Evaluation of the Efficacy and Safety of Stiripentol in Patients 6 Years and Older With Primary Hyperoxaluria Type 1, 2 or 3

Phase 3

Not yet recruiting

• Conditions: Primary Hyperoxaluria Type 1; Primary Hyperoxaluria Type 2; Primary Hyperoxaluria Type 3
• Interventions: Drug: Stiripentol Oral Capsule; Drug: Placebo Oral Capsule; Biological: Urine samples collect; Biological: Blood samples collect; Other: Kidney imaging; Other: Quality of Life questionnaires

• Registration Number: NCT06465472
• Lead Sponsor: Biocodex

Brief Summary

Evaluation of the efficacy and safety of stiripentol in patients 6 years and older with primary hyperoxaluria type 1, 2 or 3.

Detailed Description

A multicenter randomized, double-blind, placebo-controlled phase 3 study The study is designed to compare the efficacy of stiripentol to a placebo in patients 6 years and older with primary hyperoxaluria type 1, 2 or 3.

The study will be conducted in 2 periods: a 6-month, placebo-controlled, double-blind treatment period (period 1) followed by a 6-month open-label treatment period with blind maintained on results (period 2).

Patients who benefit from the treatment after the first 12 months of study treatment will be proposed to enter the open-label extension (OLE) part of the study to continue to assess the long-term efficacy and safety of stiripentol.

Study Timeline

• Status Verified: 2024-06
• Study First Submitted: 2024-06-03
• Study First Submitted QC: 2024-06-12
• Last Update Submitted: 2024-06-12
• Study First Posted: 2024-06-18
• Last Update Posted: 2024-06-18
• Study Start: 2024-08
• Primary Completion: 2030-08
• Study Completion: 2030-08

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 42

Inclusion Criteria

• 1. Diagnosed with primary hyperoxaluria disease and subtype (type 1, 2 or 3) confirmed by genetic testing
• 2. Receiving optimal management of the disease through standard of care strategies (e.g., increased fluid intake, vitamin B6, potassium citrate) with or without approved target medications (e.g., lumasiran). Patients not receiving lumasiran can only be enrolled if they are not eligible for treatment with lumasiran for the specific following reasons: contraindications, previous treatment discontinued due to lack of efficacy or poor tolerability, not meeting national or regional eligibility criteria for treatment, investigator judgement
• 3. With mean 24-hour urinary oxalate excretion from 2 valid 24-hour urine collections ≥ 0.70 mmol/24h/1.73m²
• 4. With estimated Glomerular Filtration Rate ≥ 45 mL/min/1.73 m2 (Schwartz et al., 2009 in pediatric patients and CKD-EPI in adults)
• 5. Pubescent and adult female patients must have a negative urine or serum pregnancy test within 60 days prior to first dose of study treatment if of childbearing potential. If the urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible
• 6. In France, patient affiliated with or who benefits from a social security scheme

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Exclusion Criteria

• 1. Any relevant change in the use of any component of the standard of care (fluid intake, vitamin B6, potassium citrate) in the 4 weeks prior to inclusion or if such change is planned to occur during the first 6 months of the study
• 2. If under approved targeted medications (e.g., lumasiran), treatment should have been administered for at least 6 months, with no change in dose or regimen in the 3 months prior to inclusion or ifsuch change is planned it should not occur during the first 12 months of the study
• 3. History of kidney or liver transplant

• 4. Presenting any of the following liver function tests abnormalities during the screening period:

  5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)> 2 × upper limit of normal (ULN)

  6. Total bilirubin > 1.5 x ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert's syndrome are eligible if the total bilirubin is < 2 x ULN

