DRO-200-III-20-1

Drossapharm AG

Birsweg 1, Arlesheim, Switzerland, 4144

Prof. Dr. Bruno Giannetti, Clinsearch GmbH, 41 417116376, info@clinsearch.ch

Prof. Dr. Bruno Giannetti, Clinsearch GmbH, 41 417116376, info@clinsearch.ch

No

No

No

Final

15 Oct 2021

No

Yes

04 May 2021

No

To demonstrate that the Lixim plaster applied once every 24 hours is superior to matching placebo plasters, in particular with regard to pain relief.

This clinical trial was designed and was implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including applicable European Directives, AMG and GCP-V), and with the ethical principles laid down in the Declaration of Helsinki. Every patient was informed verbally and also in writing, with a patient information leaflet explaining the nature of the study, its objectives, the study medication and potential risks, the rights and obligations of the participant and the fact that he was free to withdraw his consent at any time without giving any reason. Details of indemnity and insurance were also stated. All questions about the trial were answered to the satisfaction of the patient. Women of child bearing potential had to be informed that taking the IMP may involve unknown risks to the fetus if pregnancy occurred during the clinical trial and agree that in order to participate in the clinical trial, they must adhere to the contraception requirement for the duration of the clinical trial. Prior to the participation in the trial, a written informed consent form had to be signed and personally dated by the subject and by the person who conducted the informed consent. The patient’s information and informed consent form were available in the local language. The final trial protocol together with the patient information sheet, the informed consent form and the Investigator’s drug brochure were submitted to the involved Ethics Committees and were constituted to fulfil regulatory laws. The study was approved by all Ethics Committees before clinical trial start.

01 Sep 2020

No

No

Germany: 223

223

223

0

0

0

0

0

0

223

0

0

Treatment (overall period)

Randomised - controlled

The clinical trial was double-blind with respect to allocation to active and placebo plasters from the time of randomization until database lock, using the following methods: (1) randomization data were kept strictly confidential, accessible only to authorized persons, until the time of unblinding; (2) the identity of the treatments was concealed by the use of IMPs that were all identical in packaging, labeling, schedule of administration, appearance and odor.

Yes

Lixim 70 mg wirkstoffhaltiges Pflaster

etofenamate 70 mg medicated plaster

Cutaneous patch

Topical

One plaster of Lixim 70 mg wirkstoffhaltiges Pflaster applied topically once daily (morning or evening) to the affected side of the injured ankle for 7 (±1) days.

Lixim 70 mg wirkstoffhaltiges Pflaster

etofenamate 70 mg medicated plaster

Cutaneous patch

Topical

One plaster of Lixim 70 mg wirkstoffhaltiges Pflaster applied topically twice daily (morning and evening) to the affected side of the injured ankle for 7 (±1) days.

Placebo plaster

Cutaneous patch

Topical

The placebo plaster was identical in composition to the Lixim plaster, without the active ingredient. One placebo plaster was applied topically once daily (morning or evening) to the affected side of the injured ankle for 7 (±1) days.

Placebo plaster

Cutaneous patch

Topical

The placebo plaster was identical in composition to the Lixim plaster, without the active ingredient. One placebo plaster was applied topically twice daily (morning and evening) to the affected side of the injured ankle for 7 (±1) days.

Lixim plaster applied once daily (o.d.)

Lixim plaster applied twice daily (b.i.d.)

Placebo applied once daily (o.d.)

Placebo applied twice daily (b.i.d.)

Lixim plaster applied once daily (o.d.)

Lixim plaster applied twice daily (b.i.d.)

Placebo applied once daily (o.d.)

Placebo applied twice daily (b.i.d.)

The primary efficacy outcome was change from baseline of ankle POM assessed by Visual Analogue Scale (VAS) at Visit 5 (72 hours after initiating treatment).

Primary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

For quantitative outcomes assessed at the clinical trial site (POM, PAR, ankle swelling) and derived outcomes (change from baseline, AUC) null hypothesis was to be tested with an analysis of covariance (ANCOVA) model with baseline value as covariate and site as fixed factor. The least square mean for each treatment and the corresponding difference between least square means (Lixim plaster - placebo) with the p-value and 95 % confidence interval were to be presented from the model.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-19.1

2-sided

Standard error of the mean

2.6

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-17.2

2-sided

Standard error of the mean

2.8

Once-vs-twice-daily-comparison of (once daily active) group C vs. (twice daily active) group A: H0: μC = μA - Δ; Non-Inferiority test (by superiority test against the shifted alternative: C better than A - Δ, or analogously by assessment of the two-sided 95-confidence interval for the mean differences) at two-sided level α = 5 %; based on PP population. However, the PP population was equal to the FAS population according to the decisions taken at the BDRM.

