Clinical Trials Register

Summary
EudraCT Number:	2013-002988-25
Sponsor's Protocol Code Number:	B21CS
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-08-27
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2013-002988-25

A.3

Full title of the trial

A multicentre, open-label, non-inferiority sequential study, evaluating the efficacy, safety, tolerability and acceptability of ADV7103 compared to standard of care in distal renal tubular acidosis patients.

Multicentrické, otvorené, non-inferioritné, sekvenčné klinické skúšanie na hodnotenie účinnosti, bezpečnosti, znášanlivosti a prijateľnosti produktu ADV7103 v porovnaní so štandardnou liečbou u pacientov s distálnou renálnou tubulárnou acidózou.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study conducted in several centres, with two periods, to determine if the product ADV7103 is as least as efficacious as the standard of care in the treatment of distal renal tubular acidosis, and evaluating safety, tolerability and acceptability of ADV7103 compared to standard of care.

A.4.1

Sponsor's protocol code number

B21CS

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Advicenne Pharma
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Advicenne Pharma
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Advicenne Pharma
B.5.2	Functional name of contact point	Director of Clinical Affairs
B.5.3	Address:
B.5.3.1	Street Address	2 rue Briçonnet
B.5.3.2	Town/ city	Nîmes
B.5.3.3	Post code	30000
B.5.3.4	Country	France
B.5.4	Telephone number	33466 05 54 23
B.5.5	Fax number	33466 21 23 35
B.5.6	E-mail	cguittet@advicenne.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	ADV7103
D.3.4	Pharmaceutical form	Prolonged-release granules
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	potassium citrate
D.3.9.1	CAS number	6100-05-6
D.3.9.3	Other descriptive name	POTASSIUM CITRATE
D.3.9.4	EV Substance Code	SUB14973MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	62.78 %
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	potassium bicarbonate
D.3.9.1	CAS number	298-14-6
D.3.9.3	Other descriptive name	POTASSIUM BICARBONATE
D.3.9.4	EV Substance Code	SUB14967MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	65,98 %
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Standard of care
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	potassium citrate
D.3.9.1	CAS number	6100-05-6
D.3.9.3	Other descriptive name	POTASSIUM CITRATE
D.3.9.4	EV Substance Code	SUB14973MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mEq/kg milliequivalent(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	potassium bicarbonate
D.3.9.1	CAS number	298-14-6
D.3.9.3	Other descriptive name	POTASSIUM BICARBONATE
D.3.9.4	EV Substance Code	SUB14967MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mEq/kg milliequivalent(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sodium citrate
D.3.9.1	CAS number	6132-04-3
D.3.9.3	Other descriptive name	SODIUM CITRATE
D.3.9.4	EV Substance Code	SUB12582MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mEq/kg milliequivalent(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sodium bicarbonate
D.3.9.3	Other descriptive name	SODIUM BICARBONATE
D.3.9.4	EV Substance Code	SUB12643MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mEq/kg milliequivalent(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

distal renal tubular acidosis

E.1.1.1

Medical condition in easily understood language

Genetic disease resulting in too low blood pH

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10038535
E.1.2	Term	Renal tubular acidosis
E.1.2	System Organ Class	10038359 - Renal and urinary 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

To evaluate the relative efficacy of ADV7103 and standard of care on correcting metabolic acidosis as measured on pre-morning dose blood bicarbonate levels during 3 days of treatment at steady state (Day 2 to Day 4)

E.2.2

Secondary objectives of the trial

- To compare the efficacy of ADV7103 to standard of care on other blood bicarbonate-derived parameters given after 5 days of treatment at steady state
- To evaluate the efficacy on the reduction of hypercalciuria of ADV7103 as compared to standard of care after 4 to 5 days of treatment at steady state
- To evaluate the efficacy on the correction of hypocitraturia of ADV7103 as compared to standard of care after 4 to 5 days of treatment at steady state
- To evaluate the safety and tolerability including the gastro-intestinal tolerability of ADV7103 as compared to standard of care during 5 days of treatment at steady state
- To evaluate the acceptability (palatability, swallowing, easiness of administration) of ADV7103 as compared to standard of care for 5 days of treatment at steady state
- To evaluate the compliance to ADV7103 as compared to standard of care during 5 days of treatment at steady state

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject who has a diagnosis of distal renal tubular acidosis (acquired or inherited form) with metabolic acidosis
2. Subject male or female, including child aged between 6 months and 17 years old and adult aged ≥ 18 years old and ≤ 55 years old.

