Impetigo, Secondarily Infected Traumatic Lesions
Conditions
Brief summary
An international, multi-centre, prospective three arm parallel-group, phase II proof of concept study comparing the efficacy and safety of two dosage regimens (BID 7 days and TID 7 days) of TD1414 2% cream and one dosage regimen (BID 7 days) of Bactroban® (mupirocin) 2% cream in adults and children down to 2 years of age with impetigo or SITL. Furthermore an evaluation of the pharmacokinetics of TD1414 2% cream TID for 7 days will be performed. A total of 664 patients will be enrolled in a stepwise manner according to age groups starting with the oldest age group.
Interventions
DRUGTD1414 2% cream
BID 7 days
DRUGBactroban® (mupirocin) 2% cream
BID 7 days
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent from patient and/or legally acceptable representative has been obtained * Outpatients of any sex or ethnic origin * Patients \>= 2 years of age (depending on study step) * Patients must be suffering from primary bullous/non-bullous impetigo or SITL
Exclusion criteria
* Presence of skin diseases at or near the investigational area * Immunosuppressed state or other serious systemic disease * Signs and/or symptoms of systemic infection * Presence of skin infection/disorder not amenable to topical antibacterial treatment only * Presence of secondarily-infected animal/human bite * Presence of secondarily infected burnwound * Topical or systemic use of medicinal or other products before or during the study which in the investigators opinion could confound the evaluation of the effect of the study drugs * Known or suspected hypersensitivity to TD1414 or any of the excipients in the TD1414 2% cream * Known or suspected hypersensitivity to mupirocin or any of the excipients in the Bactroban® (mupirocin) 2% cream * Participation in any other investigational drug study or use of (an) investigational drug(s) within the 30 days or 5 half-lives (whichever is longer) prior to randomisation * Patients previously enrolled/randomised in this study * Abnormal ECG at baseline though the PR interval may be up to 220 ms, the QRS interval up to 110 ms and the QTc interval up to 450 ms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Clinical Cure According to Investigator's Assessment | At end of treatment (Day 8) | At end of treatment (Day 8), the participants had their impetigo/Secondarily Infected Traumatic Lesions (SITL) evaluated by the (sub)investigator. Investigator's assessment of severity of infections (SIRS). * Exudates/pus * Crusting * Erythema * Oedema * Tissue Warmth * Itching * Pain Each sign/symptoms of infection was assessed by use of the following 4-point scale: * 0 = absent * 2 = mild * 4 = moderate * 6 = severe The scores were summed up to a total SIRS score. Clinical cure was either of the following: * Total absence of signs and symptoms of impetigo/SITL OR * Improvement - total SIRS score reduced to \<8 and all individual clinical signs/symptoms included in the SIRS score should have been ≤4. Clinical failure was either of the following: * Signs and symptoms of impetigo/SITL that did not meet the definition of clinical cure * Unable to determine (e.g. participants who refuse clinical examination or did not show at end of treatment or follow-up). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Clinical Cure According to Investigator's Assessment | At follow up (Day 15) | At follow up (Day 15), the participants had their impetigo/SITL evaluated by the (sub)investigator. |
| Participants With Clinical Cure According to Investigator's Assessment. | At end of treatment (Day 8) and follow-up (Day 15) | At end of treatment (Day 8) and at follow-up (Day 15), the participants had their impetigo/SITL evaluated by the (sub)investigator. |
| Participants With Bacteriological Cure According to Bacteriological Samples | At end of treatment (Day 8), follow-up (Day 15) and end of treatment and follow-up | At baseline (Day 1), end of treatment (EOT), and follow-up (FU), the investigator obtained a bacteriological sample to base the assessment on. Bacteriological cure was either of the following: * Eradication of the baseline pathogen. * Presumed eradication of the baseline pathogen * Infection with a pathogen different from the baseline pathogen at EOT or FU and the participant was NOT symptomatic. Bacteriological failure was any of the following: * Documented lack of eradication of the baseline pathogen. * Documented relapse (re-infection) with the baseline pathogen * Documented super-infection, i.e. infection with a pathogen different from the baseline pathogen at EOT or FU, and the participants was symptomatic * Presumed persistence of baseline pathogen: Non-evaluable participants- participants who refused bacteriological examination or did not show at EOT or FU, and clinical failures who had no bacteriological sample to rule out bacterial infection. |
| Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | At end of treatment (Day 8), follow-up (Day 15) and end of treatment and follow-up | At end of treatment (Day 8) and at follow-up (Day 15) the participants had their impetigo/SITL evaluated by the (sub)investigator. At baseline (Day 1), end of treatment (Day 8) and at follow-up (Day 15) the investigator obtained a bacteriological sample on which an assessment of bacteriological cure was based. |
Countries
South Africa, United States
Participant flow
Pre-assignment details
An open-label treatment consisting of one arm with 4 age groups of 16 participants treated with TD1414 cream three times daily was used in a stepwise inclusion, to detect major safety issues that could prevent the study from proceeding. The participants in the open-label phase were not included the efficacy analysis or in the randomized population
Participants by arm
| Arm | Count |
|---|---|
| TD1414 BID TD1414 2% cream: two times daily (BID) 7 days | 204 |
| TD1414 TID TD1414 2% cream: three times daily (TID) 7 days | 205 |
| Bactroban® TID Bactroban® (mupirocin) 2% cream: three times daily (TID) 7 days | 205 |
| Total | 614 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Treatment | Lack of Efficacy | 2 | 0 | 0 |
| Blinded Treatment | Missing reason for withdrawal | 5 | 3 | 5 |
| Blinded Treatment | Other reasons | 2 | 0 | 2 |
| Blinded Treatment | Protocol Violation | 0 | 1 | 1 |
| Blinded Treatment | Unacceptable adverse event | 0 | 0 | 1 |
| Blinded Treatment | Withdrawal by Subject | 1 | 1 | 0 |
| Open-label TD1414 Cream TID Treatment | Adverse Event | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | TD1414 TID | Total | TD1414 BID | Bactroban® TID |
|---|---|---|---|---|
| Age, Continuous Participants assigned to open-label TD1414 TID | 18.4 years STANDARD_DEVIATION 20 | 18.4 years STANDARD_DEVIATION 20 | — | — |
| Age, Continuous Participants randomized to blinded treatment | 36.3 years STANDARD_DEVIATION 14.3 | 37.7 years STANDARD_DEVIATION 14.8 | 38.6 years STANDARD_DEVIATION 14.8 | 38.3 years STANDARD_DEVIATION 15.3 |
| Age, Customized Participants assigned to open-label TD1414 TID ≥12 to <16 years old | 16 Participants | 16 Participants | 0 Participants | 0 Participants |
| Age, Customized Participants assigned to open-label TD1414 TID ≥16 years old | 17 Participants | 17 Participants | 0 Participants | 0 Participants |
| Age, Customized Participants assigned to open-label TD1414 TID ≥2 to <6 years old | 16 Participants | 16 Participants | 0 Participants | 0 Participants |
| Age, Customized Participants assigned to open-label TD1414 TID ≥6 to <12 years old | 16 Participants | 16 Participants | 0 Participants | 0 Participants |
| Age, Customized Participants randomized to blinded treatment ≥12 to <16 years old | 11 Participants | 32 Participants | 11 Participants | 10 Participants |
| Age, Customized Participants randomized to blinded treatment ≥16 years old | 194 Participants | 582 Participants | 193 Participants | 195 Participants |
| Age, Customized Participants randomized to blinded treatment ≥2 to <6 years old | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Participants randomized to blinded treatment ≥6 to <12 years old | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 126 Participants | 377 Participants | 119 Participants | 132 Participants |
| Region of Enrollment United States | 79 Participants | 237 Participants | 85 Participants | 73 Participants |
| Sex: Female, Male Participants assigned to open-label TD1414 TID Female | 35 Participants | 35 Participants | — | — |
| Sex: Female, Male Participants assigned to open-label TD1414 TID Male | 30 Participants | 30 Participants | — | — |
| Sex: Female, Male Participants randomized to blinded treatment Female | 93 Participants | 300 Participants | 97 Participants | 110 Participants |
| Sex: Female, Male Participants randomized to blinded treatment Male | 112 Participants | 314 Participants | 107 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 17 | 5 / 16 | 2 / 16 | 3 / 16 | 61 / 203 | 49 / 205 | 34 / 204 |
| serious Total, serious adverse events | 0 / 17 | 0 / 16 | 0 / 16 | 0 / 16 | 2 / 203 | 2 / 205 | 0 / 204 |
Outcome results
Primary
Participants With Clinical Cure According to Investigator's Assessment
At end of treatment (Day 8), the participants had their impetigo/Secondarily Infected Traumatic Lesions (SITL) evaluated by the (sub)investigator. Investigator's assessment of severity of infections (SIRS). * Exudates/pus * Crusting * Erythema * Oedema * Tissue Warmth * Itching * Pain Each sign/symptoms of infection was assessed by use of the following 4-point scale: * 0 = absent * 2 = mild * 4 = moderate * 6 = severe The scores were summed up to a total SIRS score. Clinical cure was either of the following: * Total absence of signs and symptoms of impetigo/SITL OR * Improvement - total SIRS score reduced to \<8 and all individual clinical signs/symptoms included in the SIRS score should have been ≤4. Clinical failure was either of the following: * Signs and symptoms of impetigo/SITL that did not meet the definition of clinical cure * Unable to determine (e.g. participants who refuse clinical examination or did not show at end of treatment or follow-up).
