| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
|
| 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 |
|
| 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 probability of having urinary pH values ≥ 7.0 at each urination over 24h on Day 7, 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
probability of having urinary pH values ≥ 7.0 at each urination over 24h
on Day 7 after a 7-day treatment, in patients aged from 6 months to < 6
years old or not yet toilet trained. |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy
- To evaluate the effect of ADV7103 (including 3 doses of ADV7103 and placebo in B12CS) on secondary urine pH parameters over 24 hours,
with day and night periods on Day 7, after a 7-day treatment
- To evaluate the dose-response relationship of ADV7103 on urine mean
24-h pH on Day 7, after a 7 day-treatment (B12CS only).
- To evaluate the effect of ADV7103 (including 3 doses of ADV7103 and
placebo) on cystine crystalluria, in the first and second morning urine,
on Day 7, after a 7 day-treatment.
- To evaluate the dose-response relationship of ADV7103 on cystine
crystalluria, other crystalluria types, other cystinuria parameters, and
other urine metabolic markers of crystalluria in the first and second
morning urine, on Day 7, after a 7 day-treatment (B12CS only).
Safety
- To evaluate the safety and tolerability of the study products, over a 7
day-treatment.
Acceptability
- To evaluate the acceptability of the study products on Day 7, after a 7
day-treatment |
|
| 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 B12CS-B13CS 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. For patient with mild to moderate renal impairment (45≤ estimated
glomerular filtration rate (eGFR) <60 mL/min/1.73 m², according to
Schwartz formula for children and CKD-EPI for adults): normal kalaemia
(< 5.0 mmol/L), AND a body mass index (BMI) < 30 Kg/m².
6. Women of childbearing potential (WOCBP) (defined by the Clinical
Trial Facilitation Group (CTFG) as woman fertile, following menarche
until becoming post-menopausal unless permanently sterile*) using a
highly effective birth control method** until the end of study (i.e. until
36 hours after the last dose of IMP) and having a serum negative
pregnancy test at the screening, or a woman postmenopausal or a
woman surgically sterilised
7. 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.
8. Patient or parents or legal representative(s) who has/have provided
a signed written informed consent.
9. Patient of ≤17 years of age for whom the assent has been collected
or has been tried to be collected.
10. 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. |
|
| 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 B12CSB13CS
study.
2. Patient who presents kalaemia > 5.0 mmol/L.
3. Patient who presents a renal impairment as following:
- severe renal impairment (eGFR < 45 mL/min/1.73 m2 according to
Schwartz formula for children and CKD-EPI for adults),
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- mild to moderate renal impairment not stabilised (45 ≤ eGFR < 60
mL/min/1.73 m2, according to Schwartz formula for children and CKDEPI
for adults), AND a BMI ≥.30 Kg/m²
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
eplerenone, amiloride, triamterene), angiotensin converting enzyme
inhibitors, angiotensin II receptor antagonists, tacrolimus, ciclosporine,
potassium desodic salts, nonsteroidal anti-inflammatory drugs and
cardiac glycosides.
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
limited to sulfamides, quinolones and azithromycine.
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 gastrointestinal
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Main Study B12CS
The primary endpoint is the comparison between the probability of
having a urinary pH ≥ 7.0 based on each urination over 24 hours on Day
7 in an ADV7103 dose versus the probability in the placebo group.
All urinations on Day 7 from t0 to t24h with evaluable pH measures will
be included in the analysis.
Exploratory Study B13CS
The primary endpoint is the evaluation of the probability of having
urinary pH values ≥ 7.0 based on each urination over 24h on Day 7.
All urinations on Day 7 from t0 to t24h with evaluable pH measures will
be included in the analysis. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints
. Presence of cystine crystals defined as the number/proportion of
patients with at least one cystine crystal, (baseline, Day 7 and change
from baseline) by urine sample and overall on Day 7
. Absence / presence of crystals defined as the number/proportion of
patients with crystals, by urine sample, by crystal type, (baseline, Day 7
and change from baseline)
. Number of crystals by urine sample, by crystal type (baseline, Day 7
and change from baseline)
. Number of aggregates of crystals (baseline, Day 7 and change from
baseline)
. Urine free cystine concentration (mmol/L) (baseline, Day 7 and
change from baseline)
. Urine free cystine excretion (mmol/day) (baseline, Day 7 and change
from baseline)
. Urine free cystine to creatinine ratio (mmol/mmol)
. Other urine metabolic markers of crystalluria
. Presence /absence cystine free or precipitate
Safety and tolerability endpoints
. Adverse events throughout the study.
. Standard safety measures, according to the investigator site normal
ranges, at screening, in baseline (Day -1) and on Day 7/end of study
. Number of patients with hyperkaliemia (defined as plasma potassium
= 5.5 mmol/L at least once) throughout the study.
. Number of patients with ACCP granulations to be measured in the
first and second morning urines collected both before the first morning
dose (in baseline i.e. on Day -1 t24h and approximately 2 hours later, on
Day 7 t24h and approximately 2 hours later)
. Number of patients with urine tract infections
. Number/proportion of patients with plasma levels of potassium by
normality status, over the study periods
. Blood levels of potassium (kinetics) on Day 7
. Gastro-intestinal tolerability on Day 7 t24h.
Acceptability endpoints
. Palatability, to be evaluated by the patient her/himself, and with the
support of her/his parents when necessary, (baseline i.e. on Day -1
t24h, Day 7 t24h)
. Ease of swallowing, to be evaluated by the patient her/himself, and
with the support of her/his parents when necessary (baseline i.e. on Day
-1 t24h, Day 7 t24h)
. Number of daily intakes, to be evaluated by the patient her/himself,
and with the support of her/his parents when necessary (baseline i.e. on
Day -1 t24h, Day 7 t24h)
Exploratory endpoints
. See Section 3.2.1, the secondary efficacy endpoint "Volume of
crystals of cystine (Vcys)"
. Urine biologic parameters:
- urine pH (see the primary and secondary efficacy endpoints)
- urine calcium to creatinine ratio (see the secondary efficacy endpoint
"Other urine metabolic markers of crystalluria")
- urine citrate to creatinine ratio (see the secondary efficacy endpoint
"Other urine metabolic markers of crystalluria")
- urine calcium to citrate ratio (see the secondary efficacy endpoint
"Other urine metabolic markers of crystalluria")
- excretion of uric acid in urine normalised with the urinary uric acid to
creatinine ratio
- specific gravity
- urine urea
- urine osmolality
- urine cytology
To have more details, please refer to the protocole V2.0 dated 29 january
2020, part 3.2 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Acceptability, compliance and quality of life |
|
| 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) | No |
| 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 | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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