Clinical Trials Register

Summary
EudraCT Number:	2016-002033-30
Sponsor's Protocol Code Number:	ND0612L-007
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-09-19
Trial 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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2016-002033-30

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo controlled, parallel group clinical study investigating the efficacy, tolerability, and safety of two dosing regimens of continuous subcutaneous ND0612 infusion Given as adjunct treatment to oral levOdopa in patients with Parkinson’s Disease with motor fluctuations (iNDiGO)

Multicentrikus, randomizált, kettős vak, placebokontrollos, párhuzamos csoportos klinikai vizsgálat az orálisan alkalmazott levodopa kiegészítő kezeléseként adott, folyamatosan alkalmazott subcutan ND0612 infúzió két adagolási rendjének hatásossága, tolerálhatósága és biztonságossága vizsgálatára a motoros fluktuációkban (iNDiGO) szenvedő betegeknél

A.3.1

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

A clinical study investigating the efficacy, tolerability, and safety of two dosing regimens of continuous subcutaneous ND0612 infusion given as adjunct treatment to oral levodopa in patients with Parkinson’s disease with motor fluctuations

A.3.2

Name or abbreviated title of the trial where available

iNDiGO

A.4.1

Sponsor's protocol code number

ND0612L-007

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02782481

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	NeuroDerm Ltd.
B.1.3.4	Country	Israel
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	NeuroDerm Ltd.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NeuroDerm Ltd.
B.5.2	Functional name of contact point	Edith Dekel
B.5.3	Address:
B.5.3.1	Street Address	Ruhrberg Science building - Bell entrance - 5th floor - 3 Pekeris St.
B.5.3.2	Town/ city	Rehovot
B.5.3.3	Post code	7670212
B.5.3.4	Country	Israel
B.5.4	Telephone number	97289462729134
B.5.5	Fax number	97289461729
B.5.6	E-mail	edith@neuroderm.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.3.1	Product name	levodopa/carbidopa solution
D.3.2	Product code	ND0612
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Levodopa
D.3.9.1	CAS number	59-92-7
D.3.9.3	Other descriptive name	Levodopa
D.3.9.4	EV Substance Code	SUB08468MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carbidopa
D.3.9.1	CAS number	38821-49-7
D.3.9.3	Other descriptive name	CARBIDOPA
D.3.9.4	EV Substance Code	SUB06126MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7.5
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	Yes
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.3.1	Product name	levodopa/carbidopa solution
D.3.2	Product code	ND0612
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Levodopa
D.3.9.1	CAS number	59-92-7
D.3.9.3	Other descriptive name	Levodopa
D.3.9.4	EV Substance Code	SUB08468MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carbidopa
D.3.9.1	CAS number	38821-49-7
D.3.9.3	Other descriptive name	CARBIDOPA
D.3.9.4	EV Substance Code	SUB06126MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7.5
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	Yes
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	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Subjects with Parkinson’s Disease with motor fluctuations

E.1.1.1

Medical condition in easily understood language

Parkinson's disease

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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	10061536
E.1.2	Term	Parkinson's disease
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the effect of two dosing regimens of ND0612 on daily “OFF” time using subject-completed home diary assessments of motor function.

E.2.2

Secondary objectives of the trial

To determine the effect of two dosing regimens of ND0612 on daily “ON” time without troublesome dyskinesia (defined as the sum of "ON" time without dyskinesia and “ON” time with non-troublesome dyskinesia) using subject-completed home diary assessments of motor function.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

- Pharmacokinetics Sub-study: Protocol ND0612L-007 - PK Sub-study version 1.0 dated 10 July 2017.
PK Sub-study objective:To assess the PK of LD, CD, and the LD metabolite 3-OMD in 2 dosing regimens of ND0612 (high-dose and low-dose administration) together with oral adjunct therapy in a sub-study of Study ND0612L-007 performed in a sub-group of subjects at selected sites. Concentration measurements will also be performed for selected subjects receiving placebo.

