Clinical study on the effectiveness and tolerability

Controlled randomised double-blind study on the effectiveness and tolerability of

dimethicone and tetracaine comb. in patients with recurrent aphthous ulcers (1996/I)

The effectiveness and the tolerability of Bye Mouth Ulcer!™ (dimethicone 8mg/ml and hydroxyethyl cellulose 75 mg/ml) and tetracaine (1 g in 100 g solution) were investigated in patients with recurrent aphthous ulcers in a multicentric, double-blind, randomised phase II study.

 A total of 313 patients were incorporated in the study. The patients of both sexes were

required to be at least 10 years old and suffer for recurrent aphthous ulcers. The intensity

of the pain was required to reach a value of 3 cm or more on a visual analogue scale of

10 cm.

Each investigational product had to be applied to the aphthous ulcers at least four

times per day. The duration of treatment amounted to a maximum of 14 days.

A primary objective variable was the comparison of the pain intensity from day 1 to day 4.

Another primary objective variable was the tolerability of the dimethicone film-forming

substance complex in comparison with tetracaine.

In addition, the acute and long-term effect of the trial substances were recorded using

parameters such as acute effect on pain, healing time and quality of pain.

Investigations were conducted on day 1, 4, 7, 10 and day 14 during the 14-day treatment

phase. A control examination on day 2 was facultative.

The acute effect of the investigational products were documented by the pain

assessment at intervals of 1 minute, 2, 3, 4, 5, 10, 20 and 30 minutes as of application by

means of a visual analogue scale (VAS 0 cm = extremely pleasant, 10 cm = extremely

unpleasant). The patients were given a diary for the follow-up and assessment outside of

the examination appointments.

For the primary objective variable, the abatement of pain from the time of the medication

phase to day 4, the DIHEC dispersion achieved an intensity reduction of 3.73 cm on the

VAS and tetracaine achieved a reduction of 3.33 cm. A significant superiority of the

dispersion in comparison with tetracaine with respect to pain reduction could thus be

documented.

No significant differences could be determined in reducing the diameter of the aphthous

ulcers and rate of healing. With tetracaine, the healing rate amounted to 90%; that of the

dispersion containing dimethicone amounted to 85.4%. At 8.54 days, the duration of

healing was shortest with the dispersion; it was the longest with tetracaine at 8.89 days.

The overall medical assessment reflects these findings, since the dispersion containing

dimethicone was rated as being best, followed by tetracaine.

There were no significant differences for the acute course of pain after the preparations

were applied. They all exhibited a prompt onset of action which became pronounced after

only 1 minute.

Tingling sensations, feelings of numbness, cooling or burning were also enquired about

with the immediate effects. Tetracaine performed relatively poorly in the process, since

the tingling sensations were perceived by some to be unpleasant. The same also applies

to the feelings of numbness and cooling effect.

The question which the patients were posed with at the end of the study on how they felt

about the medicinal products produced results indicating that here, too, the dispersion

containing dimethicone had the best value with 2.45 cm on the VAS, followed by

tetracaine with 3.10 cm.

9.26% of the patients indicated undesired effects with the dimethicone film-forming

substance complex, while 17.92% did so with tetracaine. Burning in the mouth area was

the main issue for both products, numbness and tingling were indicated less frequently.

At the same time, it must be noted that the numbness and tingling sensation here are to

be seen as an expression of the products’ action, although they were perceived to be

undesired by the patients, meaning that this aspect is significant in assessing the

investigational products. The investigating physicians considered it probable that there

was a connection between the discomfort and the investigational products being used.

The question about immediate effects subsequent to the products’ application resulted in

fundamentally the same qualitative statements. The feeling of numbness was perceived

to be unpleasant among 26.8% of the patients treated with tetracaine. This different was

highly significant in favour of the group treated with the dispersion. Burning appeared

most frequently with tetracaine, but there were no significant differences to the other

patient group.

No severe undesired effects were detected in the entire study.

The global physicians’ assessment regarding tolerability was favourable for both

products; 90% of the patients treated with the dispersion evaluated it as being “very

good” or “good”. The dispersion placed considerably ahead of the tetracaine solution in

the tolerability evaluation (77%).

The DIHEC dispersion was rated as “good” in the assessment of the product’s

properties. Tetracaine performed more poorly.

