Clinical Trials Register

Summary
EudraCT Number:	2011-000090-32
Sponsor's Protocol Code Number:	BBR-012CS01
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2011-03-10
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

UK - MHRA

A.2

EudraCT number

2011-000090-32

A.3

Full title of the trial

A Randomised, Double-Blind, Repeat-Dose, Placebo-Controlled Phase IIa Proof of Concept Study to Investigate the Safety and Efficacy of Oral BBR-012 in Combination With Standard Medical Care in Diabetic Patients With Complicated Skin Ulceration on the Foot (Diabetic Foot Ulcer)

A.3.1

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

BBR-012 Diabetic Foot Ulcer Study

A.3.2

Name or abbreviated title of the trial where available

BBR-012 Diabetic Foot Ulcer Study

A.4.1

Sponsor's protocol code number

BBR-012CS01

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	Bridge BioResearch Rights (Jersey) Ltd
B.1.3.4	Country	United Kingdom
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	Bridge BioResearch Rights Ltd
B.4.2	Country	Jersey
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Illingworth Research Ltd
B.5.2	Functional name of contact point	Clinical Operations Manager
B.5.3	Address:
B.5.3.1	Street Address	Suite 5, Silk House, Park Green
B.5.3.2	Town/ city	Macclesfield
B.5.3.3	Post code	SK11 7QJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	4401625617447
B.5.5	Fax number	4401625468083
B.5.6	E-mail	ruth.smith@illingworthresearch.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	Yes
D.2.1.1.1	Trade name	Isoniazid Tablets BP 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	UCB Pharma Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Isoniazid
D.3.2	Product code	BBR-012
D.3.4	Pharmaceutical form	Tablet
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	ISONIAZID
D.3.9.1	CAS number	54-85-3
D.3.9.2	Current sponsor code	BBR-012
D.3.9.3	Other descriptive name	Isonicotinylhydrazine
D.3.10	Strength
D.3.10.1	Concentration unit	IU/mg international unit(s)/milligram
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.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	Tablet
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

Complicated skin ulceration on the foot in patients with diabetes.

E.1.1.1

Medical condition in easily understood language

Diabetic Foot Ulcers

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10067106
E.1.2	Term	Multiple skin ulcers
E.1.2	System Organ Class	10040785 - Skin and subcutaneous tissue 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 compare the rate of healing of DFUs, measured as percent reduction in wound area per week, after 28-days treatment with BBR-012 or placebo, in combination with standard medical therapy.

E.2.2

Secondary objectives of the trial

To compare the rate of healing of DFUs, after 12-weeks treatment, in combination with standard medical therapy.
To determine the effect of BBR-012 on clinical DFU assessment criteria over the 12-week treatment period.
To compare the number and percent of patients with healed DFU after 12-weeks treatmentin combination with standard medical therapy.
To determine the effect of BBR-012 on the level of ischaemia in the DFU after 28 days, 8-weeks- and 12-weeks treatment.
To determine whether there is any correlation between the level of ischaemia of the target DFU after 28-days, 8-weeks- and 12-weeks treatment.
To determine the effect of BBR-012 on microbiological outcome of baseline wound pathogens over the 12-week treatment period.
To evaluate the safety and tolerability of 12-weeks treatment with BBR-012 in patients with DFU.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Is a man or woman aged >or=18
2. Has diabetes mellitus, according to the American Diabetes Association criteria.
3. Has an ischaemic or neuro-ischaemic DFU below the malleolus that has a minimum length and perpendicular width of 1 cm x 1 cm. Patients with multiple DFUs may be enrolled but only one DFU (designated the target DFU) is to be studied.
4. Has received appropriate surgical and antibiotic intervention to remove all necrotic and infected bone, if previously diagnosed with osteomyelitis. Patients must be evaluated for visible signs of bone involvement (including "probe to bone") and must have had an X-ray, or other radiological investigation, of any previously osteomyelitic area to confirm resolution.
5. Patients without a detectable pedal pulse can only be enrolled if, in the opinion of investigator or vascular specialist, the patient has sufficient circulation to the affected extremity that will allow effective treatment, the patient will not require immediate or urgent amputation and the patient does not have reconstructable distal disease.
6. tcpO2 on the target DFU is >/= 25 and </= 45 mmHg.
7. ABI on the leg with the target DFU is ≥0.4.
8. Meets the following laboratory criteria:
. White blood cells (WBC) and differential white cells within the local laboratory normal range.
. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) within 2~ the upper limit of normal at baseline.
9. If female and of childbearing potential, negative pregnancy test (urine or serum) at the baseline visit and not lactating. Women of childbearing potential must use one of the
following medically acceptable methods of birth control and must agree to continue with the regimen throughout the duration of the study:
. Oral, implantable or injectable contraceptives for 3 consecutive months before the baseline visit (Visit 2).
. Total abstinence from sexual intercourse (>/= 1 complete menstrual cycle before the baseline visit).
. Intrauterine device.
. Double barrier method (condoms, sponge, diaphragm or vaginal ring with spermicidal jellies or cream).
Female and not of childbearing potential is defined as postmenopausal for >/= 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy).
10. Willing to return to the study centre for the final (follow-up) visit.
11. Provide written informed consent to participate in the study. Patients must be able to speak English fluently and to understand English.
12. Has a BMI </= 40 kg/m2.

E.4

Principal exclusion criteria

1. Has a known history of hypersensitivity to any part or constituent of the BBR-012 tablet.
2. Has any uncontrolled illnesses (e.g. active malignancy, vasculitis) that, in the opinion of the investigator, would interfere with interpreting the results of the study.
3. Has an infected DFU based on the IDSA guidelines2, i.e. presence of purulent secretions or at least two of the manifestations of inflammation (erythema, warmth, swelling or induration and pain or tenderness), and for whom, in the investigator’s judgment, intravenous or oral antibiotic therapy is required.
4. Has active osteomyelitis.
5. Has suspected gangrenous tissue of the affected limb that cannot be removed with a single debridement.
6. Has a DFU associated with prosthetic material or a device.
7. Has received any potentially effective systemic antibiotic therapy for more than 24 hours during the 72-hour period before the screening visit.
8. Is receiving, or has received within the 14 days prior to the screening visit, any concomitant topical wound therapy (e.g., topical antimicrobial therapy, topical debriding agent, topical growth factor, topical skin replacement, larvae therapy, Vacuum Assisted Closure [VAC] system therapy, or hyperbaric oxygen).
9. Has received systemic corticosteroids, immunosuppressive agents, radiation therapy or chemotherapy within the 30 days prior to the screening visit.
10. Has any condition other than peripheral neuropathy for which isoniazid use is contraindicated, i.e., hepatic impairment, renal impairment (defined as estimated glomerular filtration rate <10 mL/minute/1.73m2), hypersensitivity to isoniazid. Patients with slow acetylator status, epilepsy, history of psychosis, alcohol dependence,
malnutrition, human immunodeficiency virus, or acute porphyria may be enrolled at the discretion of the investigator.
11. Known or suspected drug or alcohol abuse or positive drugs of abuse test. If a patient has a positive drugs of abuse test for codeine that results from the patient taking codeine phosphate or a codeine-based compound product (e.g. co-codamol or similar) as prescribed for a licensed indication (analgesia, anti-motility, cough suppression), the patient may be included at the discretion of the investigator.
12. Participating in any clinical study the 12 weeks before the screening visit and that is anticipated to interfere with the objectives of the study, as judged by the investigator.
13. Donation of more than 450 mL of blood in the 3 months before the screening visit, or 1200 mL blood in the 12 months before the screening visit.
14. History of severe hypersensitivity or ongoing hypersensitivity that might affect the patient’s suitability for the study (e.g. hypersensitivity to wound dressings), as judged by the investigator.
15. History of allergy to, or insensitivity to, local anaesthetics.
16. Use of any prescribed or non-prescribed (over-the-counter) medication, including herbal medication (e.g., St. Johns Wort) that could possibly interfere with the objectives of this study (e.g., could affect the closure of chronic dermal ulceration), during 2 weeks (or 5 half-lives of the compound whichever is the longer) before the anticipated first dose of study medication. Occasional paracetamol for pain relief (maximum 2 g per 24 hours) and adrenergic nasal spray for relief of nasal congestion are allowed.
17. Having received BBR-012 or isoniazid within the 6 months prior to the screening visit.
18. Bleeding disorder or history of increased bleeding.
19. Signs or symptoms of active or latent tuberculosis based on specific history, physical examination and chest X-Ray (X-ray examination within the previous 3 months or at screening).
20. Positive IGRA test.
21. Known to be at high risk for tuberculosis, e.g. HIV positive, immunosuppressed, active malignancy.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the rate of healing of the DFU in the BBR-012 group versus the placebo group after 28 days treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days

E.5.2

Secondary end point(s)

To compare the rate of healing of DFUs, measured as percent reduction in wound area per week, after 12 weeks treatment with isoniazid (BBR012) or placebo, when combined with the standard medical therapy.
To determine the effect of BBR012 on clinical DFU assessment criteria (IDSA guidelines, composite severity score, modified ASEPSIS score, TEXAS diabetic wound score and global clinical assessment) over the 12week treatment
period.
To compare the number and percent of patients with healed DFU after 12weeks
treatment with BBR012 or placebo, when combined with the standard medical therapy.
To determine the effect of BBR012 on the degree of restriction of blood in the DFU as measured by transcutaneous partial pressure of tissue oxygenation (tcpO2) after 28 days, 8 weeks and 12weeks treatment with BBR012
in patients with DFU.
To determine whether there is any relationship between the degree of restriction of blood (ischaemia) in the affected foot as measured by tcpO2 and by ankle brachial pressure index (ABI) after 28 days, 8weeks and 12weeks
treatment with BBR012 in patients with DFU.
To determine the effect of BBR012 on microbiological outcome of baseline wound pathogens over the 12week treatment period in patients with DFU.
To evaluate the safety and tolerability of 12weeks treatment with BBR012
in patients with DFU.

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days, 8 weeks and 12 weeks

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)

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

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

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

Completion of all trial procedures by participants (e.g. last follow-up visit or questionnaire)

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.1.1.1

In Utero

F.1.1.1.1