| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe skin and skin structure infections suspected or confirmed to be caused by Gram-positive bacteria |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040872 |
| E.1.2 | Term | Skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 demonstrate that iclaprim is non-inferior to vancomycin in achieving a ≥20% reduction in lesion size at 48 to 72 hours (Early Time Point [ETP]) compared to baseline in all randomized patients (ITT). |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate non-inferiority of iclaprim compared to vancomycin in the ITT, mITT, mCE, PP, and mPP populations for the following:
1. Resolution or near resolution of ABSSSI (clinical cure, defined by a ≥90% reduction in lesion size from the size at baseline, no increase in lesion size since ETP, and no requirement for additional antibiotics [except aztreonam and metronidazole] or unplanned significant surgical procedures after ETP other than bedside wound care) at Test of Cure (TOC) visit;
2. Resolution or near resolution (≥90%) of ABSSSI at End of Therapy (EOT);
3. Resolution or near resolution (≥90%) of ABSSSI at EOT and TOC among patients with severe infection at baseline
4. Time to resolution of systemic and local signs and symptoms of ABSSSI.
5. Assess microbiological outcome in the mITT, mCE and mPP populations at EOT and TOC;
6. Establish the PK for iclaprim using population pharmacokinetics; and
7. Establish the safety profile of iclaprim in patients with ABSSSI. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years of age
2. Written informed consent to participate in the study before any study-specific screening procedures are performed. If any patient is unable to give consent, it may be obtained from an acceptable representative.
3. A bacterial infection of the skin with a lesion size area of at least 75 cm2 (lesion size measured by the area of redness, edema, or induration) and clinical evidence of at least 1 of the following:
a) Major cutaneous abscess,
b) Cellulitis/erysipelas, and/or
c) Wound infections (caused by external trauma [eg, needle sticks or insect bites]).
4. Presence of purulent or seropurulent drainage before or after surgical intervention of a woundwithin 24 hours of randomization (because surgical incision and drainage might influence treatment outcomes among patients with major cutaneous abscesses; note that patients with major cutaneous abscesses should not comprise >30% of the clinical trial population) OR
At least 3 of the following signs and symptoms within 24 hours of randomization:
a) Discharge,
b) Erythema (extending at least 2 cm beyond a wound edge in one direction),
c) Swelling and/or induration,
d) Heat and/or localized warmth, and/or
e) Pain and/or tenderness to palpation.
5. At least 1 of the following conditions within 24 hours of randomization considered to be pathogen-related:
a) Fever (>38°C/100.4°F orally, rectally, or tympanically),
b) Enlarged and/or tender proximal lymphadenopathy and/or lymphangitis,
c) Elevated total peripheral white blood cells (WBCs) >10,000/mm3,
d) >10% immature neutrophils (bands), regardless of total peripheral WBC count, or
e) A non-specific C-reactive protein greater than the upper limits of normal.
6. Venous access available for IV dosing.
7. Accessible infection site for culture.
8. If female, must either:
a) be post-menopausal for at least 1 year; or
b) have had a hysterectomy or tubal ligation; or
c) if of childbearing potential:
i. have maintained her normal menstrual pattern for the 3 months prior to study entry, and have taken hormonal contraceptives for at least 3 months prior to study entry;
or
ii. agree to use two adequate methods of birth control defined as: intrauterine device plus a barrier method (diaphragm plus spermicide, condom used by partner, vasectomized partner, or contraceptive sponge) or use 2 adequate barrier methods (condom use by partner or vasectomized partner plus diaphragm and spermicide);
or
iii. must be using another medically acceptable method of contraception and agrees to continue with the same method during the study; and
d) have a negative serum pregnancy test (serum beta-human chorionic gonadotropin [hCG]) result immediately prior to randomization. If obtaining the serum pregnancy result would cause a delay in treatment, the patient can be entered on the basis of a negative urine pregnancy test result. The urine pregnancy test must be sensitive to at least 50 mU/mL of beta-hCG, pending results of the serum test. The patient must inform the investigator if she becomes pregnant, and study medication must be withdrawn.
There are no male contraceptive requirements. |
|
| E.4 | Principal exclusion criteria |
1. ABSSSI of the following categories:
a) Severely impaired arterial blood supply such that amputation of the infected anatomical site is likely,
b) Infected diabetic foot ulcers
c) Infected decubitus ulcers,
d) Infected human or animal bites (insect bites that cause an infection are permitted),
e) Necrotizing fasciitis or gangrene,
f) Uncomplicated skin or skin structure infection (eg, simple abscesses, folliculitis, impetigo, furunculosis, or superficial cellulitis),
g) Recurrent cellulitis treated with oral suppressive therapy,
h) Self-limiting infections such as isolated folliculitis or other infection that has a high surgical incision cure rate or furunculosis or carbunculosis that is not associated with a cellulitis at least 1 cm in radius,
i) Skin and/or skin structure infection that can be treated by surgery alone,
j) Infections associated with a prosthetic device (ie, suspected or confirmed prosthetic joint infection), and
k) Suspected or confirmed osteomyelitis or septic arthritis
2. Known or suspected concurrent infection or conditions requiring systemic anti-microbial treatment, prophylaxis, or suppression therapy;
3. Known or suspected human immunodeficiency virus (HIV)-infected patients with a cluster of differentiation (CD4) count <200 cells/mm3 recorded in the last 30 to 60 days;
4. Absolute neutrophil count (ANC) <500 cells/mm3;
5. Organ transplant within the preceding 6 months;
6. Received more than one dose of a short-acting (i.e., q12h dosing or less) systemic antibiotic(s) active against Gram-positive pathogens (Appendix F) within the last 7 days, unless there is documented evidence of treatment failure OR demonstrated resistance of Gram-positive pathogens to the prior antibiotic therapy (antibiotics given for surgical prophylaxis are not included in this). Note that patients with prior short-acting systemic antibiotic(s) (i.e., q12h dosing or less) should not comprise >25% of the clinical trial population;
7. ABSSSI suspected or documented as being exclusively due to Gram-negative or anaerobic organisms based on epidemiological grounds or on direct examination of a specimen with Gram stain (mixed ABSSSI in which both Gram-positive and Gram-negative pathogens are isolated may be enrolled if the clinician suspects that the predominant causative pathogen is a Gram-positive organism);
8. ABSSSI known or suspected to be due to a fungal, parasitic or viral infection;
9. Concomitant morbidity of such severity that the patient is likely to die or present with serious medical conditions within 30 days of study entry;
10. Known or suspected local or systemic hypersensitivity to trimethoprim, iclaprim, vancomycin, or related compounds;
11. Pregnant or lactating female;
12. Severe hepatic disease (Child-Pugh Class C) or known aspartate aminotransferase (AST) or alanine transaminase (ALT) >5 times the upper limit of normal and/or bilirubin >2 times the upper limit of normal;
13. Requirement for corticosteroids >20 mg/day prednisolone or equivalent, or received corticosteroids >20 mg per day prednisolone or equivalent in the past 3 days;
14. Cardiovascular conditions and treatments:
a) Patients known to have congenital or sporadic syndromes of QTcF prolongation;
b) Type I A or III anti-arrhythmic drugs;
c) Nonsustained ventricular tachycardia (NSVT) defined as >10 consecutive ventricular beats at a rate of >120 beats per minute (bpm) with a duration of <30 seconds,
d) Bradycardia (<40 bpm), and
e) QT/QTcF interval outside the normal range defined as: QTcF >500 msec.
15. Clinically significant abnormal blood electrolyte levels, as defined below, that cannot be corrected prior to study inclusion:
a) Potassium <3.0 mmol/L (after correction has been attempted), and/or
b) Magnesium <0.5 mmol/L (1.2 mg/dL) (after correction has been attempted)
16. Previous enrollment in Study ICL-23-ABSSSI1 or Study ICL-24-ABSSSI2;
17. Receipt of any investigational agent or device within 30 days of study medication administration; or
18. Patient unable or unwilling to adhere to the study-designated procedures and restrictions. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of randomized patients who achieve an early clinical response (defined as reduction in the lesion size ≥20% compared to baseline) at 48 to 72 hours (ETP) and will be evaluated among all randomized patients (ITT population). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Resolution or near resolution of ABSSSI (ie, clinical cure, defined by a >90% reduction in lesion size from the size at baseline, no increase in lesion size since ETP, and no requirement for additional antibiotics [except aztreonam and metronidazole] or unplanned significant surgical procedures after ETP other than bedside wound care) at TOC for iclaprim (80 mg q12h) compared with vancomycin (weight-based dose) for ITT, mITT, mCE, PP, and mPP populations
2. Resolution or near resolution (≥90%) of ABSSSI at EOT for ITT, mITT, mCE, PP, and mPP populations
3. Resolution or near resolution (≥90%) of ABSSSI at EOT and TOC among patients with severe infection at baseline for ITT, mITT, mCE, PP, and mPP populations
4. Time to resolution of signs and symptoms of ABSSSI from start of treatment for ITT, mITT, mCE, PP, and mPP populations
5. Patient-level bacteriological response rate at EOT and TOC for mITT, mCE and mPP populations
6. Pathogen-level bacteriological response rate at EOT and TOC for mITT, mCE and mPP populations
7. Safety endpoints are AEs, SAEs, ECG results, liver function tests, hematology, coagulation, serum chemistry, urinalysis (UA), vital signs, and physical examinations. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Test of cure visit
2. End of treatment visit (5-14 days)
3. End of treatment visit (5-14 days) and Test of cure visit
4. Throughout the course of the study
5. End of treatment visit (5-14 days) and Test of cure visit
6. End of treatment visit (5-14 days) and Test of cure visit
7. Throughout the course of the study |
|
| 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) | 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Chile |
| Colombia |
| Germany |
| Hungary |
| Latvia |
| Poland |
| Ukraine |
| United States |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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