In terms of taste, approximately 45% of the patients rated the dispersion as “very

pleasant” or “pleasant”, while tetracaine fell off significantly. The evaluation “neutral” was

given most frequently, in nearly half of the cases with all of the patient collectives, as a

matter of fact.

The aspect of adhesion, which was important for subsequent interpretations, produced

interesting results. The dispersion received the rating of "very good/good” in 70%. The

tetracaine group performed more poorly with 60%. However, good adhesion did not

correlate with stickiness which is considered unpleasant. At 1.69 hours, the adhesion

duration was longest for the patients who received the film-forming substance

combination, followed by the tetracaine patient group, for which 1.43 hours was

measured.

The questions asked in the patient diary about the duration of the pain-abating effect after

the last application yielded practically no difference with 2.07 hours for the dispersion and

2.10 hours for tetracaine. On day 4 (primary objective variable), the patients with

tetracaine were at the forefront with 3.03 hours (2.25 hours for the Bye Mouth Ulcer!™ group).

In the critical evaluation of the data, it is conspicuous that the dispersion displayed the

best results for most of the parameters investigated. A significant difference between the

dispersion in comparison with the tetracaine solution was displayed for the main

objective criterion, namely effectiveness in pain reduction up to day 4.

It was only for the “acute pain abatement” parameter that tetracaine yielded a more rapid

effect, albeit not a significant one.

Both the medical global assessment and the patient evaluation reflected these findings.

The dispersion performed better here as well.

These initially unanticipated findings allow for two conclusions: On one hand, it was

shown that the dispersion, which does not contain components with local anaesthetic

properties, still had an effect on aphthous ulcer pain.

On the other hand, these findings permit speculations as to the mechanism of action. The

covering effect on the aphthous ulcer obviously plays the decisive role in pain reduction,

in which maximally long-lasting adhesion is to be sought after. The exposed nerve

endings receive a mechanical protection from external irritations. This mechanism of

action has more weight than the local anaesthetic effect, as the dispersion’s superiority in

comparison with the local anaesthetic indicates.

Evaluation

The study described above was conceived and conducted in accordance with GCP and

ICH guidelines. Furthermore, the multi-centric, placebo-controlled, randomised study to

investigate the effectiveness and tolerability of Bye Mouth Ulcer!™ and tetracaine comb. (or lidocaine)

was subjected to an audit with the following sub-audits:

1. Pre-trial audit:

Here, portions of the trial master files, trial plan and case report forms (CRFs) were

audited by an independent institute (Medical Control Dr. W. Reinhard). The trial plan was

examined for completeness and conformity in accordance with AMG and GCP. The trial

plan and case report forms were checked for congruency. The patient informed consent

form was checked for completeness and conformity to the applicable laws and guidelines.

A pre-trial audit certificate (27.1.97) confirmed compliance with the European GCP

guidelines.

2. On-site audit:

An audit certificate for the on-site audit in accordance with the Note for Guidance Good

Clinical Practice for Trials on Medicinal Products in the European Community (European

GCP-Guidelines) dated 29.3.1997 was conducted for the aforementioned audit at

selected centres, attesting to their proper work. The addenda referred to in the report

were checked in a follow-up to the audit recommendations. This audit was conducted by

the company Medical Control Dr. W. Reinhard.

3. Data integrity audit:

A data integrity audit was conducted on 26.9.1997 with a comparison of the raw data

listings to the original entries in the CRFs. No entry errors were detected in the process.

Required definitions were prefixed to the listing as an instruction in order to simplify the

evaluator’s work with respect to the interpretation of the entries. This audit was also

conducted by the company Medical Control Dr. W. Reinhard.

A conventional product (the local anaesthetic tetracaine) was also investigated in the

comparison arm in the methodical approach of the multicentric study in order to

incorporate everyday practice as a standard for assessment. The therapeutic effect of

dimethicone and methyl cellulose has not yet fully been clarified at present and is initially

aimed at the physical effects.

The use of a therapeutic agent is oriented based on its effect profile, defined as the ratio

of effectiveness to tolerability. The investigation conceived as phase III documents the

effect of Bye Mouth Ulcer!™ and of the conventional comparative product. Although the effectiveness

(in relation to the initial value in question) was comparable, Bye Mouth Ulcer!™ displays superiority

over the local anaesthetic tetracaine in terms of effect profile due to the low number of

undesired effects (see page 9). Last but not least, the lower number undesired effects

supports this assessment.