E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic membranous nephropathy and severe proteinuria |
Idiopatisk membranøs nefropati og svær proteinuri |
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E.1.1.1 | Medical condition in easily understood language |
Membranous nephropathy and severe proteinuria is a rare disease that attacks the small filters (glomeruli) in the kidney. This results in "leaks" and the kidneys lose protein in the urine. |
Membranøs nefropati er en sjælden sygdom, som angriber de små filtre (glomeruli) i nyrerne. Dette resulterer i "utætheder", hvor nyrerne taber protein i urinen. |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027170 |
E.1.2 | Term | Membranous nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029164 |
E.1.2 | Term | Nephrotic syndrome |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
To compare the safety of AP1189 against placebo by evaluating adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms and laboratory abnormalities.
The result of 12 weeks of treatment on 24 hours urinary protein excretion as expressed as changes in urine excretion from baseline to the end of the twelve weeks treatment period (baseline is defined as 24 h urinary protein excretion determined prior to dosing with AP1189 or placebo) |
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E.2.2 | Secondary objectives of the trial |
Result of 12 weeks treatment (Baseline to end of 12 weeks): On 24 hours urinary albumin excretion, expressed as changes in urine excretion. On fractional urine excretion of albumin (FEAlb) compared to baseline where changes in FEAlb is expressed in % compared to baseline levels. On changes in plasma albumin. No of subjects showing partial/complete remission (defined in the protocol) on the last day of treatment and four weeks after the last dose administered. On estimated GFR (eGFR) expressed as changes in GFR. On 24 hours urinary creatinine clearance CCr expressed as changes in CCr. Changes in urinary protein/albumin, P-albumin, eGFR and CCr at the four weeks post-dosing follow up visit, compared to the values at the end of dosing and baseline.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study of the pharmacokinetics (PK) of AP1189 The effects of AP1189 will be compared both within-group (compared with baseline) and against placebo by assessing: • The pharmacokinetic parameters of AP1189 following the first and last day of dosing: o Pharmacokinetic parameters (Cmax, tmax, AUC0-t, AUC0-24, AUC0-∞ (Day 1 only), Ke, and te) to be calculated based on measurement of the concentration of AP1189 in plasma with samples collected pre-dose, then 0.5 h, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0 and 8.0 h post dose.
Up to 8 subjects can participate in the PK sub-study. PK data from subjects treated for four weeks with the IMP solution and completed the PK sampling, will be analyzed together with the PK data from subjects receiving tablet treatment in the Sub-study.
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E.3 | Principal inclusion criteria |
1.Written informed consent has been obtained prior to initiating any study-specific procedures 2.Male and female subjects, 18 to 85 years of age with iMN and severe proteinuria 3.Diagnosed as anti-PLA2-Receptor positive by local laboratory within 6 months prior to inclusion and/or having a renal biopsy consistent with iMN within 24 months of inclusion 4.Severe proteinuria defined by a U-protein/creatinine ratio >3.0 g/g and/or U-albumin/creatinine ratio >2.0 g/g and P-albumin below the lower normal limit 5.eGFR > 30 ml/min/1.73m2 6.Treatment with ACE- inhibitors or angiotensin II receptor blocker for a minimum of 1 month with a stable systemic arterial blood pressure OR treatment with ACE inhibitors and/or angiotensin receptor blocker was excluded or discontinued due to hypotension, intolerance or other side effects ONLY DENNMARK AND NORWAY: 7.Females of child-bearing potential using reliable means of contraception (for detailed information see section 17.8) or are post-menopausal (menstrual periods stopped at least 12 months ahead of the enrolment in the trial) or are surgically sterilized (the procedure must have been performed at least 6 months prior to screening) 8.Females of childbearing potential with negative pregnancy test at screening and baseline ONLY SWEDEN: Post-menopausal women (menstrual periods stopped at least 12 months ahead of the enrolment in the trial) or women who are surgically sterilized (the procedure must have been performed at least 6 months prior to screening)
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E.4 | Principal exclusion criteria |
