A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB

Study Overview
=================
Brief Summary
-----------------
DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor that, when administered concurrently with an ARB, is designed to inhibit recruitment of monocytes implicated in the inflammatory chemokine environment of chronic disease. The purpose of this pivotal randomized double-blind study is to investigate the efficacy and safety of DMX-200 120 mg twice daily (BID) compared with placebo over a treatment period of 104 weeks in adult patients with FSGS who are being treated with an ARB. Given the rarity of the disease and the similarities between adults and pediatric patients with FSGS, Dimerix will also investigate the efficacy and safety of DMX 200 in adolescents aged 12 to 17 years. The double-blind period will be followed by an open-label extension (OLE) which aims to assess the long-term efficacy and safety of DMX 200 for up to 2 additional years.

Detailed Description
-----------------
This is a pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of DMX-200 in patients with FSGS. The duration of the double-blind period per patient is estimated to be maximum of 122 weeks, a Screening and Qualification period of between 6 and 14 weeks (including a 4 week period to complete the assessments required for Screening, Titration (if required, up to 4 weeks) and, 6-weeks of Stabilization, a 104-week Treatment period, and up to a 4-week off-treatment Follow-up period. The treatment duration of the OLE period per patient is estimated to be a minimum of 104 weeks (2 years) with a 4-week off-treatment Follow-up period. The total study duration (double-blind period and OLE combined) is currently estimated to be a minimum of 230 weeks.

Official Title
-----------------
A Pivotal Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of DMX-200 in Patients With Focal Segmental Glomerulosclerosis (FSGS) Who Are Receiving an Angiotensin II Receptor Blocker (ARB)

