R3R01 in Alport Syndrome Patients and Primary Steroid-Resistant Focal Segmental Glomerulosclerosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

River 3 Renal Corp.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

18 Jan 2023 → 20 Aug 2025

Decision date (initial)

2024-06-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-512964-73-00

EudraCT number

2021-004192-13

ClinicalTrials.gov

NCT05267262

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacokinetic, Efficacy

For all patients:
• To evaluate the tolerability and safety of R3R01 administered orally for 12 weeks.
For AS patients:
• To evaluate the efficacy of R3R01 in reducing proteinuria at 12 weeks in the whole AS group.
For FSGS patients:
• To evaluate the efficacy of R3R01 in reducing proteinuria at 12 weeks in the whole FSGS group.

Secondary objectives 3

1. For all patients: • To evaluate improvement in quality of life as measured by the Short Form SF-36 for adults or the pediatric quality of life inventory (PedsQL) for children (ages 12-18) and their parents/legal guardians by assessing the change from baseline to end of treatment (Day 84) and end of the follow-up period (Day 168). • To evaluate the pharmacokinetics of R3R01.
2. For AS patients:• To evaluate proteinuria complete response (UPCR <0.3g/g) at all timepoints proteinuria is measured. • To evaluate proteinuria partial response (decrease in proteinuria from baseline of ≥50%) at all timepoints proteinuria is measured.
3. For FSGS patients: • To evaluate proteinuria complete remission (UPCR <0.3g/g) at all timepoints proteinuria is measured. • To evaluate proteinuria partial remission (decrease in proteinuria from baseline of ≥50% and an absolute value of UPCR < 3.0g/g at all timepoints proteinuria is measured. • To evaluate proteinuria modified partial remission (decrease of ≥40% and UPCR < 1.5g/g) at all timepoints proteinuria is measured.

Conditions and MedDRA coding

Alport Syndrome (AS) and Primary Steroid-Resistent Focal Segmental Glomerulosclerosis (FSGS)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. All Patients: 1. Patient is able to communicate well with the investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF).
2. 2. For children to be eligible, one or both parents/legal guardians must sign a parental permission form which provides information contained in the ICF. Children capable of assent must express their willingness to participate by signing an assent form.
3. 3. If patient has received a COVID vaccination, the baseline visit must occur at least one week or more after the second/booster vaccination.
4. 4. Patients who have had active symptoms of COVID within 3 months prior to screening and are now asymptomatic for the last 2 weeks but have tested COVID PCR positive. If a patient is asymptomatic at screening but is COVID positive, then rescreening can occur after a minimum of two weeks.
5. 5. Both female patients, as well as female partners of male patients who are of child-bearing potential must be willing to not become pregnant for the complete duration of the study (>180 days) (90 days after the last dose of study medication).
6. 6. Males (including sterilized subjects) whose female partners have child-bearing potential, must agree to use male contraception (condoms) during the period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. They must agree to immediately inform the investigator if their partner becomes pregnant during the study.
7. AS Inclusion Criteria (in addition): 7. Males and females with X-Linked AS and males and females with autosomal inherited AS. a. For countries that are enrolling pediatric patients: patients from age 12 years and older. b. For countries that are not enrolling pediatric patients: patients from age 18 years and older.
8. 8. Confirmed diagnosis of AS by genetic testing and /or kidney biopsy. For patients enrolled in the US who meet all inclusion and exclusion criteria but have not had their diagnosis confirmed by genetic testing or kidney biopsy, the Sponsor will provide for patient’s genetic testing.
9. 9. UPCR ≥1.0 g/g.
10. 10. eGFR ≥ 45 mL/min/1.73m2 (using CKD-EPI equation for adults and Bedside Schwartz equation for children).
11. 11. ACEi/ARB therapy at maximum tolerated dose stable for at least 4 weeks prior to screening. ACEi/ARB dose should remain stable over the course of the study.
12. FSGS Inclusion Criteria (in addition): 12. Male or female patients, a. For countries that are enrolling pediatric patients: 12 to 75 years old at the time of signing the informed consent b. For countries that are not enrolling pediatric patients: 18 to 75 years old at the time of signing the informed consent
13. 13. Primary FSGS (without any identifiable cause, and where the FSGS is confirmed by renal biopsy) or FSGS where there is documentation of a genetic mutation in a podocyte protein associated with FSGS.
14. 14. Steroid-resistance defined as failure to achieve partial or complete remission, or experienced adverse events without acceptable clinical benefit after at least 8 weeks of adequate corticosteroid therapy for children and 12 weeks for adults.
15. 15. UPCR between 3.5g/g and 12.0g/g.
16. 16. eGFR > 45 mL/min/1.73m2 (using CKD-EPI equation for adults and Bedside Schwartz equation for children).
17. 17. If taking concomitant ACEi and/or ARB treatment, it should remain at a stable dose for a minimum of 28 days prior to enrollment and during the course of the study.

Exclusion criteria 26

1. All Patients: 1. Uncontrolled diabetes mellitus as evidenced by an HbA1c ≥ 11%. For Germany: HbA1c ≥ 8.5%.
2. 2. Uncontrolled hypertension a. Adults: (SBP ≥ 180mmHg and/or DBP ≥ 100mmHg). For Germany: (SBP ≥ 140mmHg and/or DBP ≥ 100mmHg). b. Children: ≥ 95th percentile or ≥ 130/80 mm Hg, whichever is lower, as defined in Appendix 13.8.
3. 3. Moderate or severe hepatic impairment as per Child Pugh score (See Section 9.5.4.7), except if (a) decreased serum albumin is directly related to the renal disease (resulting in a Child Pugh score of 7), and (b) no other Child-Pugh Score parameters are increased and (c) patient has no liver pathology in medical history.
4. 4. Presence of any active (i.e., with symptoms) and/or uncontrolled infection (including COVID).
5. 5. Presence of Human immunodeficiency virus (HIV).
6. 6. BMI > 40. For Germany: BMI > 35 (Obesity Class II).
7. 7. History of malignancy other than treated basal cell or squamous cell skin cancer within the past 5 years.
8. 8. History of alcohol abuse in the last 5 years or currently drinks in excess of 21 and 14 units per week for males and females, respectively.
9. 9. Received an investigational agent within 30 days or 5 half-lives prior to screening (whichever is longer).
10. 10. History of non-compliance such that patient is unlikely to be compliant with study visits, procedures or drug administration.
11. 11. Patient has had an organ transplant, is currently on an organ transplant waiting list or there is a reasonable possibility that the patient will have an organ transplant in the 6 months after screening.
12. 12. Participation in an interventional trial within the previous 3 months prior to screening or concurrent participation in a research trial.
13. 13. Patient is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of noncompliance with study visits, procedures, or drug administration) in the opinion of the investigator.
14. 14. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception as described in Section 13.3.
15. 15. Females that are lactating.
16. 16. History of hypersensitivity to study drug and/or any of its excipients
17. 17. Patients with hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
18. 18. Required concomitant use of bardoxolone, rituximab, cyclophosphamide, abatacept or sparsentan.
19. AS Exclusion Criteria (in addition): 19. Kidney disease apart from AS, e.g., diabetic nephropathy or lupus nephritis.
20. 20. Use of Bardoxolone or sparsentan treatment in the 30 days prior to screening. SGLT2 inhibitors are allowed if the patient is on a stable dose for at least 3 months prior to screening.
21. FSGS Exclusion Criteria (in addition): 21. Patient has collapsing variant of FSGS on renal biopsy.
22. 22. Patient has FSGS secondary to another condition (e.g., obesity, cardiovascular, infectious, or autoimmune disorder).
23. 23. Use of Rituximab, cyclophosphamide or abatacept treatment in the 120 days prior to screening. If taking other chronic immune-modulatory medications that are small molecules, the dosage must be stable for 4 weeks prior to screening.
24. 24. If previous Rituximab treatment is greater than 120 days from screening, CD20 cell count should be within normal limits.
25. 25. If previous other antibody treatment on a stable dose is greater than 120 days from screening, the investigator must deem administration of study drug to be safe.
26. 26. Use of sparsentan in the 30 days prior to screening. SGLT2 inhibitors are allowed if the patient is on a stable dose for at least 3 months prior to screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety and tolerability endpoints will be assessed by occurrence of adverse events (AE), changes in physical examinations, vital signs, ECGs and clinical laboratory parameters.
2. For AS patients: The change from baseline in UPCR at 12 weeks for all patients with AS.
3. For FSGS patients: The change from baseline in UPCR at 12 weeks for all patients with FSGS.

Secondary endpoints 4

1. For all patients: • Change in quality-of-life assessment from baseline to end of treatment and to the end of the follow-up period by cohort.
2. Population pharmacokinetic analysis to derive primary PK parameters (absorption rate (ka), apparent Clearance (Cl/F), apparent Volume of distriburion (V/F)), and secondary PK parameters (maximum concentration (Cmax), time of Cmax (tmax), minimum plasma concentrations (Cmin), area under the concentration time curve, elimination half-life (t1/2).
3. For AS patients: • Number of AS patients with complete response, a partial response for proteinuria (categorical assessment) at weeks 4, 8, 12, 16, 20 and 24.
4. For FSGS patients: • Number of FSGS patients with complete remission, a partial remission or a modified partial remission for proteinuria (categorical assessment) at weeks 4, 8, 12, 16, 20 and 24.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

River 3 Renal Corp.

Sponsor organisation

River 3 Renal Corp.

Address

7550 Purple Sage

City

Park City

Postcode

84098-5557

Country

United States

Scientific contact point

Organisation

River 3 Renal Corp.

Contact name

Chief Medical Operations

Public contact point

Organisation

River 3 Renal Corp.

Contact name

Chief Medical Operations

Third parties 6

Locations

4 EU/EEA countries · 8 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 59 files

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

Application history

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