Time frame: At end of treatment (Day 8)
Population: All participants randomized to blinded treatment who received at least one application of study medication were included in the efficacy analysis. Two participants (one from TD1414 BID and one from Bactroban® TID) did not receive any study medication and are therefore not included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 167 Participants |
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 36 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 184 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 21 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 174 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 30 Participants |
95% CI: [-1.59, 10.71]
95% CI: [-10.28, 3.57]
Secondary
Participants With Bacteriological Cure According to Bacteriological Samples
At baseline (Day 1), end of treatment (EOT), and follow-up (FU), the investigator obtained a bacteriological sample to base the assessment on. Bacteriological cure was either of the following: * Eradication of the baseline pathogen. * Presumed eradication of the baseline pathogen * Infection with a pathogen different from the baseline pathogen at EOT or FU and the participant was NOT symptomatic. Bacteriological failure was any of the following: * Documented lack of eradication of the baseline pathogen. * Documented relapse (re-infection) with the baseline pathogen * Documented super-infection, i.e. infection with a pathogen different from the baseline pathogen at EOT or FU, and the participants was symptomatic * Presumed persistence of baseline pathogen: Non-evaluable participants- participants who refused bacteriological examination or did not show at EOT or FU, and clinical failures who had no bacteriological sample to rule out bacterial infection.
Time frame: At end of treatment (Day 8), follow-up (Day 15) and end of treatment and follow-up
Population: Only the randomized participants that were infected with S. aureus or S. pyogenes at baseline were included in the analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| TD1414 BID | Participants With Bacteriological Cure According to Bacteriological Samples | End of treatment (Day 8) | Bacteriological cure | 66 Participants |
| TD1414 BID | Participants With Bacteriological Cure According to Bacteriological Samples | End of treatment (Day 8) | Bacteriological failure | 44 Participants |
| TD1414 BID | Participants With Bacteriological Cure According to Bacteriological Samples | Follow-up (Day 15) | Bacteriological cure | 74 Participants |
| TD1414 BID | Participants With Bacteriological Cure According to Bacteriological Samples | Follow-up (Day 15) | Bacteriological failure | 36 Participants |
| TD1414 BID | Participants With Bacteriological Cure According to Bacteriological Samples | End of Treatment and follow-up | Bacteriological cure | 57 Participants |
| TD1414 BID | Participants With Bacteriological Cure According to Bacteriological Samples | End of Treatment and follow-up | Bacteriological failure | 53 Participants |
| TD1414 TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of Treatment and follow-up | Bacteriological failure | 55 Participants |
| TD1414 TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of treatment (Day 8) | Bacteriological cure | 80 Participants |
| TD1414 TID | Participants With Bacteriological Cure According to Bacteriological Samples | Follow-up (Day 15) | Bacteriological failure | 36 Participants |
| TD1414 TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of Treatment and follow-up | Bacteriological cure | 66 Participants |
| TD1414 TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of treatment (Day 8) | Bacteriological failure | 41 Participants |
| TD1414 TID | Participants With Bacteriological Cure According to Bacteriological Samples | Follow-up (Day 15) | Bacteriological cure | 85 Participants |
| Bactroban® TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of treatment (Day 8) | Bacteriological failure | 24 Participants |
| Bactroban® TID | Participants With Bacteriological Cure According to Bacteriological Samples | Follow-up (Day 15) | Bacteriological cure | 102 Participants |
| Bactroban® TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of Treatment and follow-up | Bacteriological failure | 32 Participants |
| Bactroban® TID | Participants With Bacteriological Cure According to Bacteriological Samples | Follow-up (Day 15) | Bacteriological failure | 16 Participants |
| Bactroban® TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of treatment (Day 8) | Bacteriological cure | 94 Participants |
| Bactroban® TID | Participants With Bacteriological Cure According to Bacteriological Samples | End of Treatment and follow-up | Bacteriological cure | 86 Participants |
Secondary
Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples
At end of treatment (Day 8) and at follow-up (Day 15) the participants had their impetigo/SITL evaluated by the (sub)investigator. At baseline (Day 1), end of treatment (Day 8) and at follow-up (Day 15) the investigator obtained a bacteriological sample on which an assessment of bacteriological cure was based.
Time frame: At end of treatment (Day 8), follow-up (Day 15) and end of treatment and follow-up
Population: All participants randomized to blinded treatment who received at least one application of study medication and were infected with S. aureus or S. pyogenes at baseline were included in the analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| TD1414 BID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of Treatment and follow-up | Clinical and bacteriological cure | 52 Participants |
| TD1414 BID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of treatment (Day 8) | Clinical or bacteriological failure | 51 Participants |
| TD1414 BID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of Treatment and follow-up | Clinical or bacteriological failure | 58 Participants |
| TD1414 BID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | Follow-up (Day 15) | Clinical and bacteriological cure | 70 Participants |
| TD1414 BID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | Follow-up (Day 15) | Clinical or bacteriological failure | 40 Participants |
| TD1414 BID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of treatment (Day 8) | Clinical and bacteriological cure | 59 Participants |
| TD1414 TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of treatment (Day 8) | Clinical and bacteriological cure | 76 Participants |
| TD1414 TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of Treatment and follow-up | Clinical and bacteriological cure | 60 Participants |
| TD1414 TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | Follow-up (Day 15) | Clinical or bacteriological failure | 42 Participants |
| TD1414 TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | Follow-up (Day 15) | Clinical and bacteriological cure | 79 Participants |
| TD1414 TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of Treatment and follow-up | Clinical or bacteriological failure | 61 Participants |
| TD1414 TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of treatment (Day 8) | Clinical or bacteriological failure | 45 Participants |
| Bactroban® TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of Treatment and follow-up | Clinical or bacteriological failure | 38 Participants |
| Bactroban® TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of treatment (Day 8) | Clinical and bacteriological cure | 88 Participants |
| Bactroban® TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of treatment (Day 8) | Clinical or bacteriological failure | 30 Participants |
| Bactroban® TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | Follow-up (Day 15) | Clinical or bacteriological failure | 19 Participants |
| Bactroban® TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | End of Treatment and follow-up | Clinical and bacteriological cure | 80 Participants |
| Bactroban® TID | Participants With Clinical and Bacteriological Cure According to Investigator's Assessment and Bacteriological Samples | Follow-up (Day 15) | Clinical and bacteriological cure | 99 Participants |
Secondary
Participants With Clinical Cure According to Investigator's Assessment
At follow up (Day 15), the participants had their impetigo/SITL evaluated by the (sub)investigator.
Time frame: At follow up (Day 15)
Population: All participants randomized to blinded treatment who received at least one application of study medication were included in the efficacy analysis. Two participants (one from TD1414 BID and one from Bactroban® TID) did not receive any study medication and are therefore not included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 173 Participants |
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 30 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 188 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 17 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 185 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 19 Participants |
Secondary
Participants With Clinical Cure According to Investigator's Assessment
At Day 4 the participants had their impetigo/SITL evaluated by the (sub)investigator.
Time frame: At Day 4
Population: All participants randomized to blinded treatment who received at least one application of study medication were included in the efficacy analysis. Two participants (one from TD1414 BID and one from Bactroban® TID) did not receive any study medication and are therefore not included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 108 Participants |
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 95 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 130 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 75 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical cure | 120 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment | Clinical failure | 84 Participants |
Secondary
Participants With Clinical Cure According to Investigator's Assessment.
At end of treatment (Day 8) and at follow-up (Day 15), the participants had their impetigo/SITL evaluated by the (sub)investigator.
Time frame: At end of treatment (Day 8) and follow-up (Day 15)
Population: All participants randomized to blinded treatment who received at least one application of study medication were included in the efficacy analysis. Two participants (one from TD1414 BID and one from Bactroban® TID) did not receive any study medication and are therefore not included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment. | Clinical cure | 158 Participants |
| TD1414 BID | Participants With Clinical Cure According to Investigator's Assessment. | Clinical failure | 45 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment. | Clinical cure | 177 Participants |
| TD1414 TID | Participants With Clinical Cure According to Investigator's Assessment. | Clinical failure | 28 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment. | Clinical cure | 166 Participants |
| Bactroban® TID | Participants With Clinical Cure According to Investigator's Assessment. | Clinical failure | 38 Participants |