Clinical Trials Register

Summary
EudraCT Number:	2013-005118-36
Sponsor's Protocol Code Number:	NOH401
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-05-28
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-005118-36

A.3

Full title of the trial

A clinical study of Patients with symptomatic neurogenic orthostatic HypOtENsion to assess sustaIned effects of droXidopa therapy

A.3.1

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

A study to look at the long-term effects of droxidopa treatment in patients who experience low blood pressure when changing their posture

A.3.2

Name or abbreviated title of the trial where available

PHOENIX

A.4.1

Sponsor's protocol code number

NOH401

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01927055

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	Chelsea Therapeutics, Incorporated
B.1.3.4	Country	United States
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	Chelsea Therapeutics, Incorporated
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ICON Plc
B.5.2	Functional name of contact point	Senior Project Manager
B.5.3	Address:
B.5.3.1	Street Address	79 T.W. Alexander Drive , Research Commons Building
B.5.3.2	Town/ city	Durham
B.5.3.3	Post code	NC-27709-4353
B.5.3.4	Country	United States
B.5.4	Telephone number	1864244-2209
B.5.5	Fax number	1267519-1248
B.5.6	E-mail	Joyce.Whiteside@iconplc.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	Yes
D.2.5.1	Orphan drug designation number	EU/31/07/465; EU/31/07/466
D.3 Description of the IMP
D.3.1	Product name	Droxidopa
D.3.2	Product code	Droxidopa
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	DROXIDOPA
D.3.9.1	CAS number	23651-95-8
D.3.9.2	Current sponsor code	DROXIDOPA
D.3.9.3	Other descriptive name	(-)-threo-3-(3,4-dihydroxyphenyl)-L-serine
D.3.9.4	EV Substance Code	SUB06420MIG
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	100
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	Yes
D.2.5.1	Orphan drug designation number	EU/31/07/465; EU/31/07/466
D.3 Description of the IMP
D.3.1	Product name	Droxidopa
D.3.2	Product code	Droxidopa
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	DROXIDOPA
D.3.9.1	CAS number	23651-95-8
D.3.9.2	Current sponsor code	DROXIDOPA
D.3.9.3	Other descriptive name	(-)-threo-3-(3,4-dihydroxyphenyl)-L-serine
D.3.9.4	EV Substance Code	SUB06420MIG
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	200
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: 3
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	Yes
D.2.5.1	Orphan drug designation number	EU/31/07/465; EU/31/07/466
D.3 Description of the IMP
D.3.1	Product name	Droxidopa
D.3.2	Product code	Droxidopa
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	DROXIDOPA
D.3.9.1	CAS number	23651-95-8
D.3.9.2	Current sponsor code	DROXIDOPA
D.3.9.3	Other descriptive name	(-)-threo-3-(3,4-dihydroxyphenyl)-L-serine
D.3.9.4	EV Substance Code	SUB06420MIG
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	300
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Symptomatic neurogenic orthostatic hypotension

E.1.1.1

Medical condition in easily understood language

Patients that experience symptoms of low blood pressure when changing their posture

E.1.1.2

Therapeutic area

Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10031127
E.1.2	Term	Orthostatic hypotension
E.1.2	System Organ Class	10047065 - Vascular 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

Evaluate the clinical efficacy of droxidopa versus placebo, as demonstrated by improvements in dizziness (OHSA Item #1) from randomization over a 12 week (maximum) treatment period in patients with symptomatic neurogenic orthostatic hypotension

E.2.2

Secondary objectives of the trial

Evaluate the clinical efficacy of droxidopa versus placebo using endpoints derived from the OHQ, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S) and Boston University Activity Measure For Post-Acute Care (AM-PAC) Basic Mobility Outpatient Short Form questionnaires, as well as assessment of patient-reported falls, and BP measurements during the orthostatic standing tests.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. 18 years or older and ambulatory (defined as able to walk at least 10 meters)
2. Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary Autonomic Failure (PD, MSA, and PAF) or Dopamine Beta Hydroxylase Deficiency
3. At the Baseline visit (Visit 2), patients must demonstrate:
a. a score of at least 4 or greater on the Orthostatic Hypotension Symptom Assessment (OHSA) Item #1
b. a fall of at least 20 mmHg in their SBP, within 3 minutes of standing
4. Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care.

