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Trial registered on ANZCTR

Registration number

ACTRN12612000157875

Ethics application status

Approved

Date submitted

1/02/2012

Date registered

3/02/2012

Date last updated

25/07/2019

Date data sharing statement initially provided

25/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Effects of L-DOPS in Patients with Low- and Normal- Blood Pressure Variants of Orthostatic Intolerance.

Scientific title

Effects of L-DOPS on Noradrenaline Responses to Head-up Tilt in patients with Low- and Normal- Supine Blood Pressure Variant of Orthostatic Intolerance.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1127-6367

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Orthostatic Intolerance

Vasovagal Syncope

Neurally Mediated Syncope

Condition category

Condition code

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Neurological

Other neurological disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This study is investigating the use of L-DOPS (L-threo-dihydroxyphenylserine), a Noradrenaline precursor, in pateints with Orthostatic Intolerance.
The study design involves a baseline assessment of 24 -hour blood pressure and symptoms. Noradrenline kinetics and muscle sympathetic responses to head-up tilt are measured. A vein biopsy is performed to assess sympathetic nerve noradrenaline content.
A group of healthy controls with be recruited for comparison of baseline data only.
In the two Orthostatic Intolerance groups the baseline evaluation is followed by a 21-28 day tolerability and dose titration period. During this period there is open label adminstration of L-DOPS (oral tablets three times/day) to determine the maximum tolerated daily dose (range 300-1800mg/day) prior to a double blind placebo controlled randomisation phase.
The randomised double-blind crossover clinical evaluation of L-DOPS involves an oral tablet (active or placebo) given three times daily at the patient specific dose (range 300-1800 mg/day) determined during the open label titration period. There are two randomised 28 day dosing periods. Clinical evaluation of symptoms is performed at the conclusion of the 28 days, evaluating the final 14 days of each dosing period. The first 14-days of each period acts as a 'washout' period. Clinical evaluation includes symptom assessment and 24-hour blood pressure monitoring.
At the conclusion of the randomised double blind placebo controlled clinical evaluation period open label L-DOPS (oral tablet three times/day at the patient specific dose previously determined, range 300-1800mg/day) is given for 21 days prior to repeating a head-up tilt table test with evaluation of noradrenaline kinetics and muscle sympathetic nerve recording followed by a repeat vein biopsy.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo - for randomised double blind crossover evaluation. Idendical tablets provided by the manufacturer of L-DOPS

Control group

Placebo

Outcomes

Primary outcome [1]

50% augmentation in noradrenaline spillover at 40 degree head-up tilt following L-DOPS dosing compared with baseline.
Noradrenaline spillover is measured using a radioisotope dilution method. Radioisotope labelled noradrenaline is infused intravenously and blood samples taken from an indwelling brachial arterial catheter. Samples are taken after 30 minutes of supine rest after infusion initiation and at the conclusion of 10minutes head-up tilt at 20, 30, 40 and 60 degrees. Samples are analysed using high performance liquid chromatography (HPLC). Noradrenaline spillover is calculated from raw noradrenaline values after adjustment for the changes in noradrenaline clearance that occur during head-up tilt as calculated using the radioisotope dilution method.

Timepoint [1]

Baseline and after a minimum of 21 days open label dosing with L-DOPS following a randomised double-blind placebo controlled clinical evaluation.

Primary outcome [2]

At baseline: 50% lower noradrenaline spillover at 40 degree head-up tilt in patients with Orthostatic Intolerance compared with healthy controls.
Noradrenaline spillover is measured using a radioisotope dilution method. Radioisotope labelled noradrenaline is infused intravenously and blood samples taken from an indwelling brachial arterial catheter. Samples are taken after 30 minutes of supine rest after infusion initiation and at the conclusion of 10minutes head-up tilt at 20, 30, 40 and 60 degrees. Samples are analysed using high performance liquid chromatography (HPLC). Noradrenaline spillover is calculated from raw noradrenaline values after adjustment for the changes in noradrenaline clearance that occur during head-up tilt as calculated using the radioisotope dilution method.

Timepoint [2]

Baseline head-up tilt test.

Secondary outcome [1]

Functional status as assessed using the Orthostatic Hypotension symptom Assessment (OHSA), Orthostatic Hypotension Daily Activities Scale(OHDAS) and SF-36 Quality of Life Assessment Instrument.

Timepoint [1]

At baseline and at the conclusion of each the two 28 day clinical evaluation periods of the randomised double-blind placebo controlled crossover phse of the study.