E.4

Principal exclusion criteria

1.,Subject who presents associated proximal tubular signs (i.e. presenting for example hypophoshoremia, urinary betamicroglobulin, hyponatremia).
2. Subject who presents a kalaemia > 5.0 mmol/L.
3. Subject who presents a severe or moderate renal impairment (creatinine clearance < 45 mL/min/1.73 m2 according to Schwartz formula for the children and both Cockcrauft & Gault and MDRD formulas for adults).
4. Subject 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 diarrhea
5. Subject who takes or cannot stop (last dose on Day -1) potassium sparing diuretics (e.g. spironolactone, aldactone, amiloride, triamterene), angiotensin converting enzymes inhibitors, angiotensin II receptor antagonists, tacrolimus, potassium desodic salts

E.5 End points

E.5.1

Primary end point(s)

Average bicarbonate blood level during 3 days of treatment at steady state with ADV7103 and SoC.

E.5.1.1

Timepoint(s) of evaluation of this end point

- At the end of the SoC steady state period SP I on Day 2 t0, Day 3 t0 and Day 4 t0 (before first daily dose)
- At the end of the ADV7103 steady state period SP III on Day 2 t0, Day 3 t0 and Day 4 t0 (before first daily dose)

E.5.2

Secondary end point(s)

Efficacy endpoints:
*Bicarbonate-derived endpoints after 5 days of treatment at steady state
• For Sub-set 1, Sub-set 2, and Sub-set 3 and Sub-set 4 if feasible
- AUC0-24h: Area under the curve on Day 5 from t0 to t24h
- Cmin: Minimum concentration over 24 hours on Day 5
- Fluctuation: Maximum minus minimum concentrations over 24 hours on Day 5
• For the 4 Sub-sets
- Percentage of values below the lower normal limit on SP I and SP III Day 2 t0, Day 3 t0 and Day 4 t0.
- Number/proportion of subjets with abnormal bicarbonataemia values, i.e. patients with at least one value of bicarbonataemia below lower normal range on Day 2 t0, Day 3 t0 or Day 4 t0.
- Number/proportion of non-responders i.e. patients with all three values of bicarbonataemia below lower normal range on Day 2 t0, Day 3 t0 and Day 4 t0.

*Number of subjects presenting an hypercalciuria after 4 to 5 days of treatment at steady state
*Number of subjects presenting an hypocitraturia after 4 to 5 days of treatment at steady state

Safety endpoints:
• Number/proportion of subjects presenting adverse events, incidence and severity of adverse events during the course of the study
• Gastro-intestinal tolerability evaluated with appropriate scales (a facial hedonic scale for the youngest and a visual analogue scale (VAS) for the other subjects) at inclusion, on SP I Day 5 and on SP III Day 5
• Incidence of abnormal values on safety parameters after 5 days of treatment at steady state
- Serum ionogram (Na+, Ca2+, Cl-, K+, Mg2+, HCO3-, phosphorus, proteins, creatinine, creatinine clearance, urea, uric acid) (Inclusion, SP I and SP III Day 5)
- Kaliemia (SPII, with all bicarbonataemia samples )
- Urine ionogram (HCO3-, Na+, Cl-, K+, Mg2+, Ca2+, phosphates, proteins, urea, citrate, creatinine,) (Inclusion, SP I and SP III Day 5)
- Urine pH at each urination during investigator site visit (Inclusion, SP I and SP III Day 5 from t0 to t24h post first morning dose for hospitalised subjects, and Day 5 t0 for non-hospitalised subjects)

Acceptability endpoints

• Palatability evaluated by age-appropriate scales on SP I and SP III Day 5
- Sub-set 1 and Sub-set 2: evaluation by the subject him-self with a VAS scale
- Sub-set 3 : evaluation by the subject him-self with a facial hedonic scale, with the support of parents if needed
- Sub-set 4 : evaluation by the parents with a VAS scale
• Score of easiness to swallow with appropriate VAS scales to be completed by the subject himself or the parents on SP I and SP III Day 5
• Score of easiness of administration with an appropriate VAS scale to be completed by the subject himself or the parents on SP I and SP III Day 5
• Rate of compliance based on the diary card and study drug retrieval

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy endpoints:
Bicarbonate-derived endpoints after 5 days of treatment at steady state:
o For Sub-set 1, 9 time-points: on SPI and SP III Day 5 at t0 (just before the first morning dose) and t4h, t8h and t12h (just before the evening daily dose), t16h, t20h, t22h, t23h and t24h (just before the next morning daily dose)
o For Sub-set 2, for Sub-set 3 and Sub-set 4 if feasible, 7 time-points: on SPI and SP III Day 5 at t0h (just before the first morning dose), t4h, t8h, t12h (just before the evening dose), t16h, t20h and t24h (just before the next morning daily dose).
See Section E.5.2 for other timepoints of secondary endpoints.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Acceptability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

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)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Sequential

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

France

Italy

Serbia

Slovakia

Spain

United Kingdom

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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 months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2015-08-27.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the subject will have ended his participation in the trial, it will be proposed to him to continue taking the treatement studied by participating to an other study, coded B22CS. If he refuses, he will return to his usual treatment as before the study or to the most appropriate treatment according to the judgement of the investigator

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-10-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-05-20

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Orphan Designation Number:
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