Study Evaluating Patients With Cystinuria and Efficacy and Safety Exploratory Study in the Youngest Children

• ClinicalTrials.gov Identifier: NCT04147871
• Recruitment Status: Unknown
• First Posted: November 1, 2019
• Last Update Posted: November 1, 2019
• Sponsor: Advicenne Pharma
• Information provided by (Responsible Party): Advicenne Pharma

Study Description

Brief Summary:

This is a multicentre, randomized, controlled versus placebo, double-blinded, 4 parallel arms, dose-ranging main study, to evaluate the efficacy, safety and tolerability and acceptability of repeated doses of ADV7103, after 7 days of treatment, in patients with cystinuria, and an efficacy and safety exploratory study in the youngest children.

Condition or disease	Intervention/treatment	Phase
Cystinuria	Drug: ADV7103; Drug: Placebo	Phase 2; Phase 3

Detailed Description:

The study will target enrolling at least 15 subjects in each of the following age groups: 6 months - 5 years (B13CS part only); 6-11 years; 12-17 years and adult >18. Subjects will be in the study for up to 7 weeks.

After screening and enrollment (up to 35 days), Eligible patients will be treated will alkalinising treatment (SoC) at the well-adapted dose and regimen for 7 days. An in-patient visit is planned at the end of this period. The baseline evaluations, including urine pH and specific gravity, will be done during this inpatient visit, from Day -1 t0 to t24h. After this visit, patients are randomized in a balanced manner (1:1:1:1) to one of the 4 possible treatment arms, ADV7103 at low dose, medium dose or high dose, or ADV7103 placebo. For patients in B13CS part, a period of titration is planned before the 7 days treatment with ADV7103. No use of placebo in B13CS.

Controls of urine pH will be done at patient home with a pocket glass electrode pH-meter on fresh urines, at least twice a day: before the administration of ADV7103, in the morning at t0 and in the evening at t12h (12hrs after last ADV7103 intake and before the next dose).

Subjects will have the opportunity to subsequently enter a long-term, open label extension.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicentre, Randomized, Controlled Versus Placebo, Double-blinded, 4 Parallel Arms, Dose-ranging Main Study, to Evaluate the Efficacy, Safety and Tolerability and Acceptability of Repeated Doses of ADV7103, After 7 Days of Treatment, in Patients With Cystinuria, and an Efficacy and Safety Exploratory Study in the Youngest Children.
• Actual Study Start Date: February 1, 2019
• Estimated Primary Completion Date: August 1, 2020
• Estimated Study Completion Date: August 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: ADV7103 1.5 mEq/Kg/day; Patients receive ADV7103 twice a day.	Drug: ADV7103; Each dose of ADV7103 contains a fixed ratio of 1/3 of ADV7103-CK (potassium citrate) and 2/3 of ADV7103-BK (potassium bicarbonate) based on the mass of active substances.
Active Comparator: ADV7103 3.0 mEq/Kg/day; Patients receive ADV7103 twice a day.	Drug: ADV7103; Each dose of ADV7103 contains a fixed ratio of 1/3 of ADV7103-CK (potassium citrate) and 2/3 of ADV7103-BK (potassium bicarbonate) based on the mass of active substances.
Active Comparator: ADV7103 4.5 mEq/Kg/day; Patients receive ADV7103 twice a day.	Drug: ADV7103; Each dose of ADV7103 contains a fixed ratio of 1/3 of ADV7103-CK (potassium citrate) and 2/3 of ADV7103-BK (potassium bicarbonate) based on the mass of active substances.
Placebo Comparator: Placebo; Patients receive placebo twice a day.	Drug: Placebo; Placebo is a combination of 2 mm green coated lactose granules and 2 mm white coated lactose granules. Each dose of placebo contains a fixed ratio of 1/3 of green granules and 2/3 of white granules.

Outcome Measures

Primary Outcome Measures :

1. Percentage of urinary pH values ≥ 7.0 during 24h on Day 7 (after ADV7103 treatment period) [ Time Frame: 24 hours ]
   The primary endpoint is the comparison between the probability of having an urinary PH ≥ 7.0 based on all urinations during Day 7 in an ADV7103 dose versus the probability in the placebo group. All urinations on Day 7 with an evaluable pH measure will be included in the analysis. The study will be declared positive if the chance of having pH value ≥ 7.0 at each urination on D7 is superior with at least one ADV7103 treatment group than with placebo.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 70 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 1. Patient who has a diagnosis of cystinuria based on medical diagnosis (at least one previous orcurrent 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 female patient of childbearing potential (defined by CTFG as fertile, following menarche until becoming post-menopausal unless permanently sterile*) a highly effective birth control method should be used until the end of study plus 36 hours after the last dose of IMP.

  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.

Exclusion 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 product or that would affect the study product or that precludes his 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, 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, ciclosporine, 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 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.

Contacts and Locations

Locations

Belgium

Cliniques Universitaires Saint-Luc; Not yet recruiting

Brussels, Belgium

Contact: Vinciane De Backer 003216342201

Principal Investigator: Valentine Gillion

UZ Leuven, Gasthuisberg Hospital; Not yet recruiting

Leuven, Belgium

Contact: Caroline Huget 003216342201 caroline.huget@uzleuven.be

Principal Investigator: Elena Levtchenko

France

Centre Hospitalier Universitaire de Lyon - Hôpital Femme Mère Enfant; Not yet recruiting

Bron, France, 69500

Contact: Ségolène Gaillard 334278577 segolene.gaillard@chu-lyon.fr

Principal Investigator: Aurélie Bertholet

CHU Grenoble; Not yet recruiting

Grenoble Cedex, France, 38043

Contact (33) 4 76 76 58 94

Principal Investigator: Guylhène Bourdat-Michel

CHRU Lille; Not yet recruiting

Lille, France, 59000

Contact (33) 3 20 44 50 70

Principal Investigator: Robert Novo

CHU Pitié-Salpétrière; Not yet recruiting

Paris, France, 15013

Contact (33) 1 42 17 72 07

Principal Investigator: Isabelle Tostivint

Hôpital Necker AP-HP; Recruiting

Paris, France, 75015

Contact: Magatte Fall (33) 1 44 49 45 75 magatte.fall@aphp.fr

Principal Investigator: Bertrand Knebelmann

Hôpital Necker Enfants Malades; Not yet recruiting

Paris, France, 75015

Contact: Magatte Fall (33) 1 44 49 45 75 magatte.fall@aphp.fr

Principal Investigator: Olivia Boyer

Hôpital Ténon - Explorations fonctionnelles Mutlidisciplinaires et INSERM UMR S 1155; Not yet recruiting

Paris, France, 75020

Contact (33) 1 56 01 67 73

Principal Investigator: Emmanuel Letavernier

Hôpital Américain CHU de Reims; Not yet recruiting

Reims, France, 51092

Contact (33) 3 26 78 74 89

Principal Investigator: Christine Pietrement

CHU Reims; Not yet recruiting

Reims, France, 51100

Contact (33) 3 26 78 76 38

Principal Investigator: Philippe Rieu

CHU Purpan; Not yet recruiting

Toulouse cedex 9, France, 31059

Contact (33) 5 34 55 84 58

Principal Investigator: Stéphane Decramer

Sponsors and Collaborators

Advicenne Pharma

Investigators

• Study Chair: Luc-André Granier; Advicenne Pharma

More Information

Additional Information:

Company website 

• Responsible Party: Advicenne Pharma
• ClinicalTrials.gov Identifier: NCT04147871
• Other Study ID Numbers: B12CS-B13CS
• First Posted: November 1, 2019
• Last Update Posted: November 1, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cystinuria; Renal Aminoacidurias; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn