E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic Membranous Glomerulonephropathy (IMGN)
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E.1.1.1 | Medical condition in easily understood language |
Idiopathic Membranous Glomerulonephropathy (IMGN)
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027170 |
E.1.2 | Term | Membranous nephropathy |
E.1.2 | System Organ Class | 100000004857 |
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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 study is:
To evaluate whether belimumab can modulate proteinuria in IMGN.
To evaluate whether belimumab can modulate anti-PLA2R autoantibodies in patients with detectable baseline levels of these antibodies. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
To evaluate the safety and tolerability of belimumab 10mg/kg over a 2 year period in
IMGN.
To assess the pharmacokinetics (PK) of belimumab 10mg/kg in patients with IMGN.
To evaluate the effect of belimumab on pharmacodynamic (PD) markers and other markers of autoimmunity and their relationship with clinical measures in IMGN.
To evaluate the effect of belimumab on quality of life in IMGN. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the
following criteria apply:
1. Age & Gender: Male or female between 18 and 75 years of age
inclusive, at the time of signing the informed consent.
2. Histological diagnosis: Have clinical diagnosis of IMGN, as verified by
biopsy (either by light microscope with immuno-fluorescence, or by
electron microscope) in the last 7 years with non-active disease >3
years (non-active defined as subject not on immunosuppressants and proteinuria <2g per 24h) (biopsy results and
slides should be available for independent evaluation).
3. Autoantibody: Have positive anti-PLA2R autoantibody test results at screening.
4. Proteinuria: Have clinically active disease (nephrotic range
proteinuria) for at least 3 months prior to screening and no improvement (<30% reduction), despite supportive therapy (which should include maximal tolerated doses of ACE inhibitor or ARB unless contraindicated, and may include statins, diuretics, dietary salt restriction). During screening proteinuria must be >400mg/mmol by PCR (or >4.0g per 24 h) as measured from a 24 h urine collection and/or spot urine sample (early morning where possible) on 2 occasions at least 7 days apart.
5. Female Subjects: A female subject is eligible to participate if she is not pregnant or nursing and at least one of the following conditions apply: a. Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood
sample with simultaneous follicle stimulating hormone (FSH) > 40
MlU/mL and estradiol <40 pg/mL (<147 pmol/L) is confirmatory].
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.
Following confirmation of their post-menopausal status, they can
resume use of HRT during the study without use of a contraceptive method.
b. Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 of Protocol for an appropriate period of time (as determined by the product
label or investigator) prior to the start of dosing to sufficiently minimise the risk of pregnancy at that point. Female subjects must agree to use contraception until 16 weeks after the last dose. |
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E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Non-Idiopathic MGN or other condition affecting the kidney: If the diagnosis of MGN is secondary to other conditions, or the subject has renal impairment from a condition that is not MGN. Causes of secondary MGN include (but are not limited to):
Immune diseases: Systemic lupus erythematosus, diabetes mellitus; rheumatoid arthritis, Hashimoto’s disease, Grave’s disease, mixed connective tissue disease, Sjogren’s syndrome, primary biliary cirrhosis, bullous pemphigoid, small bowel
enteropathy syndrome, dermatitis herpetiformis, ankylosing spondylitis, graft-versushost-disease, Guillain-Barré syndrome.
Infectious or parasitic diseases: Hepatitis B, Hepatitis C, syphilis, filariasis, hydatid disease, schistosomiasis, malaria, leprosy.
Drugs and toxins: Gold, penicillamine, non-steroidal anti-inflammatory agents, mercury, captopril, formaldehyde, hydrocarbons, bucillamine.
Miscellaneous: Tumours (excluded with reasonable diligence), renal transplantation, sarcoidosis, sickle cell disease, Kimura disease, angiofollicular lymph node hyperplasia.
2.Severely reduced or deteriorating kidney function: An eGFR at
screening < 40 mL/min/1.73m2 (as determined by 4 variable version MDRD equation) or kidney function not stable (as defined by > 15% decrease in eGFR in 3 months before screening, unless due to medication change).
3. Blood Pressure: Uncontrolled hypertension defined as blood pressure (BP) > 150/90 mm Hg (treatment target ≤140/80) as assessed by either :
a. Blood pressures measured 3 times on each of at least 2 clinic visits during screening, after the patient has sat quietly for at least 5 minutes, with >50% of measurements being >150/90 or
b. Average daytime blood pressure on a 24 hour ambulatory blood pressure monitor.
