| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Genetic disease resulting in high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidney |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011778 |
| E.1.2 | Term | Cystinuria |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary objective of B12CS
- To evaluate the effect of ADV7103 at three different doses compared to placebo on the percentage of urinary pH values ≥ 7.0 during 24h after a 7-day treatment, in patients of at least 6 years of age and toilet trained.
Primary objective of B13CS
- To evaluate the effect of ADV7103 at the individual optimal dose on the percentage of urinary pH values ≥ 7.0 during 24h on after a 7-day treatment, in patients aged from 6 months to 5 years old or not yet toilet trained.
Primary objective of B13CS
- To evaluate the effect of ADV7103 at the individual optimal dose on the percentage of urinary pH values ≥ 7.0 during 24h on after a 7-day treatment, in patients aged from 6 months to 5 years old or not yet toilet trained.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of ADV7103 on secondary urine pH values (nychthemeral changes of pH; proportion/number of responders with mean pH ≥7.0 and ≥7.5; mean pH values; pH value in the first morning urines; percentage of urinary pH values ≥ 7.5 during 24h on Day 7) after a 7-day treatment.
To evaluate the dose-response relationship of ADV7103 on urine pH.
To evaluate the effect of ADV7103 on cystine crystalluria (including the volume of crystals of cystine - Vcys), other crystalluria types and other cystinuria parameters after.
To evaluate the dose-response relationship of ADV7103 on cystine crystalluria (including Vcys), other crystalluria types and other cystinuria parameters (B12CS only).
To evaluate the effect of SoC on urine parameters (pH values, cystine crystalluria other crystalluria types and other cystinuria parameters).
Safety and tolerability objectives
Acceptability objective
Exploratory objectives
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for inclusion into the study, the subjects must fulfil all of the following criteria:
1. Patient who has a diagnosis of cystinuria based on medical diagnosis (at least one previous or current episode of calculus of cystine, and/or one previous or current episode of cystine crystalluria) or on genetic diagnosis (only for patients enrolled in B13CS study).
2. Patient treated with an alkalising treatment at a well-adapted dose (defined as a daily dose deemed by the investigator aiming to maintain overtime urinary pH value ≥ 7.0 and/or compatible with an acceptable safety profile and/or patient’s constraints or compliance).
3. Patient who, when treated with a second line therapy (chelator agent), presents a disease status enabling interruption of the chelator agent during the course of the B10CS research.
4. Patient male or female, including child aged between 6 months and 17 years old and adult aged ≥ 18 years old up to 70 years old.
5. Female patient (maiden after puberty or woman) without childbearing potential, i.e. using a contraceptive method judged effective by the investigator (or surgically sterilised) if sexually active and having a negative pregnancy test at the inclusion.
6. Patient and/or parents or legal representative(s) who is(are) willing and able to participate in the study, to understand and to comply with study procedures for the entire length of the study.
7. Patient or parents or legal representative(s) who has/have provided a signed written informed consent.
8. Patient of ≤17 years of age for whom the assent has been collected or has been tried to be collected.
9. Patient who is affiliated to a social health insurance system and/or in compliance with the recommendations of the national law in force relating to biomedical research.
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| E.4 | Principal exclusion criteria |
To be eligible for inclusion into the study, the subjects must not meet any of the following criteria:
1. Patient treated with the second line therapy and who cannot stop cystine chelating agents (sulfhydryl compounds) during the B12CS-B13CS study.
2. Patient who presents kalaemia > 5.0 mmol/L.
3. Patient who presents a moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 according to Schwartz formula for the children and both MDRDs and CKD-EPI for adults).
4. Patient who presents - barring the study disease - any previous or concurrent medical condition or any laboratory or clinical findings or any other condition that in the opinion of the investigator would be negatively affected by the study medication or that would affect the study medication or that precludes participation, e.g. uncontrolled diabetes mellitus, adrenal insufficiency, cardiac impairment, repeated infections, metabolic alkalosis, chronic diarrhoea.
5. Female patient who is pregnant or breast-feeding.
6. Patient who cannot stop potassium sparing diuretics (e.g. antagonists of aldosterone as such spironolactone, canrenoate and eplenone, amiloride, triamterene), angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, tacrolimus, potassium desodic salts.
7. Patient who received any medication that could interfere with the study treatment within 4 weeks before the inclusion in the study, including angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, tacrolimus, potassium desodic salts, antibiotics.
8. Patient who received potassium sparing diuretics 6 weeks before the inclusion in the study.
9. Patient who presents contra indications to the administration of the study treatment such like known allergic reactions or hypersensitivity to the active pharmaceutical ingredients or other excipients of the formulations of the study treatment (such as lactose), history of difficult access to the oral administration route and/or conditions that may hamper compliance and/or absorption of the study treatment (e.g. any difficulty of swallowing, mal-absorption, delayed gastric emptying, oesophageal compression, intestinal obstruction or other chronic gastro-intestinal disease).
10. Patient who is admitted to hospital in emergency settings.
11. Patient who participated in a clinical trial within the last 3 months before enrolment.
12. Patient who is at risk of non-compliance in the judgment of the investigator.
13. Patient who could present any other condition, which in the opinion of the investigator, would preclude participation in the study.
14. Patient who cannot be contacted in case of emergency.
15. Patient under any administrative or legal supervision.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Percentage of urinary pH values ≥ 7.0 during 24h on Day 7 (measured with a glass electrode pH-meter).
The percentage is defined as the ratio between the number of assessments with a pH value ≥ 7.0 divided by the number of evaluable pH assessments during the time interval from t0 to t24h on Day 7.
All urinations on Day 7 with an evaluable pH measure will be included in the calculation. In case of no pH assessment or no valid pH data recording on Day 7, the latest available pH data prior to Day 7 will be used instead (see Section 9.5.9).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the all study period |
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| E.5.2 | Secondary end point(s) |
Percentage of urinary pH values ≥ 7.0 during each both 12h-periods (night and day nychthemeral changes) on Day -1 and Day 7 (measured with a glass electrode pH-meter):
- Day interval: period from t0 (just before IMP administration) to t12h (excluded) (just before IMP administration),
- Night interval: period from t12h (just before IMP administration) to t24h (just before IMP administration).
In case of no pH assessment or no valid pH data recording on Day -1 or Day 7, the latest available pH data prior to Day -1 or Day 7, respectively, will be used instead. In case of no pH assessment or no valid pH recording in one sub-interval (day or night) but data exist for the other interval, then the percentage will be reported as missing for the interval without data (see Section 9.5.9).
Proportion/number of subjects-responders during the day, the night and overall, where response is defined as an average of the available urinary pH values ≥ 7.0 and urinary pH values ≥ 7.5 (measured with a glass electrode pH-meter), on Day -1 and Day 7. Overall response is defined as a response during the day and the night and will be not taken into account for the assessment of the overall response.
In case of no pH assessment or no valid pH data recording on Day -1 or Day 7, the latest available pH data prior to Day -1 or Day 7 will be used instead. In case of no pH assessment or no valid pH data recording in one sub-interval (day or night), but data exist for the other interval, the proportion will be reported as missing for the interval without data will be not taken into account for the assessment of the overall response (see Section 9.5.9).
Proportion/number of subjects who maintain a urinary pH ≥ 7.0 in the first morning urines, defined as the planned pH assessments on Day -1 t0, Day -1 t24h, Day 7 t0 and Day 7 t24h (glass electrode pH-meter).
In case of no pH assessment or no valid pH data recording on Day -1 t0, Day -1 t24h, Day 7 t0 or Day 7 t24h, the latest equivalent available pH data prior these time-points, will be used instead (see Section 9.5.9).
Proportion/number of subjects who maintain a urinary pH ≥ 7.5 in the first morning urines, defined as the planned pH assessments on Day -1 t0, Day -1 t24h, Day 7 t0 and Day 7 t24h (glass electrode pH-meter).
In case of no pH assessment or no valid pH data recording on Day -1 t0, Day -1 t24h, Day 7 t0 or Day 7 t24h, the latest equivalent available pH data prior these time-points, will be used instead.
Percentage of urinary pH values ≥ 7.5 during 24 h and during each both 12h-periods (night and day nychthemeral changes) on Day -1 and on Day 7 (measured with a glass electrode pH-meter).
The percentage is defined as the ratio between the number of assessments with a pH value ≥ 7.5 divided by the number of evaluable pH assessments during the corresponding time intervals: from t0 to t24h, from t0 to t12h excluded, or from t12h to t24h, on Day -1 or Day 7.
All urinations on Day -1 or on Day 7 with an evaluable pH measure will be included in the calculation. In case of no pH assessment or no valid pH data recording on Day -1 or Day 7, the latest available pH data prior to Day -1 or Day 7, respectively, will be used instead (see Section 9.5.9).
Following endpoints will be based on or derived from the volume of crystals of cystine (Vcys) that will be measured for each of the 4 urine collections: in the first and second morning urines collected both before the first morning dose, on Day -1 t24h (i.e. Day 1 t0) and approximately 2 hours later, and on Day 7 t24h and approximately 2 hours later, by examination of the well-homogenised fresh urine samples set in a Malassez cell by light microscopy:
- Vcys values
- Incidence of Vcys > 3000 µ3/mm3
Following endpoints will be based on other parameters of cystine crystalluria and other crystalluria types that will be measured for each of the 4 urine collections: in the first and second morning urines collected both before the first morning dose, on Day -1 t24h (i.e. Day 1 t0) and approximately 2 hours later, and on Day 7 t24h and approximately 2 hours later:
- Absence / presence of cystine crystals
- Incidence of cystine crystals including morphological appearance, size (average, minimal and maximal)
- Incidence of aggregates of cystine crystals including number, size (average and maximal)
- Incidence of other types of crystals
Cystinuria, expressed as urine free cystine concentration (mol/mol, mg/mg), urine free cystine excretion, and urinary cystine to creatinine ratio, measured for each of the 4 urine collections: in the first and second morning urines collected both before the first morning dose, on Day -1 t24h (i.e. Day 1 t0) and approximately 2 hours later, and on Day 7 t24h and approximately 2 hours later.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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