Clinical Trials Register

Summary
EudraCT Number:	2017-003054-16
Sponsor's Protocol Code Number:	DDZ-BOND-2017
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2018-04-10
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

Germany - BfArM

A.2

EudraCT number

2017-003054-16

A.3

Full title of the trial

Randomized double-blind, placebo-controlled parallel group study over 12 months to assess the effects of treatment with benfotiamine on morphometric, neurophysiological, and clinical measures in type 2 diabetes patients with mild to moderate symptomatic polyneuropathy - BOND Study

Eine randomisierte, doppelblinde, placebokontrollierte Phase-IIa-Studie über 12 Monate zur Beurteilung der Wirksamkeit von Benfotiamin in Hinblick auf morphometrische, neurophysiologische und klinische Parameter in Patienten mit Diabetes Mellitus Typ 2 und leichter bis mittelgradiger symptomatischer Polyneuropathie - BOND Studie

A.3.1

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

Study over 12 months to assess the effects of Treatment with benfotiamine on symptoms and consequences in type 2 Diabetes patients with mild to moderate symptomatic polyneuropathy.

Studie über 12 Monate zur Beurteilung der Wirksamkeit von Benfotiamin in Hinblick auf die Symptome und Folgen einer diabetischen peripheren Neuropathie in Patienten mit Diabetes Mellitus Typ 2 und leichter bis mittelschwerer symptomatischer Polyneuropathie - BOND Studie

A.3.2

Name or abbreviated title of the trial where available

BOND Study

BOND Studie

A.4.1

Sponsor's protocol code number

DDZ-BOND-2017

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	Wörwag Pharma GmbH & co. KG
B.1.3.4	Country	Germany
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	Wörwag Pharma GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Wörwag Pharma GmbH & co. KG
B.5.2	Functional name of contact point	Clinical Operations Manager
B.5.3	Address:
B.5.3.1	Street Address	Flugfeld-Allee 24
B.5.3.2	Town/ city	Böblingen
B.5.3.3	Post code	71034
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049070316204416
B.5.5	Fax number	0049070316204419
B.5.6	E-mail	claudia.reule@woerwagpharma.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	milgamma mono 300
D.2.1.1.2	Name of the Marketing Authorisation holder	Wörwag Pharma GmbH & Co. KG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	milgamma mono 300
D.3.4	Pharmaceutical form	Coated 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	BENFOTIAMINE
D.3.9.1	CAS number	22457-89-2
D.3.9.4	EV Substance Code	SUB05716MIG
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	Coated 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

diabetic polyneuropathy

sympthomatische diabetische polyneuropathie

E.1.1.1

Medical condition in easily understood language

Nerve damaging disorders associated with diabetes mellitus

Schädigung multipler Nerven (Polyneuropathie), die als Komplikation eines bestehenden Diabetes mellitus entsteht

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10012685
E.1.2	Term	Diabetic polyneuropathy
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Effects of 12 months treatment with benfothiamin in comparison to Placebo on Corneal confocal microscopy (CCM): corneal nerve fiber length (CNFL)

E.2.2

Secondary objectives of the trial

Effects of 12 months treatment with benfothiamin in comparison to Placebo on :
• Corneal nerve fiber density
• Skin biopsy
• Motor and sensory nerve conduction velocity
• Vibration perception threshold
• Warm and cold thermal detection thresholds
• Cardiovascular autonomic function tests
• Spontaneous baroreflex sensitivity
• Pupillography
• Neuropad
• Sudoscan
• Lightguide tissue spectrophotometry
• Neuropathy Disability Score • Neuropathy Impairment Score – Lower Limbs
• Michigan Neuropathy Screening Instrument • Modified Toronto Clinical Neuropathy Score
• Neuropathy Symptom Score • Total Symptom Score (TSS)
• Neuropathic Pain Symptom Inventory
• 11-Point numerical pain rating scale
• Brief Pain Inventory
• Survey of Autonomic Symptoms
• Patient Global Impression of Change
• Physical functioning
• Quality of life
• safety Routine Parameters
• Thiamin analytics

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Informed consent signed and dated
• Diabetes mellitus type 2 according to the American Diabetes Association criteria (2017), lasting ≥1 year
• Stable diabetes metabolism, defined as no metabolic decompensation within the last 3 months (severe hypoglycemia with unconsciousness, ketoacidosis)
• According to the investigator’s opinion no further optimizing potential in diabetic control
• Age: ≥18 years
• Neuropathic symptoms ≥6 months
• Presence of mild to moderate diabetic sensorimotor polyneuropathy (DSPN) with Neuropathy Disability Score (NDS) 3-8 points confirmed by at least one of the following: reduced sural sensory nerve conduction velocity (SNCV), sural sensory nerve action potential (SNAP), peroneal motor nerve conduction velocity (MNCV), tibial MNCV
• Measurable sural SNCV, peroneal MNCV or tibial MNCV above detection limit
• CNFL <1SD below the mean of control subjects
• At least 1 palpable pulse of posterior tibial artery or dorsal artery on each side of the foot
• Stable diabetes medication without optimizing potential
• Stable insulin dose for insulin-dependent patients within the last 3 months
• HbA 1c <9.5%
• Acceptable contraceptive measures with female patients in childbearing potential
• Ability to meet the study center visits for the study Duration

E.4

Principal exclusion criteria

• Subjects with secondary forms of diabetes such as due to pancreatitis
• Contraindications, known allergy, or hypersensitivity to benfotiamine or other ingredients of the study medication or local anesthetics
• Neuropathy of any cause other than diabetes which might interfere with neurological assessment
• Severe pain other than of neuropathic origin that might impair the assessment of neuropathic pain
• Diseases with mixed pain components
• Pain level >9 over 24 h on a numerical 11-Point rating scale
• Proximal asymmetric neuropathy or neuropathic symptoms of the trunk or proximal lower limbs
• Foot ulcer or infection
• Currently active or history of alcohol abuse (defined as an intake of more than 24 units of alcohol per week; one unit of alcohol equals approximately 250 ml of beer, 100 ml of wine or 35 ml of spirits) or drug addiction (including soft drugs like cannabis products)
• Peripheral arterial occlusive disease Fontaine stage II-IV
• Neoplasms
• Renal failure (serum creatinine > (above) 120 µmol/l or 1.4 mg/dl)
• As judged by the investigator, serious and/or unstable coronary heart disease (unstable angina, myocardial infarction within the preceding 6 months), congestive heart failure of New York Heart Association Class III or worse, uncontrolled hypertension, history of congenital QT-syndrome within family, history of stroke (within the preceding 6 months)
• Uncontrolled high blood pressure (DBP >95 mmHg and/or SBP >160 mmHg), unless clearly documented to be white-coat hypertension
• Clinical or laboratory evidence of hepatic dysfunction or disease; laboratory evidence defined as any of the following parameters: alkaline phosphatase, ALT, AST or bilirubin >3x ULN, except for a mild rise in bilirubin considered to be due to Gilbert’s condition.
• Generalized immune diseases (e.g. HIV-positive, autoimmune diseases, connective tissue diseases)
• Endocrine diseases like hyper- or hypothyroidism
• Treatment, lasting at least 5 days or longer, with alpha-lipoic acid, B-vitamins, evening primrose oil, or deproteinized hemoderivates of calf blood, containing low-molecular weight compounds of up to 5.000 Da or with other substances with interaction to the study product (e.g. 5-fluorouracil) or affecting study endpoints within the last 3 months before screening, except for daily intake of B-vitamins amounting to less than 1500 % of the recommended daily allowance (RDA) lasting until one month prior to screening.
• Treatment with cutaneous electrical nerve stimulation, muscle stimulation or acupuncture within the last month
• Treatment of neuropathic pain with antidepressants, anticonvulsants, sodium channel blockers, opioids, neuroleptics, and capsaicin 8% patch within the last 3 months prior to screening , except for a monotherapy with Gabapentin, Pregabalin or Duloxetin without relevant dose change within the last 2 months prior to screening and during the study.
• Mental, psychiatric or other conditions compromising data collection and understanding of written or oral instructions during the study
• Present or previous chronic alcohol abuse and/or abuse of other drugs
• Pregnant women or nursing mothers
• Participation in another clinical trial study within the last 3 months
• Ability and willingness to abstain from alcohol and from engaging in strenuous physical activity from 24 hours prior to each visit until discharge from the unit
• Blood donation within the last 3 months before or during the study

E.5 End points

E.5.1

Primary end point(s)

Corneal confocal microscopy (CCM): corneal nerve fiber length (CNFL)

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, after 6 and 12 months

E.5.2

Secondary end point(s)

Corneal nerve fiber density
• Skin biopsy
• Motor and sensory nerve conduction velocity
• Vibration perception threshold
• Warm and cold thermal detection thresholds
• Cardiovascular autonomic function tests
• Spontaneous baroreflex sensitivity
• Pupillography
• Neuropad
• Sudoscan
• Lightguide tissue spectrophotometry
• Neuropathy Disability Score • Neuropathy Impairment Score – Lower Limbs
• Michigan Neuropathy Screening Instrument • Modified Toronto Clinical Neuropathy Score
• Neuropathy Symptom Score • Total Symptom Score
• Neuropathic Pain Symptom Inventory
• 11-Point pain rating scale
• Brief Pain Inventory
• Survey of Autonomic Symptoms
• Patient Global Impression of Change
• Physical functioning
• Quality of life
• safety Routine Parameters
• Thiamin analytics

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, after 6 and 12 months

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

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.8.5

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

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.1.2.1

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:

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

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Departement of Biometry and Epidemioloy
G.4.3.4	Network Country	Germany
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	BioTeSys GmbH
G.4.3.4	Network Country	Germany

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-06-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-27

P. End of Trial
P.	End of Trial Status	Restarted

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