Conditions
-----------------
FSGS

Intervention / Treatment
-----------------
* Drug: DMX-200
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
DOUBLE BLIND PERIOD Inclusion Criteria: Patients must be 12 to 80 years old A diagnosis of primary FSGS, genetic FSGS, or FSGS of undetermined cause. Confirmed by kidney biopsy or documentation of a genetic mutation in a podocyte protein associated with FSGS Must be either receiving an ARB at the maximal tolerated dose or willing to transition If taking corticosteroids, the dosage must be stable for ≥4 weeks prior to Screening and during Stablization If taking aldosterone inhibitors, mineralocorticoid receptor antagonists, direct renin inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, or endothelin receptor antagonists (ERAs, including dual antagonists), the dose and regimen must be stable for ≥12 weeks prior to Screening and during Stablization Urine PCR >1.5 g/g (>169.5 mg/mmol) or 24-hour total protein >1.5 g/day based on 24-hour urine collection during Screening. Estimated GFR ≥25 mL/min/1.73 m2 at Screening Seated blood pressure ≤160/100 mm Hg (mean of 3 values) (patients ≥18 years of age) or between the 5th and 95th percentile for age, sex, and height 29 (patients <18 years of age) at Screening. Body weight ≥35 kg (all patients) AND a BMI ≤40 kg/m2 (patients ≥18 years of age) or between the 5th and 98th percentile for age and sex (patients <18 years of age) at Screening. A female patient is eligible to participate if she is not pregnant or planning to become pregnant during the study, not breastfeeding, and at least one of the following conditions applies: Is not of childbearing potential If of childbearing potential and beginning at menarche, agrees to use a highly effective method of contraception consistently during the treatment period. A male patient with a female partner of childbearing potential is eligible to participate if he agrees to use acceptable contraception A patient or parent/legal guardian (as appropriate) who is capable of giving signed informed consent, and where required, the patient is capable of providing assent. Exclusion Criteria: Has FSGS secondary to another condition. History of type 1 diabetes mellitus, or uncontrolled type 2 diabetes mellitus (defined as glycated hemoglobin [HbA1c] >8%) History of lymphoma, leukemia, or any active malignancy within the past 2 years Active clinically significant hepatobiliary disease. Documented history of heart failure (New York Heart Association Class III/IV) or a major adverse cardiac event within 12 weeks prior to Screening. Has a physical, medical, or psychological condition, that in the opinion of the Investigator, may interfere with the evaluation the study. The patient has a history of alcohol or illicit drug use disorder within 1 year prior to Screening. Had a prior organ transplant or stem cell transplant, with the exception of corneal transplant. Positive screening assessment for viral hepatitis B surface antigen, or anti-hepatitis C virus antibody AND positive HCV RNA, or human immunodeficiency virus 1 and 2. Serum potassium levels >5.5 mmol/L at Screening. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2 × upper limit of normal (ULN) at Screening Treatment with immunosuppressant biological drugs, calcineurin inhibitors, cyclophosphamide, azathioprine, or mycophenolate mofetil within 12 weeks prior to Screening. History of serious side effects or allergic response to an angiotensin II antagonist or has a known sensitivity to any components in the Investigational Product. Unable to swallow oral medication. Prior participation in any Dimerix-sponsored DMX-200 clinical study. Participation in a clinical study with an Investigational Product within 28 days or 5 half-lives (whichever is longer) prior to Screening or plans to participate in another study during the course of this study. Are study site personnel directly affiliated with this study and their immediate families. OLE PERIOD Inclusion Criteria: A patient or parent/legal guardian (as appropriate) who is capable of giving signed informed consent, and where required, the patient is capable of providing assent. Patients who have completed participation in the double-blind period, including the Week 104 visit, and who may derive benefit from (continued) treatment with DMX-200, and/or continued follow-up The patient received blinded Investigational Product throughout the duration of the double-blind period up to the Week 104 visit The patient continues to meet the contraceptive requirements Exclusion Criteria: The patient has met the criteria for permanent IP discontinuation or study discontinuation Any safety concerns identified during the double-blind period which, in the Investigator's opinion, may interfere with the patient's continued participation during the OLE period.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DMX-200 (repagermanium)<br>Patients will receive 120 mg immediate release capsules of DMX-200 twice daily during the treatment period (104 weeks) OLE: Patients will receive 120 mg immediate release capsules of DMX-200 twice daily during the OLE period (108-212 weeks) | Drug: DMX-200<br>* DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor.<br>* Other names: Repagermanium;|
| Placebo Comparator: Placebo<br>Patients will receive 120 mg immediate release capsules of Placebo twice daily | Drug: Placebo<br>* Patients will receive 120 mg capsules of Placebo twice daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of DMX-200 in terms of urine PCR in patients with FSGS who are receiving an ARB. | Percent change in urine PCR (based on 24-hour urine collection) | Baseline to Week 35 | 
| Evaluate the efficacy of DMX-200 in terms of eGFR slope in patients with FSGS who are receiving an ARB (Analysis at week 35 and Week 104). | Slope of eGFR | Baseline to Week 104 | 
| OLE - Assess the long-term safety and tolerability of open-label treatment with DMX-200 in patients with FSGS who are receiving an ARB. | Incidence and severity of treatment-related AEs and any AESIs and SAEs following long-term treatment with DMX-200. | Double-blind baseline to Week 216 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the incidence and severity of AEs with treatment of DMX-200 in patients with FSGS who are receiving an ARB. | Incidence and severity of AEs and clinically significant changes following treatment with DMX-200 compared with placebo. | Baseline to Week 104 | 
| To evaluate the effect of DMX-200 on kidney function parameters including proteinuria in patients with FSGS who are receiving an ARB. | Proportion of responders and non-responders following treatment with DMX-200 compared with placebo. Proportion of patients on treatment with DMX-200 compared with placebo that meet a composite endpoint of worsening in kidney function. | Baseline to Week 104 | 
| OLE - Assess the long-term efficacy of open-label treatment with DMX-200 in patients with FSGS who are receiving an ARB. | Slope of eGFR and percent change in urine PCR | From Week 108 (Baseline) at each visit | 
| OLE - Evaluate the long-term effect of open-label treatment with DMX-200 on kidney function parameters in patients with FSGS who are receiving an ARB. | Proportion of patients on treatment with DMX-200 that meet a composite endpoint of worsening in kidney function. | Double blind baseline to Week 216 |