4. Prior Therapy: Have received treatment with the therapies (as per protocol page 39-see table) at the times specified prior to Day 0:
Corticosteroid dose represents prednisolone or prednisolone equivalent.
5. Transplantation: Have history of a major organ transplant (e.g heart, lung, kidney,liver) or hematopoietic stem cell/marrow transplant.
6. Cancer: Have a history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
7. Acute or chronic infection: Have required management of acute or chronic infections, as follows:
• Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).
• Hospitalisation for treatment of infection within 60 days prior to Day 0.
• Use of parenteral (IV or IM) antibiotics (anti-bacterials, anti-virals, antifungals, or anti-parasitic agents) within 60 days prior to Day 0.
8. Liver disease: Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
9. Other diseases/conditions: Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to IMGN (i.e., cardiovascular, pulmonary, haematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.
or
Have a planned surgical procedure or a history of any other medical disease (e.g. cardiopulmonary), laboratory abnormality, or condition (e.g. poor venous access) that, in the opinion of the investigator, makes the subject unsuitable for the study.
10. Positive serology: Have a historically positive HIV test or test positive at screening for HIV. Serologic evidence of Hepatitis B (HB) infection based on the results of testing for HBsAg, anti-HBc and anti-HBs as follows:
• Patients positive for HBsAg are excluded.
• Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody and with no history of Hepatitis B vaccination are excluded.
• Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies are excluded.
• Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody are excluded.
Positive test for Hepatitis C antibody confirmed on the same sample with a Hepatitis C RIBA immunoblot assay if available. Subjects who are positive for hepatitis C antibody, and who are negative when the Hepatitis C RIBA immunoblot assay is performed on the same sample, will be eligible to participate.
Subjects who are positive for Hepatitis C antibody and who have a
positive or indeterminate result when the Hepatitis C RIBA immunoblot assay is performed on the same sample, or where the Hepatitis C RIBA assay is not available, will not be eligible to participate. For remaining list of exclusion criteria see Protocol page 39 |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline in proteinuria levels at week 28
• Change from baseline in anti-PLA2R autoantibody titres at week 28
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Change from baseline in proteinuria levels
• Change from baseline in anti-PLA2R autoantibody titres
• Change from baseline in urine levels of belimumab
• Incidence of complete or partial remission
-Complete remission: PCR <30mg/mmol (proteinuria <0.3g/24h) with no worsening in renal function (estimated glomerular filtration rate (eGFR) reduction from baseline <15%)
-Partial remission: PCR <350mg/mmol (proteinuria <3.5g/24h) but ≥30mg/mmol (proteinuria ≥0.3g/24h) AND decrease of >50% from Day 0 baseline, together with no worsening in renal function (eGFR reduction from baseline <15%)
• Time to complete or partial remission
• Duration of complete or partial remission
• Incidence of proteinuria relapse (PCR >350mg/mmol AND increase of 50% from lowest remission level, in those subjects who had previously achieved any type of remission)
• Incidence of anti-PLA2R autoantibody remission:
-Full response: Antibody undetectable
-Partial response: Reduction in titres by 50%
• Time to anti-PLA2R autoantibody remission
• Incidence of anti-PLA2R autoantibody relapse (antibody detectable after previously undetectable)
• Change from baseline in eGFR levels
• Change from baseline in serum creatinine levels
• Change from baseline in levels of serum albumin
• Change from baseline in levels of cholesterol
• Incidence of oedema (extending beyond calf)
• Serum belimumab Cmax, Cmin, AUC(0-2), and urine Ae(0-24)
• Change from baseline in SF-36 v2 Quality of Life (QoL) questionnaire score
• Pharmacodynamic/biomarker endpoints may include Urine membrane attack complex (MAC), B Cell and T Cell sub-populations, BLyS levels, cytokines/chemokines (may include but not limited to IL-21, IL-17, IL-4, IL-10, IFN-Gamma), antigen specific lymphocyte response, autoantibody profile, change in transcriptomic profile or other markers of IMGN or autoimmune pathology, as data permit.
• Safety and tolerability as assessed by evaluation of adverse events (AE), clinical laboratory assessments (clinical chemistry, haematology and urinalysis), vital signs and immunogenicity. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 12, 28, 52, 76 and 104 (dependent on endpoint) |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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The end of the study is defined as the last subject’s last visit. |
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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |