| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pain and inflammation due to Grade I or Grade II acute sprain of the lateral ankle |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pain and inflammation due to ankle sprain |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061218 |
| E.1.2 | Term | Inflammation |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10024453 |
| E.1.2 | Term | Ligament sprain |
| E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
|
| 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 assess efficacy of MFC51123 gel over placebo as measured by Area Under the Curve of Pain Intensity on Movement (walking 5 steps on flat surface) for the period from 24 to 72 hours of treatment (AUC1-3days). |
|
| E.2.2 | Secondary objectives of the trial |
| Please see secondary endpoints detailed in section E.5.2. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Consent: Subject 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.
2. Age: Subject is from 16 to 65 years of age.
3. Compliance: Subject understands and is willing, able and likely to comply with all study procedures and restrictions.
4. General Health: Subject is in good general and mental health with, in the opinion of the investigator or medically qualified designee:
a) No clinically significant and relevant abnormalities of medical history or physical examination.
b) No condition that would impact on the subject’s safety or wellbeing or affect his or her ability to understand and follow study procedures and requirements.
5. Diagnosis:
a) Subject has a Grade I or Grade II acute sprain of the lateral ankle within 24 hours of Visit 1
b) Subject has self-assessed pain intensity at the site of the ankle sprain that is ≥ 5 as measured on an 11-point numerical rating scale
c) Subject has a peri-malleolar edema (sub-malleolar perimeter difference of ≥ 20mm between injured and uninjured ankle
6. Contraception: Females of childbearing potential who are, in the opinion of the investigator, practicing a reliable method of contraception. For the purposes of this study, reliable contraception is defined as abstinence, oral contraceptive, either combined or progestogen alone OR injectable progestogen OR implants of
levonorgestrel OR estrogenic vaginal ring OR percutaneous contraceptive patches OR intrauterine device or intrauterine system OR double barrier method (condom or occlusive cap [diaphragm or cervical vault caps] plus
spermicidal agent [foam, gel, film, cream, suppository]) OR male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject. |
|
| 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. Subject has treated the ankle sprain with treatment such as oral or other topical pain relief medications, massage or physical therapy since experiencing the ankle sprain. The application of ice to the affected ankle
prior to visit 1 is allowed.
4. Subject has other acute or chronic pain disorders, which may confound the study pain evaluations.
5. Subject suffered from a grade I-III ankle sprain at the same ankle or any other significant injuries (based on investigator’s judgment), or surgeries at the same ankle or foot within 30 days from the current injury. Pain and instability exist at the same ankle due to previous sprain or other trauma. Ligament hyperlaxity occuring at the same ankle due to connective tissue diseases, e.g. Marfan’s syndrome, Down’s syndrome, Ehlers-Danlos Syndrome, etc.
6. Subject has injury to both ankles or to both medial and lateral ligaments of the same ankle.
7. Allergy/Intolerance: Subject has known or suspected hypersensitivity, allergy, intolerance or contraindication to the use of any of the study medications (or closely related compounds), any of their stated ingredients or any topical medications before.
8. Subject is currently taking or has taken within the previous three months medications or herbal supplements likely, on available evidence, to interfere with the validity of subject-rated assessments.
9. Subject has a medical history of renal or hepatic disease, a current active peptic ulcer or a history of upper gastrointestinal bleeding or perforation related to previous NSAID therapy.
10. Clinical Study/Experimental Medication:
a) Subject has participated in another clinical study or received an investigational drug within 30 days of Visit 1.
b) Subject has previously participated in this study.
11. Substance abuse: Subject has a recent history (within the last 2 years) of alcohol or other substance abuse.
12. Personnel: Subject is an employee of the sponsor or the study site or members of their immediate family. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To assess efficacy of MFC51123 gel over placebo as measured by Area Under the Curve of Pain Intensity on Movement (walking 5 steps on flat surface) for the period from 24 to 72 hours of treatment (AUC1-3days). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Period from 24 to 72 hours of treatment (AUC1-3days). |
|
| E.5.2 | Secondary end point(s) |
To compare the effect on AUC1-3days of MFC51123 gel vs. 1% diclofenac sodium gel and vs. 3% menthol gel; 1% diclofenac sodium gel vs. 3% menthol gel and vs. Placebo.
To assess pain relief as measured by pain relief score (PRS), as well as pain intensity as measured by Numerical Rating Scale (NRS) scores for pain on movement and pain at rest at 10, 30, 60 minutes and 4, 6, 12, 18 and 24 hours of treatment and twice daily from 2nd to 10th day of treatment.
To compare time to onset of pain relief as measured by time to reach “a little” or “perceptible” pain relief (PRS ≥ 1) confirmed by meaningful pain relief (PRS ≥ 2) at the same time points as PRS/NRS.
To assess Sum of Pain Intensity Difference (SPID), Pain Intensity Difference (PID) and Total Pain Relief (TOTPAR) for periods 0 - 6, 0 - 12 hours and 0 to 1, 1 to 3, and 0 to 7 days after initial treatment between treatment groups.
To compare time to onset and the duration of cooling and soothing sensations among treatments in the first 6 hour time-period post-first dose (at 10, 30, 60 minutes, 4 and 6 hours after initial treatment).
To compare the skin temperature of the sprained ankle at baseline (just prior to treatment) and at scheduled intervals (at 10, 30, 60 minutes, 4 and 6 hours after initial treatment) in 20% of subjects in Stratum 2 [18-65 year old subjects].
To compare the thermal images of the sprained ankle at baseline (just prior to treatment) and at scheduled intervals (1, 4 and 6 hours post initial treatment) of 20% of the skin temperature sub-group subjects (4% of subjects in each treatment group) by FLIR camera.
To compare the proportion of subjects with “a little” or “perceptible” pain relief (PRS ≥ 1) confirmed by meaningful relief at 6, 12 and 18 hours, and 1, 2 and 3 days after initial treatment.
To compare the proportion of subjects with “definite” or “meaningful” pain relief (PRS ≥ 2) at day 2, 3 and 4 after initial treatment for each arms.
To assess ankle swelling reductions by measuring perimeter changes of the injured ankle from baseline (at visit 1) using “figure-of-eight” method at treatment days 3, 7 and 10.
To compare treatment groups for the date of complete recovery (the day when subject experiences complete relief of ankle pain and has no limitation of movement at the injured ankle joint).
To assess the maximal NRS score (NRSmax) and NRS value at 72 hours after initial treatment (NRS72hrs) for each treatment.
To assess Patient's Global Assessment in Response to Treatment (PGART), treatment satisfaction and response to questions about sensory features of the gels.
To compare the rate, time to first dose and total dose of rescue medication taken between treatment groups.
To assess the frequency and intensity of adverse events in all treatmentgroups. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints of evaluation for each of the secondary endpoints are detailed in the section above. |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 8 |
| 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 | No |
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
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