E.4

Principal exclusion criteria

1. Score of 23 or lower on the mini-mental state examination (MMSE)
2. Concomitant use of vasoconstricting agents for the purpose of increasing blood pressure;
a. Patients taking vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine must stop taking these drugs at least 2 days or 5 half-lives (whichever is longer) prior to their baseline visit (Visit 2) and throughout the duration of the study
3. Known or suspected alcohol or substance abuse within the past 12 months
4. Women who are pregnant or breastfeeding
5. Women of childbearing potential (WOCP) who are not using at least one method of contraception with their partner
6. Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic, or have these measurements at their Baseline Visit (Visit 2). Sustained is defined as measurements persistently greater at 2 separate measurements at least 10 minutes apart with the subject supine and at rest for at least 5 minutes
7. Untreated closed angle glaucoma
8. Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study)
9. Any significant uncontrolled cardiac arrhythmia
10. History of myocardial infarction, within the past 2 years
11. Current unstable angina
12. Congestive heart failure (NYHA Class 3 or 4)
13. Diabetic autonomic neuropathy
14. History of cancer within the past 2 years other than a successfully treated, non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ
15. Gastrointestinal condition that may affect the absorption of study drug (e.g., ulcerative colitis, gastric bypass)
16. Any major surgical procedure within 30 days prior to the Baseline visit (Visit 2)
17. Previously treated with droxidopa within 30 days prior to the Baseline visit (Visit 2)
18. Currently receiving any other investigational drug or have received an investigational drug within 30 days prior to the Baseline visit (Visit 2)
19. Any condition or laboratory test result, which in the Investigator's judgment, might result in an increased risk to the patient, or would affect their participation in the study
20. The Investigator has the ability to exclude a patient if for any reason they feel the subject is not a good candidate for the study or will not be able to follow study procedures

E.5 End points

E.5.1

Primary end point(s)

Relative mean change in OHSA Item #1 from Randomization (Visit 4) to Week 1 (Visit 5).

E.5.1.1

Timepoint(s) of evaluation of this end point

Visits 4 and 5

E.5.2

Secondary end point(s)

1. Relative mean change in OHSA Item #1 from Randomization (Visit 4) to Week 12 (Visit 8)
2. Patient reported falls from Randomization (Visit 4) to Week 12 (Visit 8)
3. Change in standing blood pressure (systolic and diastolic) from Randomization (Visit 4) to Week 12 (Visit 8)
4. Relative mean change in the OHQ Composite score and individual item scores from Randomization (Visit 4) to Week 12 (Visit 8)
5. Relative mean change in the Global assessment evaluations using the clinician-recorded and patient-recorded CGI-S scales from Randomization (Visit 4) to Week 12 (Visit 8)
6. Relative mean change in the Global assessment of improvement of disease status using the clinician recorded and patient-recorded CGI-I scales from Week 1 (Visit 5) to Week 12 (Visit 8)
7. Relative mean change in the AM-PAC Basic Mobility Outpatient Short Form score from Randomization (Visit 4) to Week 12 (Visit 8)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Relative mean change in OHSA Item #1 from Randomization to Week 12 - Visits 6, 7 and 8
2. Patient reported falls - Visits 6, 7 and 8
3. Change in standing blood pressure - Visits 6, 7 and 8
4. Relative mean change in the OHQ Composite score and individual item scores - Visits 6, 7 and 8
5. Relative mean change in the Global assessment evaluations - Visits 6, 7 and 8
6. Relative mean change in the Global assessment of improvement of disease status - Visits 6, 7 and 8
7. Relative mean change in the AM-PAC Basic Mobility Outpatient Short Form score - Visits 6, 7 and 8

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

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

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

Yes

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.8.5

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

Canada

Czech Republic

France

Germany

Italy

Spain

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

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.1.3

Elderly (>=65 years)

Yes

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.4.2.2

In the whole clinical trial

450

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)

None

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

2014-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-10-20

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