| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Analgesia induced by dental extraction |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10044049 |
| E.1.2 | Term | Dental pain and sensation disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the analgesic efficacy of theobromine + paracetamol versus paracetamol alone. |
|
| E.2.2 | Secondary objectives of the trial |
To summarise pharmacokinetic data (AUC0-6 hrs, Cmax, tmax) for theobromine and for paracetamol (alone and in combination with theobromine).
To summarise the frequency of micturation for theobromine + paracetamol and for paracetamol alone.
To summarise safety data for theobromine + paracetamol and for paracetamol alone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Age
Aged from 18 years up to 60 years inclusive.
2) Weight
A body weight of 50 - 110 kg inclusive.
3) Contraception
Females of childbearing potential who are, in the opinion of the investigator, practising a reliable method of contraception. They should have been established on this method since last menses or for 30 days prior to the screening visit at the start of the study and for the duration of the study.
4) Diagnosis
a) Patients must have a partial or fully impacted lower third molar as verified by oral examination and dental X-rays.
b) Experience moderate to severe pain as demonstrated using a VRS and confirmed by VAS (a score of at least 40 mm on a 100 mm scale) after undergoing surgical removal of one partial or fully impacted lower third molar under local anaesthetic. (Patients may also have the ipsilateral maxillary third molar of the upper jaw removed if warranted by the dental surgeon).
5) Compliance
Understands and is willing, able and likely to comply with all study procedures and restrictions.
6) Consent
Demonstrates understanding of the study and willingness to participate as evidenced by voluntary written informed consent and has received a signed and dated copy of the informed consent form.
7) General Health
Good general health with (in the opinion of the investigator) no clinically significant and relevant abnormalities of medical history or physical examination. |
|
| E.4 | Principal exclusion criteria |
1) Pregnancy
Women who are pregnant or who have a positive urine pregnancy test.
2) Breast-feeding
Women who are breast-feeding.
3) Disease/Illness
a) Current or recurrent disease that could affect the action, absorption or disposition of the study medication.
b) Current dental oral disease that, in the opinion of the investigator, could cause complications that may affect the study.
c) Has any psychiatric or other medical disorders which, in the opinion of the investigator, is likely to prevent completion of the study or to prevent the full understanding and reporting of pain relief.
d) Any disease that requires the patient to adhere to a low sodium diet.
4) Medications
a) Patients who have taken any analgesics or non-steroidal anti-inflammatory drugs within 24 hrs prior to the administration of the study treatment (48 hrs for long-acting drugs).
b) Patients taking any sedative or anxiolytic treatments within 24 hrs prior to administration of study treatment.
c) Patients who have taken caffeine-containing food, drinks or medications within 12 hrs prior to administration of the study treatment.
d) Use of any medication which, in the opinion of the investigator, is likely to interfere with the action, absorption or disposition of the study treatment e.g. microsomal enzyme inducers, prokinetic agents such as metoclopramide or domperidone.
e) Patients for whom the use of ibuprofen, paracetamol or local anaesthetic is contraindicated.
5) Unresponsive to paracetamol
Patients who are known, by questioning, to consistently have an inadequate response to paracetamol.
6) Allergy/Intolerance
a) Known or suspected intolerance or hypersensitivity to paracetamol, theobromine or excipients of the formulations or any related compounds.
b) Known or suspected intolerance or hypersensitivity to the rescue medication, ibuprofen, or to the local anaesthetic used for surgery.
7) Clinical Study/Experimental Medication
a) Participation in another clinical study or receipt of an investigational drug within 30 days of the screening visit at the start of the study.
b) Previous participation in this study.
8) Substance abuse
Recent history (within the last 2 years) of alcohol, analgesic or other substance abuse. Abuse is defined as self reported, diagnosed or treated.
9) Personnel
An employee of the sponsor or the study staff at the site or their immediate family. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
The primary endpoints in assessing efficacy will be:
• Total Pain Relief (TOTPAR) to 1, 2, 4 and 6 hrs.
TOTPAR = SUM(Rt x (timet - timet-1)), where Rt = pain relief score at time t, and timet = time in hours.
In this proof-of-principle pilot study, consistent trends in favour of paracetamol + theobromine versus paracetamol alone (as measured by total pain relief during the 6 hr assessment period) will be deemed a positive result and may warrant further investigation in a larger study.
Safety
The assessment of safety will be based on adverse events reported by all patients following dosing with the study medication. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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