Clinical Trials Register

Summary
EudraCT Number:	2012-001430-34
Sponsor's Protocol Code Number:	10-TT-EP-003
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-05-04
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

Germany - BfArM

A.2

EudraCT number

2012-001430-34

A.3

Full title of the trial

Therapeutic effectiveness, safety and tolerability of Tonsilotren tablets
in patients (6 to 60 years old) with chronic tonsillitis.
A randomized, international, multicenter, controlled clinical trial.

A.3.1

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

Therapeutic effectiveness, safety and tolerability of Tonsilotren tablets
in patients (6 to 60 years old) with chronic inflammation of palatine tonsils.
A randomized, international, multicenter, controlled clinical trial.

A.3.2

Name or abbreviated title of the trial where available

TocTo (Tonsilotren in chronic Tonsillitis)

A.4.1

Sponsor's protocol code number

10-TT-EP-003

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	Deutsche Homöopathie-Union, DHU-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	Deutsche Homöopathie-Union, DHU-Arzneimittel 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	Deutsche Homöopathie-Union, DHU-Arzneimittel GmbH & Co. KG
B.5.2	Functional name of contact point	Medical Affairs & Clinical Research
B.5.3	Address:
B.5.3.1	Street Address	Ottostr. 24
B.5.3.2	Town/ city	Karlsruhe
B.5.3.3	Post code	76227
B.5.3.4	Country	Germany
B.5.4	Telephone number	00490721409301
B.5.5	Fax number	0049072140938781
B.5.6	E-mail	sabine.dejaegere@dhu.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	Yes
D.2.1.1.1	Trade name	Tonsiotren H (Tabletten)
D.2.1.1.2	Name of the Marketing Authorisation holder	Deutsche Homöopathie-Union, DHU-Arzneimittel 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.3.4	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	Atropinum sulfuricum trit. D5
D.3.9.2	Current sponsor code	Atropinum sulfuricum trit. D5
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12.50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hepar sulfuris trit. D3
D.3.9.2	Current sponsor code	Hepar sulfuris trit. D3
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	10.00
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Kalium bichromicum trit. D4
D.3.9.2	Current sponsor code	Kalium bichromicum trit. D4
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	50.00
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Silicea trit. D2
D.3.9.2	Current sponsor code	Silicea trit. D2
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5.00
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mercurius bijodatus trit. D8
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	25.00
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	Yes
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic tonsillitis

E.1.1.1

Medical condition in easily understood language

Chronic inflammation of palatine tonsils

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10009152
E.1.2	Term	Chronic tonsillitis
E.1.2	System Organ Class	10021881 - Infections and infestations

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 primary objective of the study is to assess the therapeutic effectiveness of Tonsilotren in the treatment of chronic tonsillitis when used in addition to conventional symptomatic treatment (test group) in comparison to conventional symptomatic treatment alone (control group).

E.2.2

Secondary objectives of the trial

The secondary objective of the study is to assess safety and tolerability of Tonsilotren treatment in chronic tonsillitis.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females aged from 6 to 60 years;
2. Diagnosed chronic tonsillitis characterized by:
- the presence of at least three of five local symptoms at visit 1:
o Hyperemia of the anterior palatine arches;
o Edema of angle where the anterior and posterior palatine arches join each other;
o Caseous purulent plug and / or purulent exudates in the tonsillar crypts;
o Friable tonsils or indurated tonsils or scarred adhesions between the tonsils and the palatine arches;
o Enlarged submandibular lymph nodes.
- At least three acute throat infections within the past twelve months, or two acute throat infections during each of the two last years, documented in the patient file;
Definition and criteria for accepted documentation of acute throat infection in the patient file: Diagnoses and / or corresponding codes J02 and J03 according to WHO ICD-10. Also documentation in referral letters is accepted. If exact number of events is not given, information (date and diagnosis of each event) should be obtained by contact with referral person and documented.
3. Signed informed consent according to the applicable law;
4. Willingness and ability to comply with all procedures of the trial.