- Pharmacogenetics Sub-study: Protocol ND0612L-007 - PGx Sub-study version 1.0 dated 03 July 2017
PGx Sub-study objective: To analyze the correlation of potential genetic variations and clinical treatment responses to study drug (e.g. efficacy, pharmacokinetics, tolerability and safety features).

E.3

Principal inclusion criteria

1. Male and female PD subjects of any race aged at least 30 years
2. PD diagnosis consistent with the UK Brain Bank Criteria.
3. Modified Hoehn & Yahr scale in “ON” state ≤3
4. Subjects must experience motor fluctuations and experience an average of at least 2 hours daily in the “OFF” state
5. Subject treatment is stable with at least 4 doses/day of LD/DDI (or at least 3 doses/day of Rytary) and according to the Investigator judgment, motor fluctuations cannot be further improved by adjusting oral LD medications.
6. Subjects must be on stable doses of all their anti-PD medications for at least 28 days before Baseline (Day 1).
7. Subject and/or study partner must demonstrate ability to keep accurate diary entries of PD symptoms (“ON-OFF” diaries) with at least 75% concordance with the study rater by the end of the diary training session at the end of the screening period.
8. Mini Mental State Examination (MMSE) score > 24.
9. Female subjects must be surgically sterile (hysterectomy, bilateral oophorectomy, or tubal ligation), postmenopausal (defined as cessation of menses for at least 1 year), or willing to practice a highly effective method of contraception.

E.4

Principal exclusion criteria

1. Atypical or secondary parkinsonism.
2. Acute psychosis or troublesome hallucinations in past 6 months.
3. Subjects with a clinically significant or unstable medical, surgical, psychiatric condition or laboratory abnormalities which, in the opinion of the Investigator or the EAC, represents a safety risk, makes the subject unsuitable for study entry or potentially unable to complete all aspects of the study.
4. Clinically significant ECG abnormalities.
5. Renal or liver dysfunction that may alter drug metabolism including Screening visit serum levels of creatinine >1.5 mg/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2x upper limit of normal (ULN), total bilirubin >2.5 mg/dL.
6. Positive serum serology for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) at the Screening visit
7. Any malignancy in the 5 years prior to randomization excluding basal cell carcinoma of the skin or cervical carcinoma in situ that have been successfully treated
8. Use of prohibited medications as per protocol
9. Subjects who have previously undergone treatment for PD with a neurosurgical intervention (e.g., pallidotomy, thalamotomy, transplantation, deep brain stimulation procedures), Duodopa/Duopa, or continuous dopaminergic or apomorphine infusion.
10. Subjects with skin lesions that might interfere with a subcutaneous treatment regimen.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the change from Baseline to Week 16 in the mean percentage of “OFF” time during waking hours, based on subject's home diary assessments on 3 consecutive days before the visit.
The “OFF” time will also be presented as hours normalized to 16 waking hours.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 16 visit

E.5.2

Secondary end point(s)

The key secondary efficacy endpoint is the change from Baseline to Week 16 in the mean percentage of “ON” time without troublesome dyskinesia during waking hours, based on subject's home diary assessments on the 3 consecutive days before the visit. "ON" time without troublesome dyskinesia is defined as the sum of "ON" time without dyskinesia and “ON” time with non-troublesome dyskinesia.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 16 visit

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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)

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

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

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

Chile

Czech Republic

Denmark

France

Germany

Hungary

Israel

Italy

Netherlands

Poland

Portugal

Russian Federation

Serbia

Spain

Ukraine

United Kingdom

United States

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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)

Yes

F.1.3.1

Number of subjects for this age range:

192

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

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

111

F.4.2.2

In the whole clinical trial

240

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 16 week treatment period, subjects will be offered the option to continue in a treatment extension period of 48 weeks in which open-label ND0612 will be administered according to the dosing regimen the subject was initially allocated to (either high dose or low dose ND0612). In the first 4 weeks of the Treatment Extension Period(Weeks 16-20) treatment with adjunct oral LD/DDI should be adjusted as needed following similar guidelines as mentioned for the Adjustment Period in Weeks 1-4.

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

2017-11-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-25

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