• 5. Recent (4 weeks before the screening visit) or planned change in eating habits
• 6. Intermittent fasting planned during the 6 first months of the study period (e.g., Ramadan)
• 7. Other medical conditions or comorbidities, treatment, which in the opinion of the investigator, would interfere with study compliance or data interpretation
• 8. Presenting any significant biological or clinical anomalies that are not compatible with participation in the study according to the investigator
• 9. History of severe allergy, asthma, skin rashes, intolerance to lactose or hypersensitivity to the study treatments
• 10. Treatment affecting hepatic metabolism (i.e., cimetidine, ketoconazole, fluconazole, itraconazole, phenytoin, rifampicin, rifabutin) that is ongoing or has been taken in the month prior to the selection visit
• 11. Treatment affecting the renal tubule (probenecid, β-lactam, etc.,) that is ongoing or has been taken in the two weeks prior to the start of the study
• 12. Contraindications to stiripentol as defined in the applicable Investigator's Brochure (i.e. patients presenting a hypersensitivity to the active substance or any excipients)
• 13. Patient at risk of pregnancy, pregnant or breastfeeding female
• 14. Patient under guardianship or curatorship
• 15. Patient under the protection of the Court or deprived of liberty
• 16. Patient participating in another interventional clinical trial which could interfere with the trial's results or impact the other trial's results; or within the last 30 days or 5 half-lives of the study investigational treatment, whichever is longer, prior to the urinary sampling during the screening period, or are in follow-up of another clinical study prior to randomization
• 17. Patient whose current state of health does not allow him/her to give consent

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stiripentol	Stiripentol Oral Capsule	Patients in this arms will receive 50 mg/kg/day oral stiripentol during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then continue the same treatment for the following 6 months (period 2).
Stiripentol	Urine samples collect	Patients in this arms will receive 50 mg/kg/day oral stiripentol during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then continue the same treatment for the following 6 months (period 2).
Stiripentol	Blood samples collect	Patients in this arms will receive 50 mg/kg/day oral stiripentol during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then continue the same treatment for the following 6 months (period 2).
Stiripentol	Kidney imaging	Patients in this arms will receive 50 mg/kg/day oral stiripentol during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then continue the same treatment for the following 6 months (period 2).
Stiripentol	Quality of Life questionnaires	Patients in this arms will receive 50 mg/kg/day oral stiripentol during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then continue the same treatment for the following 6 months (period 2).
Placebo	Placebo Oral Capsule	Patients in this arms will receive 50 mg/kg/day oral placebo during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then patients receiving placebo will switch over the 6 to 12 month-period to stiripentol (period 2).
Placebo	Urine samples collect	Patients in this arms will receive 50 mg/kg/day oral placebo during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then patients receiving placebo will switch over the 6 to 12 month-period to stiripentol (period 2).
Placebo	Blood samples collect	Patients in this arms will receive 50 mg/kg/day oral placebo during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then patients receiving placebo will switch over the 6 to 12 month-period to stiripentol (period 2).
Placebo	Kidney imaging	Patients in this arms will receive 50 mg/kg/day oral placebo during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then patients receiving placebo will switch over the 6 to 12 month-period to stiripentol (period 2).
Placebo	Quality of Life questionnaires	Patients in this arms will receive 50 mg/kg/day oral placebo during the first 6 months double-blind placebo-controlled study period 1 (Day 1 through Month 6) then patients receiving placebo will switch over the 6 to 12 month-period to stiripentol (period 2).

Primary Outcome Measures

Name	Time	Method
% change in 24-hour urinary oxalate excretion corrected for body surface area (BSA) determined from 24-hour urine sample collections	% change in 24-hour urinary oxalate excretion between baseline value and value at month 6	% change in 24-hour urinary oxalate excretion in mg/kg corrected for body surface area (BSA) between baseline and Month 6 and determined from 24-hour urine sample collections

