Clinical Trials Register

Summary
EudraCT Number:	2012-000201-72
Sponsor's Protocol Code Number:	1
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-04-13
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

UK - MHRA

A.2

EudraCT number

2012-000201-72

A.3

Full title of the trial

The Effects of Inorganic Nitrite on cardiac and skeletal muscle: Physiology, Pharmacology and Therapeutic Potential. Peripheral Arterial Disease

A.3.1

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

The Effects of Inorganic Nitrite on skeletal muscle: Physiology, Pharmacology and Therapeutic Potential in patients suffering from Intermittent Claudication.

A.3.2

Name or abbreviated title of the trial where available

Effects of Inorganic Nitrite on skeletal muscle: PAD

A.4.1

Sponsor's protocol code number

A.5.4

Other Identifiers

Name:

Professor M.P. Frenneaux

Number:

Nitrite Study

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	University of Aberdeen
B.1.3.4	Country
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medical Research Council
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point	Holland
B.5.3	Address:
B.5.3.1	Street Address	University of Aberdeen
B.5.3.2	Town/ city	Polwarth Building Room 0.055
B.5.3.3	Post code	AB25 2DZ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01224437073
B.5.5	Fax number	01224437069
B.5.6	E-mail	g.holland@abdn.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	University of Aberdeen
B.1.3.4	Country
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medical Research Council
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Aberdeen
B.5.2	Functional name of contact point	Frenneaux
B.5.3	Address:
B.5.3.1	Street Address	Room 3:045, Polwarth Building
B.5.3.2	Town/ city	School of Medicine and Dentistry
B.5.3.3	Post code	AB25 2ZD
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01224437970
B.5.5	Fax number	01224437964
B.5.6	E-mail	m.p.frenneaux@abdn.ac.uk

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	Inorganic Sodium Nitrate
D.3.4	Pharmaceutical form	Capsule
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	Sodium Nitrate Powder
D.3.9.1	CAS number	7631-99-4
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mmol millimole(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7
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
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

Peripheral arterial Disease

E.1.1.1

Medical condition in easily understood language

Pain on exercising due to poor blood supply of muscle-Intermittent Claudication

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective: to determine the effect of inorganic Sodium Nitrate (daily dose of 7mmol) for six weeks compared to placebo in respect of:
1) treadmill absolute walking distance.
2) and quality of life in patients with stable intermittent claudication

and in a subgroup of 20 patients:
4) Skeletal muscle perfusion will be assessed using MRI
5) Skeletal muscle biopsies will be taken to assess mitochondrial function

E.2.2

Secondary objectives of the trial

Secondary objectives: In order to define the mechanism(s) responsible the following will be assessed:
1) Plasma markers of angiogenesis, NO signaling and anaerobic metabolism
2) Markers of endothelial function
3) Markers of platelet activity

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients with stable intermittent claudication 1) of at least 3 months duration 2) with clinical findings of peripheral vascular disease and 3) an ABPI<0.9.
Strict attention will be paid to secondary prevention measures and patients will be advised to exercise regularly. Patients will not be offered supervised exercise therapy. Dietary nitrite/nitrate intake will be assessed via a short questionnaire. Patients with a high dietary intake will not be excluded from the study as we wish to assess the effects or oral sodium nitrate supplementation on platelet function irrespective if a patient’s diet.
They should be able to walk for at least one minute on a treadmill using the Skinner-Gardner protocol and the variability in absolute claudication distance (ACD) between two consecutive baseline tests performed within a two week period should be less than 25%.
Patients must be on a statin and aspirin for at least six weeks prior to being enrolled in this study. Patients on pentoxyifylline, cilostazol, or dietary supplements such as omega-3 fatty acids and l-arginine will require a 1 month washout period prior to enrolment.

E.4

Principal exclusion criteria

Patients with the following will be excluded:
• rest pain or ulceration
• recent arterial revascularisation (within the past 3 months)
• other co-morbidities that may impede the patient’s ability to perform an exercise test (arthritis, severe coronary artery disease or chronic obstructive pulmonary disease)
• Patients on clopidogrel
• oral nitrate preparations

E.5 End points

E.5.1

Primary end point(s)

Primary end points: Clinical outcome measures
1. Maximal walking distance and initial claudication distance will be assessed using the Skinner Gardner variable-grade constant speed treadmill protocol will be performed twice at baseline, and following 6 weeks of placebo/sodium nitrate.
2. Quality of life: Generic SF36, disease specific VascuQOL and Walking impairment questionnaire: will be measured at baseline, and 6 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

The treadmill test will be performed twice prior to the patient starting the study and once at 6 weeks. The Quality of life questionnaires will be performed at baseline and after six weeks of treatment.

E.5.2

Secondary end point(s)

Secondary end point: In order to define the mechanism(s) responsible for anti-ischaemic effects in the legs a series of studies will be conducted to assess whether these are related to improved perfusion, and if so whether this is due to increased angiogenesis of whether these effects are attributable to effects on skeletal muscle mitochondrial function.
1 Plasma markers of angiogenesis, NO signaling and anaerobic metabolism: Plasma concentrations of VEGF, nitrite, nitrate, and lactate will be measured prior to and immediately after maximum walking distance in all patients.
2. Markers of endothelial activity: vWF and soluble P selectin (all patients)
3. Pulse wave velocity & stiffness index: PWV will be measured by the fully automated micromedical pulse trace PWV (PT 4000, Rochester, Kent) and stiffness index is measured via the use of photoplethysmography (all patients). This will be measured prior to exercise.
Blood pressure: measured by the Datascope accutor plus (Datascope Medical company).Three supine blood pressure measurements will be taken 1 minute apart after a 10 minute rest, and the average of these readings will be used in the analysis. This will be recorded just prior to measuring the pulse wave velocity
5. Platelet function assays: In 100 patients platelet aggregation measured by Ultegra RPFA point of care and flow cytometry ( P-selectin expression, fibrinogen binding with and without ADP stimulation and platelet-monocyte aggregtes) will be measured prior to and immediately after maximum walking distance

In a subgroup of 20 patients:
1. Skeletal muscle perfusion will be assessed using MRI (subgroup of 20 patients)
2. Skeletal muscle biopsies will be taken – for analysis of glycogen and triglyceride content, expression and acivity of metabolic enzymes, UCP expression and mitochondrial electron transport chain function as described above.In addition we will stain the biopsies for the cell surface markers CD34+ and CD31+, the ratio providing a measure of new vessel formation (collaboration with Prof A. Ahmed Edinburgh), and we will also measure capillary density. (subgroup of 20 patients)

E.5.2.1

Timepoint(s) of evaluation of this end point

All secondary measurements are to be performed at baseline and after six weeks of treatment.

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

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

Mechanistic

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)

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

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

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

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

The definition of the end of trial is the last patient's final visit.

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

F.1.1