E.4

Principal exclusion criteria

1. Presence of acute throat infection at inclusion;
2. Presence of peri-tonsillar abscess;
3. Presence of acute and chronic otitis, adenoiditis, sinusitis of all types, odontological infection, bronchial and lung disease (e.g. bronchitis, bronchial asthma, cystic fibrosis), tuberculosis or known allergic manifestations in the throat and / or mouth;
4. Obstruction in the pharynx due to enlargement of tonsils (causing severe sleep disorders e.g. sleep apnea);
5. Presence of severe cardiovascular, renal or hepatic disease, as well as gastroesophageal reflux, unstable diabetes mellitus, hyperthyroidism, cerebrovascular or other active bleeding, Human Immunodeficiency Virus (HIV) infection, mononucleosis of each severity, or oropharyngeal gonorrhea;
6. History of non-steroidal anti-inflammatory drugs (NSAIDs) intolerance (e.g. bronchospasm, asthma, rhinitis, urticaria, gastrointestinal bleeding or perforation), hematogenetic dysfunction of unknown origin, repeated peptic ulcera or hemorrhages;
7. History or presence of all kind of serious streptococcal complications (rheumatic heart disease, glomerulonephritis, joint pain, arthritis);
8. Previous surgery in the past six months or need for surgery of the nose or paranasal sinuses, adenoids and / or tonsils;
9. Evidence of any malignant disease during the past five years before enrolment into the trial;
10. Presence of neurological and / or psychiatric diseases (e.g. depressive episode) interfering with evaluation of quality of life and assessment in the patient's diary;
11. Treatment with systemic acting antibiotics, glucocorticosteroids or medications with immunomodulating activities during the past four weeks and treatment with NSAIDs as well as locally on the tonsils acting antibiotics, glucocorticosteroids or immunomodulators during the past week prior to enrolment into the trial;
12. Known or suspected hypersensitivity to chromium, mercury or any other ingredient and / or excipient of Tonsilotren as well as lactose and / or fructose intolerance and known intolerance towards leather and jewelry metals as well as towards dental metal fillings and vaccines;
13. Heavy smoking (>= 20 cigarettes per day) or known or suspicion to or presence of drug addiction including alcohol abuse;
14. Women of childbearing potential without adequate contraception or women, who want to become pregnant, are pregnant or breast-feeding;
15. Prior enrolment into this trial;
16. Participation in another clinical trial during the past three months prior to enrolment into the trial;
17. Incapability of understanding nature, meaning and consequences of the trial;
18. Patients in custody by juridical or official order;
19. Patients, who are members of the staff of the study center, staff of the sponsor or involved Clinical Research Organizations (CROs), the investigator him- / herself or close relatives of the investigator.

E.5 End points

E.5.1

Primary end point(s)

1. Mean period of time between consecutive acute throat infections within one year.

An acute throat infection must be confirmed by the investigator. It is defined by the presence of fever (axillary temperature >= 37.5°C), throat hyperemia (e.g. pharynx, tonsils, etc.) and difficulty in swallowing / sore throat.
Patients are instructed to visit their investigator for an additional visit in case they feel sick with acute complaints in the upper respiratory tract. Investigators are requested to document primary diagnosis. Acute throat infections are limited to all diagnoses in accordance with codes J02 and J03 of WHO ICD-10 (e.g. acute pharyngitis, acute tonsillitis, adenotonsillitis, or tonsillopharyngitis) and may be of viral or bacterial origin.
Relapses of acute throat infection within 7 days after end of its treatment belong to the originating acute throat infection and do not count separately.
Time between two acute throat infections will be calculated using first day of infection as reference point.
Evaluation year is defined as period between visit 3 (week 8) and visit 9 (week 60). Withdrawals until visit 3 will be replaced.

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 9 (week 60).

E.5.2

Secondary end point(s)

2. Number of days with either sore throat / difficulties in swallowing or halitosis or exhaustion (infection-related complaints e.g. fatigue, weakness, sleeping disorders, decreased appetite, lack of concentration or decreased productivity) on the basis of patient diary in each single treatment period and each follow-up period;
3. Number of URTIs within one year ;
4. Severity of chronic tonsillitis symptoms as evaluated by the investigator at each regular study visit ;
5. Frequency of antibiotics consumption due to acute throat infections;
6. Days with analgetics consumption due to acute throat infections;
7. Effect of treatment on performance of normal daily activity in each single treatment and each follow-up period based on the information given in the patient's diary;
8. Patient's quality of life using a 5-item rating scale (very good, good, moderate, poor, very poor) at each regular visit except visit 2;
9. Treatment outcome according to Integrative Medicine Outcome Scale (IMOS) at each post-baseline study visit except visit 2;
10. Tolerability of treatment at the end of each study treatment period (evaluation in test group only);
11. Adverse events including incidence of tonsillitis’ complications (rheumatic fever, rheumatic heart disease, glomerulonephritis, arthritis).

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to each individual endpoint, see section E.5.2.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Add-on trial: all patients: conventional symptomatic treatment, test group additionally Tonsilotren.

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Conventional symptomatic treatment

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Ukraine

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

Time point of study data base closure.

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

Yes

F.1.1

Number of subjects for this age range:

160

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children / adolescents between 6 and 17 years of age will be enrolled, but not in Germany.

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

160

F.4.2.2

In the whole clinical trial

240

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)

Plan for treatment of subject after end of participation is not different from expected normal treatment of chronic tonsillitis.

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

2012-08-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-08-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-08-14

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