Secondary Outcome Measures

Name	Time	Method
% change in 24-hour urinary oxalate excretion corrected for body surface area (BSA) determined from 24-hour urine sample collections	% change in 24-hour urinary oxalate excretion between baseline value and value at month 3	% change in 24-hour urinary oxalate excretion in mg/kg corrected for body surface area (BSA) from baseline to Month 3 and determined from 24-hour urine sample collections
Absolute change in 24-hour urinary oxalate excretion in mg/kg corrected for body surface area (BSA) from baseline to Month 3 and Month 6	Absolute change in 24-hour urinary oxalate excretion between baseline value to Month 3 and Month 6 values.	Absolute change in 24-hour urinary oxalate excretion in mg/kg corrected for BSA from baseline to Month 3 and Month 6
Change in 24-hour urine oxalate/creatinine ratio from baseline to Month 3 and Month 6	Change in 24-hour urine oxalate/creatinine ratio between baseline value to month 3 and month 6 values	Concentration of 24-hour urine oxalate and 24-hour urine creatinine will be combined to report urine oxalate/creatinine ratio from baseline to Month 3 and Month 6. The concentrations will be determined using a validated assay
% of patients with urinary oxalate lower than 1.5 x upper limit of normal (ULN)) at Month 3 and Month 6	At 3 and 6 months of treatment.	%of patients with near normalisation of 24-hour urinary oxalate level corrected for BSA (defined as urinary oxalate lower than 1.5 x upper limit of normal (ULN)) at Month 3 and Month 6)
% of patients with normalisation of 24-hour urinary oxalate level corrected for bode surface area at Month 3 and Month 6	At 3 and 6 months of treatment.	% of patients with near normalisation of 24-hour urinary oxalate level corrected for BSA (defined as urinary oxalate lower than 1.5 x upper limit of normal (ULN)) at Month 3 and Month 6)
Blood samples for assessment of change in estimated glomerular filtration rate (eGFR in mL/min/1.73m2) from baseline to Month 6	Change in estimated glomerular filtration rate (eGFR) between baseline value and month 6 value	Blood samples for assessment of change in estimated glomerular filtration rate (eGFR). EGFR (mL/min/1.73m2) will be calculated from baseline to Month 6
Occurrence of and frequency of kidney stone events during the follow-up of the patient	From start of participation of the patient to end of the study (Month 60)	Number of and frequency of kidney stone events reported during the follow-up of the patient
Change in urine oxalate/creatinine ratios as assessed in spot urine collections between baseline and Month 6	From start of participation of the patient to end of the study (Month 60)	Urine oxalate/creatinine ratios will be calculated from the oxalate and creatinine levels measured in spot urine collected during patients' hospitalizations or at home. The concentrations will be determined using a validated assay.
Change in biological parameters : oxalate concentration measured in urinary spots collections between baseline and Month 6	From baseline to 6 months of treatment.	Change in oxalate concentration, related to kidney stone formation, measured in urinary spots collections between baseline and Month 6
Change in biological parameters : creatinine concentration measured in urinary spots collections between baseline and Month 6	From baseline to 6 months of treatment.	Change in creatinine concentration, related to kidney stone formation, measured in urinary spots collections between baseline and Month 6
Absolute change in quality of life measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire	At baseline and every 6 months until the end of the study (Month 60)	Absolute change in the Pediatric Quality of Life Inventory (PedsQL \[the generic and kidney failure (KF) modules\]) for patients \< 18 years of age (at screening) which is a 23 items 5-point Likert scale from: 0 (Never) to 4 (Almost always). Scores are transformed on a scale from 0 to 100 so higher score means better health.
Absolute change in quality of life measured by the Kidney Disease Quality of Life Questionnaire (KDQOL)	At baseline and every 6 months until the end of the study (Month 60)	Absolute changes in the Kidney Disease Quality of Life Questionnaire (KDQOL) for patients ≥ 18 years of age (at screening) which is a 36 items survey with five subscales. Scores are transformed on a scale from 0 to 100 so higher score means better health.
Change in quality of life measured by the Euro Quality of Life Health State Profile Questionnaire (EQ-5D)	At baseline and every 6 months until the end of the study (Month 60)	Change in Euro Quality of Life Health State Profile Questionnaire (EQ-5D) is a standardized instrument consisting of a questionnaire. Scoring of the questionnaire is based on degrees of disability. Higher scores indicate better health status.
Change in quality of life measured by the Euro Quality of Life Health State Profile Visual Analog Scale (VAS) : EQ-5D	At baseline and every 6 months until the end of the study (Month 60)	Change in EQ-5D Visual Analog Scale EQ-5D is a standardized instrument consisting of a visual analog scale pertaining to 5 dimensions. Scoring of the visual analog scale is based on a visual scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher scores indicate better health status.