Investigator*s judgment, may be associated with increased risk to the subject or may interfere with study assessments or outcomes.
13. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions.
14. Participation in another interventional clinical study within 4 weeks prior to screening and/or receipt of investigational drugs within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to screening.
15. Subjects randomized and treated in a previous voclosporin clinical study.
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 | EUCTR2016-004045-81-NL |
| ClinicalTrials.gov | NCT03021499 |
| CCMO | NL60796.056.17 |