Clinical trial NCT06465472: Evaluation of the Efficacy and Safety of Stiripentol in Patients 6 Years and Older With Primary Hyperoxaluria Type 1, 2 or 3
Official title: Evaluation of the Efficacy and Safety of Stiripentol in Patients 6 Years and Older With Primary Hyperoxaluria Type 1, 2 or 3
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Primary Hyperoxaluria Type 1
Primary Hyperoxaluria Type 2
Primary Hyperoxaluria Type 3
Keywords: Stiripentol
Primary Hyperoxaluria
Oxalate
Lead sponsor: Biocodex
Sponsor class: INDUSTRY
Collaborators: name: Exystat
First posted: 2024-06-18
Enrollment: 42
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study will be conducted in 2 periods: a 6-month, placebo-controlled, double-blind treatment period on which the primary endpoint will be evaluated (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 4 years open-label extension (OLE) part of the study to continue to assess the long-term efficacy and safety of stiripentol.
Primary purpose: TREATMENT

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.

Eligibility criteria: Screening Criteria :

* 1. Male or female patients aged ≥ 6 years at the time of consent signature
* 2. Diagnosed with primary hyperoxaluria (type 1, 2 or 3) documented as per standard methods
* 3. With last estimated Glomerular Filtration Rate ≥ 45 mL/min/1.73 m2
* 4. Able to understand and willing to comply with study requirements and to provide written informed consent. In case of patient under the age of legal consent, the legal guardian(s) must provide informed consent and the patient should provide assent as per local and national requirements
* 5. Female patients with contraception (intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, surgical sterilization of male partner, established use of oral, implantable, injectable, or transdermal hormonal methods of contraception, a double-barrier method (combination of male condom with cap, diaphragm, or sponge, in conjunction with spermicide) or true sexual abstinence

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

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:

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

Primary outcomes:
measure: % change in 24-hour urinary oxalate excretion corrected for body surface area (BSA) determined from 24-hour urine sample collections
timeFrame: % change in 24-hour urinary oxalate excretion between baseline value and value at month 6
Secondary outcomes:
measure: % change in 24-hour urinary oxalate excretion corrected for body surface area (BSA) determined from 24-hour urine sample collections
timeFrame: % change in 24-hour urinary oxalate excretion between baseline value and value at month 3
measure: 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
timeFrame: Absolute change in 24-hour urinary oxalate excretion between baseline value to Month 3 and Month 6 values.
measure: Change in 24-hour urine oxalate/creatinine ratio from baseline to Month 3 and Month 6
timeFrame: Change in 24-hour urine oxalate/creatinine ratio between baseline value to month 3 and month 6 values
measure: % of patients with urinary oxalate lower than 1.5 x upper limit of normal (ULN)) at Month 3 and Month 6
timeFrame: At 3 and 6 months of treatment.
measure: % of patients with normalisation of 24-hour urinary oxalate level corrected for bode surface area at Month 3 and Month 6
timeFrame: At 3 and 6 months of treatment.
measure: Blood samples for assessment of change in estimated glomerular filtration rate (eGFR in mL/min/1.73m2) from baseline to Month 6
timeFrame: Change in estimated glomerular filtration rate (eGFR) between baseline value and month 6 value
measure: Occurrence of and frequency of kidney stone events during the follow-up of the patient
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Change in urine oxalate/creatinine ratios as assessed in spot urine collections between baseline and Month 6
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Change in biological parameters : oxalate concentration measured in urinary spots collections between baseline and Month 6
timeFrame: From baseline to 6 months of treatment.
measure: Change in biological parameters : creatinine concentration measured in urinary spots collections between baseline and Month 6
timeFrame: From baseline to 6 months of treatment.
measure: Absolute change in quality of life measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire
timeFrame: At baseline and every 6 months until the end of the study (Month 60)
measure: Absolute change in quality of life measured by the Kidney Disease Quality of Life Questionnaire (KDQOL)
timeFrame: At baseline and every 6 months until the end of the study (Month 60)
measure: Change in quality of life measured by the Euro Quality of Life Health State Profile Questionnaire (EQ-5D)
timeFrame: At baseline and every 6 months until the end of the study (Month 60)
measure: Change in quality of life measured by the Euro Quality of Life Health State Profile Visual Analog Scale (VAS) : EQ-5D
timeFrame: At baseline and every 6 months until the end of the study (Month 60)
Other outcomes:
measure: Height in meters
timeFrame: At baseline and every 3 months until the end of the study (Month 60)
measure: Weight in kilograms
timeFrame: At baseline and every 3 months until the end of the study (Month 60)
measure: Changes in liver function tests (clinical laboratory parameters)
timeFrame: From start of participation of the patient to the end of the study
measure: Complete blood count with differential
timeFrame: At baseline and every months until the end of the study (Month 60)
measure: Frequency and nature of adverse events
timeFrame: From baseline to the end of the study (Month 60)
measure: Change in 24-hour urinary glyoxylate, glycine and glycolate
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Change from baseline (percent and absolute) in 24-hour urine oxalate excretion, percentage of time that 24-hour urinary oxalate ≤ 1.5 x ULN, 24-hour urine oxalate/creatinine ratios and eGFR
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: PK parameters : volume of distribution of stiripentol
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: PK parameters : clearance of stiripentol
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Exposure parameters : Peak Plasma Concentration (Cmax) of stiripentol
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Exposure parameters : Minimum Plasma Concentration (Cmin) of stiripentol
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Exposure parameters : Area under the plasma concentration versus time curve (AUC) of stiripentol
timeFrame: From start of participation of the patient to end of the study (Month 60)
measure: Change in plasma oxalate concentrations
timeFrame: At baseline and every three Months until month 12
measure: Change in plasma vitamin B6 concentrations
timeFrame: At baseline and every three Months until month 12
measure: Change in nephrocalcinosis as assessed by kidney imaging
timeFrame: At baseline and every 6 months until the end of the study (Month 60)
measure: Change in bone conditions during the follow-up
timeFrame: At Baseline and at Month 3,6 and 12
measure: Prediction of urinary oxalate excretion at exposure of clinical interest for stiripentol from a PK/PD model
timeFrame: At baseline and every 6 months until month 12
measure: Change in patient, caregiver and investigator impact and experiences as evaluated by patient and investigator experience surveys
timeFrame: At baseline and every 6 months until end of the study (Month 60)
Locations:
Study officials:
affiliation: Chief Scientific Officer
name: Oana BERNARD, MD
role: STUDY_DIRECTOR
References: