A phase 3 clinical study to evaluate if the drug iclaprim is safe and effective in comparison with vancomycin when used to treat acute skin infections caused by suspected or confirmed gram-positive bacteria

• Register: EUCTR
• Last refreshed on: 16 October 2017
• Main ID: EUCTR2015-002687-16-CZ
• Date of registration: 19/01/2016
• Prospective Registration: Yes
• Primary sponsor: Motif BioSciences Inc.
• Public title: A phase 3 clinical study to evaluate if the drug iclaprim is safe and effective in comparison with vancomycin when used to treat acute skin infections caused by suspected or confirmed gram-positive bacteria
• Scientific title: A Phase 3, randomized, double-blind, multicenter study to evaluate the safety and efficacy of intravenous iclaprim versus vancomycin in the treatment of acute bacterial skin and skin structure infections suspected or confirmed to be due to Gram-positive pathogens. REVIVE-2 - REVIVE-2
• Date of first enrolment: 05/05/2016
• Target sample size: 600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002687-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Belgium, Brazil, Chile, Croatia, Czech Republic, Estonia, Hungary, Lithuania, Mexico, Portugal, Romania, Turkey, United States

Contacts

• Name: Clinical Trials Information
• Affiliation: Motif BioSciences

• Name: Clinical Trials Information
• Affiliation: Motif BioSciences

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 400
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 200

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) Bradyc

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens.
MedDRA version: 19.1 Level: PT Classification code 10040872 Term: Skin infection System Organ Class: 10021881 - Infections and infestations

Intervention(s)

Product Name: iclaprim / iclaprim mesylate
Product Code: MTF-100 / MTF-100.001
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: iclaprim mesylate
CAS Number: 474793-41-4
Other descriptive name: ICLAPRIM MESYLATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 12.8-

Trade Name: Vancomycin Hydrochloride for Injection, USP
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Vancomycin Hydrochloride
CAS Number: 1404-90-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Primary Outcome(s)

Main Objective: 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).

Timepoint(s) of evaluation of this end point: 48 to 72 hours

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).

Secondary Objective: 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.

Secondary Outcome(s)

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

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.

Secondary ID(s)

ICL-24-ABSSSI2

Source(s) of Monetary Support

Motif BioSciences Inc.