1.Participation in any other study involving investigational drug(s) during the study and within 4 weeks prior to study entry 2.Clinical findings that in the opinion of the investigator would suggest condition(s) other than iMN as a major cause of severe proteinuria 3.Major surgery within 8 weeks prior to screening or planned surgery within one month following randomization 4.Blood pressure with systolic pressure above 160 mmHg and/or diastolic pressure above 100 mmHg despite antihypertensive treatment will in all cases be considered “uncontrolled” 5.Treated with systemic (oral, intramuscular or IV) corticosteroids, or other immune suppressive, or immune modulating compounds within 4 weeks (8 weeks for IV cyclophosphamide) prior to screening (and during the entire treatment period and until the final visit) 6.Treated with rituximab within 12 months of screening 7.Evidence of active malignant disease (except basal cell carcinoma of the skin that has been excised and cured). 8.Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids 9.Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal disease 10.Pregnant women or nursing (breastfeeding) mothers 11.History of alcohol, drug, or chemical abuse within the 6 months prior to screening 12.Any condition that in the view of the investigator would suggest that the patient is unable to comply with study protocol and procedures (e.g., psychiatric disorders, dementia) ONLY SWEDEN: 13.Females of child-bearing potential |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety Objective and Endpoints: To compare the safety of AP1189 against placebo by evaluating adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms and laboratory abnormalities.
Primary Efficacy Objective and Endpoints: The result of 12 weeks of treatment on 24 hours urinary protein excretion as expressed as changes in urine excretion from baseline to the end of the twelve weeks treatment period (baseline is defined as 24 h urinary protein excretion determined prior to dosing with AP1189 or placebo).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
AE and SAE will be registered at all visits/phone calls and the biochemestry, hematology and thyroid blood samples will be taken at Visit (V) 1, 2, 3, 4, 5 and 6.
24-hour urinary protein excretion will be measured at V2, 4, 5 and 6. |
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E.5.2 | Secondary end point(s) |
•The result of 12 weeks of treatment on 24 hours urinary albumin excretion as expressed as changes in urine excretion from baseline to the end of the twelve weeks treatment period (baseline is defined as 24 h urinary albumin excretion determined prior to dosing with AP1189 or placebo) •The result of 12 weeks of treatment on fractional urine excretion of albumin (FEAlb) compared to baseline (where FEAlb is defined as Clearance of Albumin/Clearance of Creatinine expressed in %; (FEAlb=CAlb/ CCr x 100)) where changes in FEAlb is expressed in % compared to baseline levels (ΔFEAlb = FEAlb, four weeks- FEAlb, baseline) •The result of 12 weeks of treatment on changes in plasma albumin from baseline to the end of the twelve weeks treatment period •The number of subjects who show partial or complete remission on the last day of treatment and four weeks after the last dose administered, defined as: oComplete Remission: Urinary protein excretion <0.3 g/d accompanied by a normal P-albumin concentration, and a normal P-creatinine value oPartial Remission: Urinary protein excretion <3.5 g/d and a 50% or greater reduction from peak values accompanied by an improvement or normalization of the P-albumin concentration and stable P-creatinine value •The result of 12 weeks of treatment on estimated GFR calculated from both P-creatinine and P-cystatin C expressed as changes in GFR from baseline to the end of the twelve weeks treatment period •The result of 12 weeks of treatment on 24 hours urinary creatinine clearance CCr expressed as changes in CCr from baseline to the end of the twelve weeks treatment period •Changes in the above-defined parameters (urinary protein/albumin, P-albumin, GFR and CCr) at the four weeks post-dosing follow up visit, compared to the values at the end of dosing and baseline |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Urinary albumin, protein and creatinine: at V.1, 2, 4, 5 and 6. Plasma albumin: at V. 1, 2, 4, 5 and 6. Estimated GFR (eGFR): at V. 2, 4, 5 and 6.
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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 | 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 |
Pharmacokinetic data will, for the subjects receiving treatment with tablets, be collected in up to 8 subjects, a PK Sub-study |
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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) | 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 | 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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |