Clinical Trials Register

Summary
EudraCT Number:	2012-000066-37
Sponsor's Protocol Code Number:	NM-V-101
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-05-04
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

Czechia - SUKL

A.2

EudraCT number

2012-000066-37

A.3

Full title of the trial

Double-blind, randomized, placebo-controlled study on efficacy, safety and tolerability of ancrod in patients with sudden sensorineural hearing loss

Dvojitě zaslepená, randomizovaná, placebem kontrolovaná studie účinnosti, bezpečnosti a snášenlivosti přípravku ancrod u pacientů s náhlou sensorineurální ztrátou sluchu

A.3.1

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

Efficacy, safety, and tolerability of Ancrod in patients with sudden hearing loss

A.3.2

Name or abbreviated title of the trial where available

n.a.

A.4.1

Sponsor's protocol code number

NM-V-101

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01621256

A.5.4

Other Identifiers

Name:

n.a.

Number:

n.a.

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	Nordmark Arzneimittel 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	Nordmark Arzneimittel GmbH & Co
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	Nordmark Arzneimittel GmbH & Co. KG
B.5.2	Functional name of contact point	Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	Pinnauallee 4
B.5.3.2	Town/ city	Uetersen
B.5.3.3	Post code	25436
B.5.3.4	Country	Germany
B.5.4	Telephone number	494122712926
B.5.5	Fax number	494122712740
B.5.6	E-mail	kristin.forssmann@nordmark-pharma.de

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	Ancrod (Viprinex TM)
D.3.2	Product code	NM-V
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ANCROD
D.3.9.1	CAS number	9046-56-4
D.3.9.2	Current sponsor code	Venotrombin A
D.3.9.3	Other descriptive name	Agkistrodon serine protease
D.3.9.4	EV Substance Code	SUB00525MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	70
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

sudden sensorineural hearing loss (SSHL)

E.1.1.1

Medical condition in easily understood language

hearing loss

E.1.1.2

Therapeutic area

Diseases [C] - Ear, nose and throat diseases [C09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10040016
E.1.2	Term	Sensorineural hearing loss
E.1.2	System Organ Class	100000013775

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of this study is to evaluate the efficacy of ancrod treatment on hearing ability in patients suffering from SSHL.
The primary objective of this study is to determine the efficacy of ancrod as primary treatment of SSHL compared to placebo in patients with unilateral sudden sensorineural hearing loss as determined by audiometry.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to evaluate:
− The relationship between biomarkers and clinical efficacy.
− The safety and tolerability of ancrod.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet all of the following inclusion criteria in order to be eligible for this study:
1. Unilateral idiopathic sudden sensorineural hearing loss ≥30 dB in at least 2 consecutive frequencies in the affected ear or ≥20 dB in 3 consecutive frequencies based upon evaluation of 8 frequencies, 0.125, 0.25, 0.5, 1, 2, 4, 6, and 8 kHz, compared to the contralateral ear.
2. Symmetric hearing prior to onset of SSHL, according to patient’s recollection.
3. Patients with hearing loss not greater than 90dB at 0.125, 0.25, 0.5, 1, 2, 4, 6, and 8 kHz.
4. Enrollment has to be accomplished within 7 days after SSHL onset.
5. Male or female aged ≥18 to ≤70 years.
6. Women of childbearing potential who are sexually active with opposite partners have to perform adequate contraception with a combination of a highly effective method of birth control and additional barrier contraception. [Highly effective method of birth control is defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly for the entire study duration: combined (oestrogen and gestagen) oral contraceptives, hormone implants, hormone injectables, or hormone containing intrauterine device that needed to be in place for a period of at least 2 months prior to screening. Additional barrier contraception (at least the following methods are allowed: condom of the male, diaphragm with spermicide, portio cap with spermicide) has to be used for the duration of the trial, defined as from the time of screening to at least 10 days after Day 6 (Visit 4) of the double-blind treatment phase. A single barrier method is not acceptable. Women of non-childbearing potential can be included if surgically sterile (documented complete hysterectomy or bi-tubal ligations) or post-menopausal >1 year.]
7. Men of reproductive potential must use condoms. In addition, the female partner should also be on a safe hormonal contraception (e.g. combined oral contraceptives, hormone implants, hormone injectables or hormone containing intrauterine device) or use a barrier contraception (e.g. intrauterine device, diaphragm or portio cap with spermicide), if she is of childbearing potential.
8. Ability to understand and to follow the study protocol.

E.4

Principal exclusion criteria

The presence of any of the following will exclude a patient from study enrolment:
1. Pregnant or breast-feeding female.
2. positive pregnancy test before receiving study drug
3. Body weight >140 kg.
4. Bilateral SSHL.
5. Incomplete recovery after previous SSHL.
6. Due to history of physical efforts suspected perilymph fistula or membrane rupture.
7. Previously existing, known retrocochlear hearing loss.
8. Any history of any ear operation or local inflammatory disease in the past one year
9. History of blunt or penetrating ear trauma, head trauma, barotrauma, or acoustic trauma immediately preceding SSHL.
10. History of Menière’s disease, autoimmune hearing loss, radiation-induced hearing loss, endolymphatic hydrops.
11. Treatment with steroids for any reason within the preceding 30 days.
12. History of chronic inflammatory diseases or autoimmune diseases e.g. rheumatic disease, including rheumatoid arthritis, scleroderma, lupus erythematosus, polymyalgia rheumatica, polyarteritis nodosa, temporal/giant cell arteritis, Sjögren’s syndrome, or ulcerative colitis and Crohn’s disease.
13. History of unstable angina, coronary artery stenting or bypass grafting within three months of enrolment, transient ischemic attacks or stroke within four weeks of enrolment.
14. Prior chemotherapy or treatment with immunosuppressant drugs (azathioprine, chlorambucil, cyclophosphamide, or other alkylating agents), cyclosporine, etanercept, infliximab, interferon or any therapy with drugs known as ototoxic (e.g. aminoglycosides, cisplatin, loop diuretics, quinine etc.) in the past 6 months.
15. Gastrointestinal pathology: lesions liable to bleed such as active peptic ulcer disease, inflammatory bowel disease, history of gastrointestinal bleeding, or recent hemorrhage at any anatomical site requiring medical intervention.
16. Screening plasma fibrinogen level of <180 mg/dL.
17. Known disorder of platelet function or coagulation abnormality.
18. Platelet count of <100,000/mm3.
19. Severe liver disease.
20. Hepatic failure (e.g., aspartate aminotransferase (SGOT) or alanine aminotransferase (SGPT) ≥3 × upper limit of normal [ULN])
21. Treatment with hyperbaric oxygen within one week prior to study drug.
22. Renal insufficiency (e.g., blood urea nitrogen or creatinine ≥2 × ULN) or patients on renal dialysis.
23. Use of another investigational drug within 30 days prior to SSHL onset.
24. Any other serious medical condition that might interfere with subject evaluation over the 90-day study period, based on the investigator’s judgment, e.g. planned surgical intervention or any other condition which might give doubt for non-completing the study e.g. planned holiday, distance between investigational center and place of origin.
25. Known hypersensitivity to the drug substance or excipients.
26. Blood or blood product infusion within one week prior to study drug.
27. Use of any prohibited drug listed in chapter 6.4.1 and 6.4.2 of this study protocol.
28. Immunoglobulin infusion 4 weeks prior to study drug.
29. Planned treatment using intramuscular injections (e.g. vaccinations, vitamin B therapy)
30. Conditions associated with an increased risk of hemorrhaging such as major surgery, history of hemorrhagic stroke, intracranial hematoma, subarachnoid hemorrhage, diabetic retinopathy, retinopathy grade 3 or worse, known hemostatic disorders.
31. Uremia and renal colic with calculus, cerebrovascular accident, and history of neurosurgery
32. History of malignant hypertension and/or diastolic pressure > 105 mmHg
33. Acute pericarditis
34. Subacute bacterial endocarditis
35. Septicemic states with or without evidence of diffuse intravascular coagulation
36. History of clinically relevant immediate-type allergy (type I) with respect to e.g. mildew, (house dust) mite, cockroach, hymenoptera venom, dog, cow and honeydew melon.
37. Hearing loss of infectious or oncology origin

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure for this study is the change in pure tone audiogram (PTA) in the affected ear from screening until Day 8. The PTA will be calculated as the arithmetic mean of air conduction thresholds at the affected consecutive frequencies in the frequency range of 0.125 to 8 kHz. A non-affected frequency within two affected frequencies will be included.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 8

E.5.2

Secondary end point(s)

Secondary outcome measures will include:
− Change in word recognition score from screening to Day 8, Day 30 and Day 90.
− Change of audiogram in the affected ear from screening to Day 30 and Day 90.
− Change in fibrinogen concentration from screening to Day 2 and Day 8.
− Change in biomarkers from screening to Day 8.
− Patient assessment of change in hearing impairment.
− Physician assessment of change in hearing impairment.
− Change in tinnitus severity.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 2, 8, 30, 90

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

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

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

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

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.1.1.2

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

115

F.4.2.2

In the whole clinical trial

115

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)

The post study treatment should be done by the treating physician according to basic medical services. In case of premature study-drop out a final medical examination should be done in the study centre.

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

2015-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-09-18

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