Lixim plaster applied once daily (o.d.) v Lixim plaster applied twice daily (b.i.d.)

160

Pre-specified

-1.9

2-sided

Change from baseline of ankle POM on VAS at Visit 3 (24 hours after initiating treatment).

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-12.7

2-sided

Standard error of the mean

2.3

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-8.9

2-sided

Standard error of the mean

2.4

Change from baseline of ankle POM on VAS at Visit 4 (48 hours after initiating treatment).

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-17.2

2-sided

Standard error of the mean

2.6

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-13.7

2-sided

Standard error of the mean

2.6

Change from baseline of ankle POM on VAS at Visit 6 (96 hours after initiating treatment).

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-20.4

2-sided

Standard error of the mean

2.4

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-18.6

2-sided

Standard error of the mean

2.8

The changes in POM on VAS from baseline to Visit 7.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-17.1

2-sided

Standard error of the mean

2.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-13.6

2-sided

Standard error of the mean

2.3

The patient was asked to sit down on a chair with the injured leg touching the ground. After five minutes of sitting in this position, the extent of ankle pain was evaluated by the patient in answer to the question: “How would you describe your ankle pain right now?” (“Wie würden Sie Ihre Schmerzen in Ihrem Sprunggelenk in diesem Moment beschreiben?“). The patient drew a perpendicular line on a 100 mm Visual Analogue Scale (VAS) with anchors at 0 = “no pain (keine Schmerzen)” and 100 = “Extreme pain (extreme Schmerzen)” to reflect the pain intensity at rest.

Secondary

Pain-at-rest (PAR) was evaluated at Visits 1-7.

Placebo applied once daily (o.d.) v Lixim plaster applied once daily (o.d.)

111

Pre-specified

-1.7

2-sided

Standard error of the mean

1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-3.3

2-sided

Standard error of the mean

1.2

The areas-under-the-curve (AUCs) over time between baseline (0 h) and the first 24 hours after initiating treatment were calculated by means of the trapezoidal rule for pain-on-movement measured by VAS as secondary efficacy variables. Lower AUC values represent less pain and therefore a better clinical outcome.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-161.5

2-sided

Standard error of the mean

31.4

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-83.1

2-sided

Standard error of the mean

35.2

The areas-under-the-curve (AUCs) over time between baseline (0 h) and the first 48 hours after initiating treatment were calculated by means of the trapezoidal rule for pain-on-movement measured by VAS as secondary efficacy variables. Lower AUC values represent less pain and therefore a better clinical outcome.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-493.5

2-sided

Standard error of the mean

77.7

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-351.9

2-sided

Standard error of the mean

85.1

The areas-under-the-curve (AUCs) over time between baseline (0 h) and the first 72 hours after initiating treatment were calculated by means of the trapezoidal rule for pain-on-movement measured by VAS as secondary efficacy variables. Lower AUC values represent less pain and therefore a better clinical outcome.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-927

2-sided

Standard error of the mean

131.5

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-723.2

2-sided

Standard error of the mean

143.3

The areas-under-the-curve (AUCs) over time between baseline (0 h) and the first 96 hours after initiating treatment were calculated by means of the trapezoidal rule for pain-on-movement measured by VAS as secondary efficacy variables. Lower AUC values represent less pain and therefore a better clinical outcome.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-1399.5

2-sided

Standard error of the mean

181.5

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-1153.1

2-sided

Standard error of the mean

202.5

Ankle swelling was evaluated by the Figure-of-eight-method. The Figure-of-eight-method was reproduced by using bony landmarks about the ankle. Common sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the Figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling. Each ankle was measured three times and the average was calculated. The difference in this average between ankles tracked the natural course of disease. The differences between the active groups and the placebo group were a measure of treatment efficacy.

Secondary

Ankle swelling was evaluated at Visits 1-7.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-0.1

2-sided

Standard error of the mean

0.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-0.1

2-sided

Standard error of the mean

0.1

Ankle swelling was evaluated by the Figure-of-eight-method. The Figure-of-eight-method was reproduced by using bony landmarks about the ankle. Common sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the Figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling. Each ankle was measured three times and the average was calculated. The difference in this average between ankles tracked the natural course of disease. The differences between the active groups and the placebo group were a measure of treatment efficacy.

Secondary

Ankle swelling was evaluated at Visits 1-7.

Placebo applied once daily (o.d.) v Lixim plaster applied once daily (o.d.)

111

Pre-specified

-0.2

2-sided

Standard error of the mean

0.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

0

2-sided

Standard error of the mean

0.1

Ankle swelling was evaluated by the Figure-of-eight-method. The Figure-of-eight-method was reproduced by using bony landmarks about the ankle. Common sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the Figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling. Each ankle was measured three times and the average was calculated. The difference in this average between ankles tracked the natural course of disease. The differences between the active groups and the placebo group were a measure of treatment efficacy.

Secondary

Ankle swelling was evaluated at Visits 1-7.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-0.2

2-sided

Standard error of the mean

0.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-0.1

2-sided

Standard error of the mean

0.1

Ankle swelling was evaluated by the Figure-of-eight-method. The Figure-of-eight-method was reproduced by using bony landmarks about the ankle. Common sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the Figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling. Each ankle was measured three times and the average was calculated. The difference in this average between ankles tracked the natural course of disease. The differences between the active groups and the placebo group were a measure of treatment efficacy.

Secondary

Ankle swelling was evaluated at Visits 1-7.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-0.2

2-sided

Standard error of the mean

0.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-0.1

2-sided

Standard error of the mean

0.1

Ankle swelling was evaluated by the Figure-of-eight-method. The Figure-of-eight-method was reproduced by using bony landmarks about the ankle. Common sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the Figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling. Each ankle was measured three times and the average was calculated. The difference in this average between ankles tracked the natural course of disease. The differences between the active groups and the placebo group were a measure of treatment efficacy.

Secondary

Ankle swelling was evaluated at Visits 1-7.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-0.2

2-sided

Standard error of the mean

0.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-0.1

2-sided

Standard error of the mean

0.1

Ankle swelling was evaluated by the Figure-of-eight-method. The Figure-of-eight-method was reproduced by using bony landmarks about the ankle. Common sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the Figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling. Each ankle was measured three times and the average was calculated. The difference in this average between ankles tracked the natural course of disease. The differences between the active groups and the placebo group were a measure of treatment efficacy.

Secondary

Ankle swelling was evaluated at Visits 1-7.

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-0.2

2-sided

Standard error of the mean

0.1

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

0

2-sided

Standard error of the mean

0.1

SPID was calculated using following equation: Σ PIDi x (ti+1 – ti), with PIDi=[POM on VAS at Visit i] - [POM on VAS at Visit 1 (BL)] and t=time of Visit i. A higher score indicated less pain.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-178

2-sided

Standard error of the mean

44

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-120.8

2-sided

Standard error of the mean

41.7

SPID was calculated using following equation: Σ PIDi x (ti+1 – ti), with PIDi=[POM on VAS at Visit i] - [POM on VAS at Visit 1 (BL)] and t=time of Visit i. A higher score indicated less pain.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-633.5

2-sided

Standard error of the mean

92.8

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-445

2-sided

Standard error of the mean

97.9

SPID was calculated using following equation: Σ PIDi x (ti+1 – ti), with PIDi=[POM on VAS at Visit i] - [POM on VAS at Visit 1 (BL)] and t=time of Visit i. A higher score indicated less pain.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Lixim plaster applied once daily (o.d.) v Placebo applied once daily (o.d.)

111

Pre-specified

-1093.1

2-sided

Standard error of the mean

145.5

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-859.3

2-sided

Standard error of the mean

159.2

SPID was calculated using following equation: Σ PIDi x (ti+1 – ti), with PIDi=[POM on VAS at Visit i] - [POM on VAS at Visit 1 (BL)] and t=time of Visit i. A higher score indicated less pain.

Secondary

POM was assessed at 24, 48, 72, 96, and 168 hours measured by 100 mm VAS – clinic visit

Placebo applied once daily (o.d.) v Lixim plaster applied once daily (o.d.)

111

Pre-specified

-1581.9

2-sided

Standard error of the mean

195

Lixim plaster applied twice daily (b.i.d.) v Placebo applied twice daily (b.i.d.)

112

Pre-specified

-1311.2

2-sided

Standard error of the mean

217.9

Adverse events (AEs) were recorded throughout the clinical trial from randomization on.

24.1

Lixim plaster applied once daily (o.d.)

Lixim plaster applied twice daily (b.i.d.)

Placebo applied once daily (o.d.)

Placebo applied twice daily (b.i.d.)