Topically Applied Bisphosphocin Nu-3 on Infected Diabetic Ulcers of Subjects With Type I or II Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
Phase I/IIa, five cohort ascending dose with two dosing arms per cohort, study in Type I or II diabetes mellitus subjects with a chronic infected diabetic ulcer defined as having a DUSS score of 0 to 3 and DFI wound score of 1 to 3.

Detailed Description
-----------------
The study is designed to run the cohorts in series with the completion of the first cohort before initiating the next dosing level. At all study visits the ulcer will be visually examined for any changes and photographed using the Aranz Medical Silhouette™ system that will calculate area and depth of the ulcer. In Arm 1, eligible subjects will be treated with a single application of Nu-3 or placebo in 4 to 1 ratio to judge the initial safety of Nu-3 over a brief one (1) hour interval and 24-hr interval post application. Bisphosphocin Nu-3 will be applied topically to the chronic infected ulcer, covered with a non-abrasive bandage following the initial observation period. The subject will be released with verbal instructions to leave the bandage on the wound and return for a follow up visit within 24h ± 2h. At the follow up visit, the bandage will be removed, the ulcer visually examined and the subject cleared for the MAD Arm 2 based on the recommendation of the PI and absence of any SAEs. In Arm 2, eligible subjects which are those who have been approved by the PI after the Visit 2 examination will be instructed in the proper application of bisphosphocin Nu-3. The subjects will be observed applying the first dose in the clinic to ensure compliance. Subjects will then be given a 7 day supply and sent home to continue treatment. Visit 4 or earlier in the case of any adverse events, subjects will return to the clinic for an examination, including visual examination of the ulcer, vital signs, adverse events, photo documentation, collection of a sample for microbiology and concomitant medication use. A final follow up visit will be scheduled +7 days after last dose of study medication (Day 15) for a complete examination as described above.

Official Title
-----------------
A Phase I/IIa, Randomized Double Blind, Placebo-Controlled, Dose Escalating Study to Evaluate the Safety and Tolerability of Topically Applied Bisphosphocin Nu-3 on Infected Diabetic Ulcers of Subjects With Type I or II Diabetes Mellitus

Conditions
-----------------
Diabetic Foot Infections

Intervention / