A Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Treatment With AP1189 in Patients With iMN and Severe Proteinuria

Study Overview
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Brief Summary
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This study is an exploratory, randomized, double-blind, multicenter, placebo-controlled study with repeated doses of AP1189. The study population will consist of patients with idiopathic membranous nephropathy (iMN) and severe proteinuria who are on ACE inhibitor or angiotensin II receptor blocker treatment.

Detailed Description
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This study is an exploratory, randomized, double-blind, multicenter, placebo-controlled study with repeated doses of AP1189. The study population will consist of patients with idiopathic membranous nephropathy (iMN) and severe proteinuria who are on ACE inhibitor or angiotensin II receptor blocker treatment. Following a successful screening, subjects who fulfill the enrollment criteria will be randomized in a 2:1 ratio in group A and B: Group A (12 subjects): AP1189 dose 100 mg, once daily for 12 weeks (28 days) as an add-on to any ongoing treatment, including ACE inhibitors/ angiotensin II receptor blocker Group B (6 subjects): placebo for 12 weeks (28 days) as an add-on to any ongoing treatment including ACE inhibitors/ angiotensin II receptor blocker.

Official Title
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An Exploratory, Randomized, Double-blind, Multicenter, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AP1189 Versus Placebo Administered for 12 Weeks as an add-on to Patients, in ACE Inhibitor or Angiotensin II Receptor Blocker Treatment, With Idiopathic Membranous Nephropathy and Severe Proteinuria

Conditions
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Nephrotic Syndrome Due to Idiopathic Membranous Nephropathy, Severe Proteinuria Due to Idiopathic Membranous Nephropathy

Intervention / Treatment
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* Drug: 100 mg AP1189
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent has been obtained prior to initiating any study-specific procedures Male and female subjects, 18 to 85 years of age diagnosed with iMN within 6 months prior to inclusion Diagnosed as anti-PLA2-Receptor positive by local laboratory within 6 months prior to inclusion Severe proteinuria defined by a U-protein/creatinine ratio >3.0 g/g and/or U-albumin/creatinine ratio >2.0 g/g and a P-albumin below the lower normal limit eGFR > 30 ml/min/1.73m2 Treated with ACE- inhibitors or angiotensin II receptor blocker for a minimum of 1 months 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 effect Only Denmark and Norway: Females of child-bearing potential using reliable means of contraception or are post-menopausal Females of childbearing potential with negative pregnancy test at screening and baseline Only Sweden: Post-menopausal women or women who are surgically sterilized. Exclusion Criteria: Participation in any other study involving investigational drug(s) during the study and within 4 weeks prior to study entry Clinicial findings that in the opinion of the investigator would suggest condition(s) other than iMN as a major cause of severe proteinuria Major surgery within 8 weeks prior to screening or planned surgery within 1 month following randomization 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 Treated with systemic corticosteroids, or other immune suppressive, or immune modulating compounds within 4 weeks prior to screening and during the entire treatment period and until the final visit Treated with rituximab within 12 months of screening Evidence of active malignant disease Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disease Pregnant women or nursing mothers History of alcohol, drug, or chemical abuse within the 6 months prior to screening Any condition that in the view of the investigator would suggest that the patient is unable to comply with study protocol and procedures Only Sweden: Females of child-bearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Exploratory, randomized, double-blind, multi-center, placebo-controlled 12-weeks study with repeated doses of AP1189
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg AP1189<br>100 mg AP1189. The treatment is a 12-weeks treatment. Each daily dose will be administered as a tablet | Drug: 100 mg AP1189<br>* 100 mg AP1189 tablet<br>|
| Experimental: Placebo<br>Placebo. The treatment is a 12-weeks treatment. Each daily dose will be administered as a tablet | Drug: Placebo<br>* Matching placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event | Evaluation of Adverse Event | Week 12 | 
| Serious Adverse Events | Evaluation of Serious Adverse Events | Week 12 | 
| ALAT change in plasma samples | Evaluation of ALAT compared with baseline | Week 12 | 
| ASAT change in plasma samples | Evaluation of ASAT compared with baseline | Week 12 | 
| Total bilirubin change in plasma samples | Evaluation of total bilirubin compared with baseline | Week 12 | 
| Alkaline phosphatase change in plasma samples | Evaluation of alkaline phosphatase compared with baseline | Week 12 | 
| Protein change in 24 hours urinary protein excretion | Change of protein in urine excretion compared to baseline measured in 24 h urinary protein excretion | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Albumin change in 24 hours urinary protein excretion | Change of albumin in urine excretion compared to baseline measured in 24 h urinary protein excretion | Week 12 |