An exploratory, randomized, double-blind, multicenter, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and efficacy of AP1189 daily doses versus placebo administered for 12 weeks as an addon to patients, in ACE inhibitor or angiotensin II receptor blocker treatment, with idiopathic membranous nephropathy and severe proteinuria

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Synact Pharma ApS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

31 Aug 2020 → ongoing

Decision date (initial)

2024-10-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-518384-36-00

EudraCT number

2020-000971-18

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

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).

Secondary objectives 7

1. Result of 12 weeks treatment (Baseline to end of 12 weeks): On 24 hours urinary albumin excretion, expressed as changes in urine excretion.
2. Result of 12 weeks treatment (Baseline to end of 12 weeks): Result of 12 weeks treatment (Baseline to end of 12 weeks):
3. Result of 12 weeks treatment (Baseline to end of 12 weeks): On changes in plasma albumin.
4. Result of 12 weeks treatment (Baseline to end of 12 weeks): Number of subjects showing partial/complete remission (defined in the protocol) on the last day of treatment and four weeks after the last dose administered.
5. Result of 12 weeks treatment (Baseline to end of 12 weeks): On estimated GFR (eGFR) expressed as changes in GFR.
6. Result of 12 weeks treatment (Baseline to end of 12 weeks): On 24 hours urinary creatinine clearance CCr expressed as changes in CCr.
7. Result of 12 weeks treatment (Baseline to end of 12 weeks): 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 XML File Identifier: Uj0njDPhQ3qJXFMMvCufrdyCYKo= Page 16/28 dosing and baseline.

Conditions and MedDRA coding

Idiopathic membranous nephropathy and severe proteinuria

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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
7. ONLY DENNMARK AND NORWAY: Females of child-bearing potential using reliable means of contraception (for detailed information see section 17.8) or are postmenopausal (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. ONLY DENNMARK AND NORWAY: Females of childbearing potential with negative pregnancy test at screening and baseline
9. 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)

Exclusion criteria 13

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)
13. ONLY SWEDEN: Females of child-bearing potential

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. To compare the safety of AP1189 against placebo by evaluating adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms and laboratory abnormalities.
2. 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).

Secondary endpoints 7

1. 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)
2. 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)
3. The result of 12 weeks of treatment on changes in plasma albumin from baseline to the end of the twelve weeks treatment period
4. 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. Partial 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.
5. 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
6. 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
7. Changes in the above-defined parameters (urinary protein/albumin, Palbumin, GFR and CCr) at the four weeks post-dosing follow up visit, compared to the values at the end of dosing and baseline.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Synact Pharma ApS

Sponsor organisation

Synact Pharma ApS

Address

Dronninggaards Alle 136

City

Holte

Postcode

2840

Country

Denmark

Scientific contact point

Organisation

Synact Pharma ApS

Contact name

Thomas Jonassen

Public contact point

Organisation

Synact Pharma ApS

Contact name

Thomas Jonassen

Third parties 1

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications