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

Primary Hyperoxaluria Type 1 Clinical Trial

— CRYSTAL  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06465472
• Other study ID #: CRYSTAL - STP226
• Secondary ID: 2023-508062-15-0
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: August 2024
• Est. completion date: August 2030

Study information

• Verified date: June 2024
• Source: Biocodex
• Contact: Pauline DECIMA
• Phone: 03.44.86.82.28
• Email: p.decima[@]biocodex.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 42
• Est. completion date: August 2030
• Est. primary completion date: August 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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, ß-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

Related Conditions & MeSH terms

• Hyperoxaluria, Primary
• Primary Hyperoxaluria Type 1
• Primary Hyperoxaluria Type 2
• Primary Hyperoxaluria Type 3

Intervention

Drug:
• Stiripentol Oral Capsule
The target dose of stiripentol will be 50 mg/kg/day with a maximum dose of 3,000 mg/day. Patients allocated to the Stiripentol group will receive this treatment during the first 6 months, and in continuation up to 12 months.
• Placebo Oral Capsule
Placebo capsules will be administered for the first 6 months. Then patients will switch to stiripentol over the 6- to 12-month period.

Biological:
• Urine samples collect
Collections of urine over 24 hours and the first urine in the morning (spot urines) will be carried out. Urine collections will be performed either during hospitalizations, or at home if appropriate conditions are met.
• Blood samples collect
Series of blood samples will be taken (serum pregnancy test, Primary Hyperoxaluria genetic characterization, clinical laboratory assessments, vitamin B6 dosage, plasma oxalate dosage, stiripentol pharmacokinetics)

Other:
• Kidney imaging
Kidney imaging will be obtained. Renal ultrasounds will be compulsory for all patients.
• Quality of Life questionnaires
Kidney Disease Quality of Life Questionnaire : KDQOL-36 for patients =18 years of age at screening, and the Pediatric Quality of Life Inventory (PedsQL) including the generic and KF modules (parent and/or self-report versions) for patients <18 years of age at screening. EQ-5D: a standardized instrument consisting of a questionnaire and a visual analog scale pertaining to 5 dimensions. Scoring of the questionnaire is based on degrees of disability. 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. The EQ-5D-5L questionnaire (will be utilized in patients =18 years of age at screening, and the EQ-5D-Y questionnaire will be utilized in patients <18 years of age at screening, where available.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Biocodex	Exystat

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Height in meters	Changes in height in meters	At baseline and every 3 months until the end of the study (Month 60)
Other	Weight in kilograms	Changes in weight in kilograms	At baseline and every 3 months until the end of the study (Month 60)
Other	Changes in liver function tests (clinical laboratory parameters)	Changes in liver function tests (AST, ALT, GGT, ALP, Bilirubin (total and direct))	From start of participation of the patient to the end of the study
Other	Complete blood count with differential	Changes in complete blood count with differential ( blood test results)	At baseline and every months until the end of the study (Month 60)
Other	Frequency and nature of adverse events	Collect of the frequency and nature of adverse events	From baseline to the end of the study (Month 60)
Other	Change in 24-hour urinary glyoxylate, glycine and glycolate	Change in 24-hour urinary glyoxylate, glycine and glycolate	From start of participation of the patient to end of the study (Month 60)
Other	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	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	From start of participation of the patient to end of the study (Month 60)
Other	PK parameters : volume of distribution of stiripentol	PK parameters : volume of distribution of stiripentol based on appropriate PK sampling scheme (on Month 0, Month 6 and Month 12), and further determined through a population PK (popPK) approach	From start of participation of the patient to end of the study (Month 60)
Other	PK parameters : clearance of stiripentol	PK parameters : clearance of stiripentol based on appropriate PK sampling scheme (on Month 0, Month 6 and Month 12), and further determined through a population PK (popPK) approach	From start of participation of the patient to end of the study (Month 60)
Other	Exposure parameters : Peak Plasma Concentration (Cmax) of stiripentol	Peak Plasma Concentration (Cmax) of stiripentol based on appropriate PK sampling scheme (on Month 0, Month 6 and Month 12), and further determined through a population PK (popPK) approach	From start of participation of the patient to end of the study (Month 60)
Other	Exposure parameters : Minimum Plasma Concentration (Cmin) of stiripentol	Minimum Plasma Concentration (Cmin) of stiripentol based on appropriate PK sampling scheme (on Month 0, Month 6 and Month 12), and further determined through a population PK (popPK) approach	From start of participation of the patient to end of the study (Month 60)
Other	Exposure parameters : Area under the plasma concentration versus time curve (AUC) of stiripentol	Area under the plasma concentration versus time curve (AUC) of stiripentol based on appropriate PK sampling scheme (on Month 0, Month 6 and Month 12), and further determined through a population PK (popPK) approach	From start of participation of the patient to end of the study (Month 60)
Other	Change in plasma oxalate concentrations	Change in plasma oxalate concentrations	At baseline and every three Months until month 12
Other	Change in plasma vitamin B6 concentrations	Change in plasma vitamin B6 concentrations	At baseline and every three Months until month 12
Other	Change in nephrocalcinosis as assessed by kidney imaging	Change in nephrocalcinosis as assessed by kidney imaging	At baseline and every 6 months until the end of the study (Month 60)
Other	Change in bone conditions during the follow-up	Change in bone conditions during the follow-up based on questions from the investigator to the patient collected in the CRF	At Baseline and at Month 3,6 and 12
Other	Prediction of urinary oxalate excretion at exposure of clinical interest for stiripentol from a PK/PD model	Prediction of urinary oxalate excretion at exposure of clinical interest for stiripentol from a PK/PD model	At baseline and every 6 months until month 12
Other	Change in patient, caregiver and investigator impact and experiences as evaluated by patient and investigator experience surveys	Change in patient, caregiver and investigator impact and experiences as evaluated by patient and investigator experience surveys	At baseline and every 6 months until end of the study (Month 60)
Primary	% 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 in mg/kg corrected for body surface area (BSA) between baseline and Month 6 and determined from 24-hour urine sample collections	% change in 24-hour urinary oxalate excretion between baseline value and value at month 6
Secondary	% 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 in mg/kg corrected for body surface area (BSA) from baseline to Month 3 and determined from 24-hour urine sample collections	% change in 24-hour urinary oxalate excretion between baseline value and value at month 3
Secondary	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 in mg/kg corrected for 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.
Secondary	Change in 24-hour urine oxalate/creatinine ratio from baseline to Month 3 and Month 6	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	Change in 24-hour urine oxalate/creatinine ratio between baseline value to month 3 and month 6 values
Secondary	% of patients with urinary oxalate lower than 1.5 x upper limit of normal (ULN)) at Month 3 and Month 6	%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)	At 3 and 6 months of treatment.
Secondary	% of patients with normalisation of 24-hour urinary oxalate level corrected for bode surface area at Month 3 and Month 6	% 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)	At 3 and 6 months of treatment.
Secondary	Blood samples for assessment of change in estimated glomerular filtration rate (eGFR in mL/min/1.73m2) from baseline to Month 6	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	Change in estimated glomerular filtration rate (eGFR) between baseline value and month 6 value
Secondary	Occurrence of and frequency of kidney stone events during the follow-up of the patient	Number of and frequency of kidney stone events reported during the follow-up of the patient	From start of participation of the patient to end of the study (Month 60)
Secondary	Change in urine oxalate/creatinine ratios as assessed in spot urine collections between baseline and Month 6	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.	From start of participation of the patient to end of the study (Month 60)
Secondary	Change in biological parameters : oxalate concentration measured in urinary spots collections between baseline and Month 6	Change in oxalate concentration, related to kidney stone formation, measured in urinary spots collections between baseline and Month 6	From baseline to 6 months of treatment.
Secondary	Change in biological parameters : creatinine concentration measured in urinary spots collections between baseline and Month 6	Change in creatinine concentration, related to kidney stone formation, measured in urinary spots collections between baseline and Month 6	From baseline to 6 months of treatment.
Secondary	Absolute change in quality of life measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire	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.	At baseline and every 6 months until the end of the study (Month 60)
Secondary	Absolute change in quality of life measured by the Kidney Disease Quality of Life Questionnaire (KDQOL)	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.	At baseline and every 6 months until the end of the study (Month 60)
Secondary	Change in quality of life measured by the Euro Quality of Life Health State Profile Questionnaire (EQ-5D)	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.	At baseline and every 6 months until the end of the study (Month 60)
Secondary	Change in quality of life measured by the Euro Quality of Life Health State Profile Visual Analog Scale (VAS) : EQ-5D	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.	At baseline and every 6 months until the end of the study (Month 60)