Clinical Trials Register

Summary
EudraCT Number:	2017-000905-19
Sponsor's Protocol Code Number:	Rec0/0438-IT-CL0491
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-10-18
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

Portugal - INFARMED

A.2

EudraCT number

2017-000905-19

A.3

Full title of the trial

EFFECTS OF TWO DIFFERENT DOSES OF REC 0/0438 ADMINISTERED BY INTRA-VESICAL INSTILLATION IN PATIENTS WITH NEUROGENIC DETRUSOR OVERACTIVITY DUE TO SPINAL CORD INJURY: A REPEATED DOSES, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY

A.3.1

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

A study in male and female patients with neurogenic detrusor overactivity due to spinal cord injury to evaluate the effects of two different doses of REC 0/0438 administered by intra-vesical injection.

A.4.1

Sponsor's protocol code number

Rec0/0438-IT-CL0491

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	Recordati S.p.A
B.1.3.4	Country	Italy
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	Recordati S.p.A
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Recordati S.p.A
B.5.2	Functional name of contact point	Senior Clinical Project Leader
B.5.3	Address:
B.5.3.1	Street Address	Via M. Civitali 1
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20148
B.5.3.4	Country	Italy
B.5.4	Telephone number	003902487871
B.5.5	Fax number	00390248787668
B.5.6	E-mail	casi.m@recordati.it

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	Rec 0/0438
D.3.4	Pharmaceutical form	Powder for intravesical solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	-
D.3.9.1	CAS number	905985-64-0
D.3.9.2	Current sponsor code	REC 0/0438
D.3.9.4	EV Substance Code	SUB168091
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	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	Rec 0/0438
D.3.4	Pharmaceutical form	Powder for intravesical solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	-
D.3.9.1	CAS number	905985-64-0
D.3.9.2	Current sponsor code	REC 0/0438
D.3.9.4	EV Substance Code	SUB168091
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for intravesical solution
D.8.4	Route of administration of the placebo	Intravesical use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

neurogenic detrusor overactivity due to spinal cord injury

E.1.1.1

Medical condition in easily understood language

The neurogenic detrusor overactivity is a disease and event affecting the nervous systems controlling the lower urinary tract, that leads to urinary incontinence and poor quality of life.

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10005059
E.1.2	Term	Bladder neurogenic
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to investigate the safety and tolerability of repeated doses of Rec 0/0438 administered by intravesical instillation for four weeks in subjects suffering from NDO

E.2.2

Secondary objectives of the trial

Secondary objectives of the study are to study pharmacokinetics and pharmacodynamics parameters.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female subjects aged ≥18 years and ≤65 years.
2. Female subjects must be either sterile or, if with child–bearing potential, must have a pregnancy test negative and commit to the use of a highly effective method of birth control (see Appendix 15.6) for the duration of the study, and until at least 1 month after the last dose of study medication. Male subjects must be willing to use male contraception (condom) to avoid pregnancies of their female partner of childbearing potential throughout the entire duration of the study, and for 3 months after the last dose of study medication.
3. Suffering from NDO due to SCI at upper motor neuron level (below C6) and emptying the bladder performing clear intermittent self-catheterization (CISC).
4. Subjects classified in group A, B, or C, of the ASIA (American Spinal Injury Association) impairment scale.
5. Stable therapy for NDO in the last thirty days (Subjects should maintain the therapy stable for the duration of the study).
6. At least 1 incontinence episode/day despite current treatment, according to what is reported in the Bladder Diary filled in by the subject.
7. Subjects with diastolic blood pressure values between 60 and 99 mmHg (both inclusive), and systolic blood pressure values between 90 and 159 mmHg (both inclusive). Blood pressure measurement must be performed in subjects with an empty bladder.
8. Subjects with stable concomitant medication treatment at baseline.
9. Written informed consent must be given by subjects before any study related investigational procedures is performed.

E.4

Principal exclusion criteria

1. Breastfeeding women.
2. Treatment with injection of botulinum toxin, unless in the opinion of the Investigator the bladder activity has returned to pre-treatment level.
3. Use of prohibited concomitant medications, such as drugs that could affect immunoassay testing (systemic corticosteroids: prednisone, budesonide, prednisolone; calcineurin inhibitors: cyclosporine, tacrolimus; mTOR inhibitors: sirolimus, everolimus; IMDH inhibitors: azathioprine, leflunomide, mycophenolate; biologics: abatacept, adalimumab, anakinra , certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab; monoclonal antibodies: basiliximab, daclizumab, muromonab) or initiation of therapy with drugs affecting lower urinary tract symptoms (such as alpha-blockers, tadalafil 5 mg oad). If already present at Screening visit, therapy with drugs affecting lower urinary tract symptoms must be maintained stable through the study period (Note: occasional treatment with PDE-5 inhibitors for erectile dysfunction should be avoided between Screening visit and Day 8 and between Day 25 and 28).
4. History of cerebro- or cardio-vascular diseases (TIA, stroke, hypertensive encephalopathy, angina pectoris, MI, cardiac by-pass, CHF NYHA classes III and IV).
5. Uncontrolled type 1 or type 2 diabetes (Hb A1c >8 %).
6. Moderate to severe renal impairment (estimated creatinine clearance <60 mL/min by the Cockcroft-Gault equation).
7. Moderate to severe liver impairment (any liver function test: AST, ALT, GGT, Bilirubin >2.5 times the upper limit of normal).
8. Hemodynamically significant valve disease, including aortic stenosis or clinically significant ventricular or supraventricular arrhythmia, heart rate >100 beats/min.
9. Clinically important abnormal laboratory findings during the run-in period, including: Haemoglobin <10 g/dL; Serum Potassium >5.5 mmol/L; Serum Sodium <132 mmol/L.
10. Symptomatic active urinary tract infection (i.e. cloudy and/or malodorous urine, chills, fever, increased muscle spasticity or increased autonomic dysreflexia, letargy, hypotension, malaise).
11. Evidence of any neoplastic disease.
12. History of allergy, hypersensitivity or intolerance to drugs.
13. Participation in an investigational drug study within 30 days prior to the screening assessment.
14. Any other diseases or conditions, that according to the Investigator’s opinion, make the subject unable to comply with protocol requirements, or unable to complete the study or increases the risk to the subject or which prevents optimal participation in achieving the objectives of the study.

E.5 End points

E.5.1

Primary end point(s)

SAFETY endpoints, which will be evaluated on an ongoing basis are:
• Clinically relevant findings in post-dose physical examination, vital signs and ECG.
• Clinically relevant changes in post-dose laboratory tests.
• Adverse events.
• Immunogenicity to Rec 0/0438.

E.5.1.1

Timepoint(s) of evaluation of this end point

SAFETY:
on an ongoing basis

E.5.2

Secondary end point(s)

PHARMACOKINETICS endpoint:
The systemic exposure after single (Day 1) and repeated (Day 7) once daily intravesical instillations of Rec 0/0438 (Cmax, AUC) will be evaluated:
•A blood sample will be collected at screening and Three blood samples (6 mL each) will be collected on the day of first administration and on the 7th day of administration between 0.5-1 hour, between 2-3 hours and between 4-6 hours post dose, in order to determine if systemic exposure occurs.
•Urine collection will be performed on Screening visit, and at the first and second voiding after drug administration on Day 1 and Day 7.
PHARMACODYNAMIC endpoint:
Urodynamic parameters (day -1 and day 28±4):
•Change from baseline in Maximum Cystometric Capacity (MCC – main pharmacodynamic parameter)
•Change from baseline in Maximum Detrusor Pressure (Pdetmax)
•Change from baseline in Volume at first involuntary detrusor contraction (VpmaxIDC)
•Change from baseline in Bladder Compliance (BC)
•Change from baseline in Detrusor Leak Point Pressure (DLPP).
Bladder Diary parameters (for 3 days before baseline, day 7 and day 28):
•Change from baseline in the number of daily urinary incontinence (UI) episodes.
•Change from baseline in mean volume per catheterization (total volume voided in 24 hours divided by the number of catheterizations).

E.5.2.1

Timepoint(s) of evaluation of this end point

PHARMACOKINETICS D1 and D7
PHARMACODYNAMIC:
Urodynamic parameters (day -1 and day 28±4)
Bladder Diary parameters (for 3 days before baseline, day 7 and day 28)

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

phase I/II

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	36
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	10
F.4.2	For a multinational trial
F.4.2.1	In the EEA	36
F.4.2.2	In the whole clinical trial	36

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

2017-12-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-01-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-03-27

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