Eligibility

Key inclusion criteria

Participants with Orthostatic Intolerance

1.Age 18-50

2.Clinical disorder of orthostatic intolerance in association with syncope or recurrent presyncope.

a.An underlying medical condition causing these symptoms has been excluded, in particular structural heart disease, Addison’s disease and hypothyroidism.
b. Symptoms will have been present and occurring at least weekly for > or = 6 months. Symptoms include lightheadedness, weakness, blurred vision, syncope or presyncope.

3.Clinical Phenotype consistent with either Low- or Normal- Supine BP Vasovagal syncope;
a. Low- Supine Blood Pressure is defined as a typical (two or more BP readings by a medical practitioner) supine blood pressure of < or= 100 mmHg
b. Normal-Supine Blood Pressure is defined as a typical supine blood pressure of > or = 110 and < or = 140 mmHg

Healthy Control Participants for Basline comparison only ( no drug phase):

Aged between 18- 50 years.
No history of fainting or symptoms such as light-headedness, blurred vision, nausea or palpitations in association with standing.

Minimum age

18 Years

Maximum age

50 Years

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

Participants with Orthostatic Intolerance:
1. Age <18 or > 50
2. Pregnant or Breastfeeding women
3. Women of childbearing potential who are not using medically accepted contraception;
Reproductive potential: Female subjects should be either postmenopausal
(amenorrhea for at least 12 consecutive months), surgically sterile,
or women of child-bearing potential (WOCP) who are using or agree to use
acceptable methods of contraception. Acceptable contraceptives include
intrauterine devices (IUDs), hormonal contraceptives (oral, depot, patch or
injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.

4. Sexually active males whose partner is a WOCP and who do not agree to use
condoms for the duration of the study and for 30 days after the last dose;

5. Inability to withhold pressor medications for the duration of the study. Pressor medications, (eg Fludrocortisone, Midodrine, Dihydroergotamine, Pseudoephedrine, Licorice Extract, Butcher’s Broom, Cold and Flu remedies, Diet pills, NSAIDs, pyridostigmine) must be ceased for 2 weeks prior to the commencement of the study and withheld for the entire duration of the study.

6. Antidepressant medications including: tricyclics and tetracyclic antidepressants, SSRI/ SNRI/ NRI’s, MAO inhibitors;

7. Medications known to lower blood pressure that cannot be withheld for the duration of the study, eg beta -blockers;

8. Presence of structural heart disease – including ischaemic heart disease.

9. Hypertension (supine SBP > or =140 mmHg)

10. Diabetes

11. Gastrointestinal illness that may impair absorption of the study drug.

12. Known or suspected hypersensitivity to the study medication or any of its ingredients;

13. In the investigator’s opinion, have clinically significant abnormalities on clinical examination or laboratory testing;

Healthy Control Participants:
Age<18 or >50 years
Necessary Medication other than the oral controaceptive pill
Pregnant or Breastfeeding

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Randomisation is performed through pharmacy and concealed from the investigators.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomisation. The randomisation table is created by computer software in pharmacy.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Crossover

Other design features

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

15/02/2012

Actual

15/02/2012

Date of last participant enrolment

Anticipated

Actual

2/04/2014

Date of last data collection

Anticipated

Actual

15/08/2014

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Charities/Societies/Foundations

Name

BakerIDI Heart and Diabetes Institute

Address

Baker IDI Heart and Diabetes Institute
PO Box 6492, St Kilda Road Central
Victoria 8008

Country

Australia

Secondary sponsor category [1]

Hospital

Name [1]

Alfred Health

Address [1]

The Alfred

P.O Box 315
Prahran. Vic. 3181

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Th Alfred Research and Ethics Committee

Ethics committee address [1]

The Alfred Hospital, 
55 Commercial Road, 
Melbourne, 
Victoria 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

23/11/2011

Ethics approval number [1]

1/11/0395

Summary

Brief summary

Difficulty in maintaining the upright posture is called Orthostatic Intolerance. Orthostatic Intolerance may result in fainting or symptoms such as light-headedness, blurred vision, nausea and palpitations. These symptoms come on when standing or sitting, particularly for prolonged periods or time or in warm weather, and are relieved by lying down. They are often associated with an abnormal blood pressure or heart rate response to sitting or standing. 

Our research to date has looked in detail at two clinical groups with these symptoms. Both of these groups have overall normal nervous system function, but with intermittent difficulty in maintaining the upright posture. One group always has very low blood pressure (Low Supine Blood Pressure Orthostatic Intolerance) and the other normal blood pressure (Normal Supine Blood Pressure Orthostatic Intolerance). 

Our studies have particularly looked for differences in the way a part of the nervous system called the sympathetic nervous system responds to the upright posture in these two groups when compared to healthy control participants. The sympathetic nervous system, the stimulant arm of the nervous system is responsible for our “flight and fight” response to a threatening situation.  The sympathetic nervous system is also crucial in the control of blood pressure and allows us to stand upright and supply blood to our vital organs, including the brain, in the face of gravity that pulls blood towards our legs.

We have found that people with these two forms of Orthostatic Intolerance do not release as much of the main chemical messenger of the sympathetic nervous system – called noradrenaline - into their circulation in response to upright posture when compared with healthy control participants.  We have found distinct differences between these two groups and between each group and healthy control participants in the processing pathways for noradrenaline.

Current medical treatments for these forms of Orthostatic Intolerance have focused on increasing blood volume by increasing dietary salt or by the use of a medication (Fludrocortisone) that make the body retain salt and fluid. In addition medications that act to tighten blood vessels with standing (Midodrine or Dihydroergotamine) may also be used. These medications can be very helpful for some patients but are often not tolerated due to side effects and many patients continue to experience symptoms even with these medications. None of these medications has been proven to be of benefit in randomised trials to date. 
This trial will be comparing a new treatment – L-DOPS (Droxidopa) – with placebo (a tablet that appears the same as the L-DOPS tablets but contains no active ingredients) in patients with the two forms of Orthostatic Intolerance described above. L-DOPS is a nerve transmitter precursor that is converted by the body to noradrenaline, the main nerve messenger of the sympathetic nervous system. L-DOPS is an experimental treatment. This means it is not approved for patients with Low- or Normal- supine blood pressure Orthostatic Intolerance in Australia or other parts of the world. L-DOPS has been marketed in Japan since 1989 for use in patients with Parkinson Disease and Orthostatic Intolerance. L-DOPS remains an investigational drug in the United States and Australia. Current trials in the United States and Canada are studying its benefit in blood pressure regulation disorders in Parkinson disease and in symptoms in patients with Chronic Fatigue syndrome and Fibromyalgia (a condition associated with painful muscles).

This study will include:

20 Healthy control Participants

28 Participants with Low supine Blood Pressure Orthostatic Intolerance

28 Participants with Normal Supine Blood Pressure Orthostatic Intolerance

All participants will be studied through the Alfred Baker Medical Unit at the Alfred Hospital

The purpose of this research is twofold:
1.	The baseline assessment will compare the way the sympathetic nervous system responds to the ‘stress’ of the upright posture in healthy control participants and participants with the two different clinical presentations of Orthostatic Intolerance described above. These responses will be correlated with the individual pattern of nerve proteins and nerve transmitter levels - obtained from a forearm vein biopsy- in the participants. This part of the study is to being performed to confirm our previous findings in a larger group of participants and to provide baseline measurements for the participants with Orthostatic Intolerance who will participate in the second phase of the study.
2.	The second phase of the study is to assess whether the nerve transmitter replacement L-DOPS(Droxidopa) is able to improve symptoms and normalise the sympathetic nervous system response to upright posture in participants with the low- and normal- supine blood pressure variants of Orthostatic Intolerance.

Trial website

Trial related presentations / publications

Publications in preparation

Public notes

Contacts

Principal investigator

Name

Prof Murray Esler

Address

Human Neurotransmitters Laboratory BakerIDI PO Box 6492, St Kilda Road Central Victoria 8008

Country

Australia

Phone

+61 3 8532 1111

Fax

Murray.Esler@bakeridi.edu.au

Contact person for public queries

Name

Dr Susan Corcoran

Address

Human Neurotransmitters Laboratory
BakerIDI
PO Box 6492,
St Kilda Road Central
Victoria 8008

Country

Australia

Phone

+61 3 85321111

Fax

Susan.Corcoran@bakeridi.edu.au

Contact person for scientific queries

Name

Dr Susan Corcoran

Address

Human Neurotransmitters Laboratory
BakerIDI
PO Box 6492,
St Kilda Road Central
Victoria 8008

Country

Australia

Phone

+61 3 8532 1111

Fax

Susan.Corcoran@bakeridi.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Individual data may be made available if requested. Trail commenced in 2012 and recruitment completed in 2014. the consent form did not cover public sharing of data from the study.

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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No additional documents have been identified.

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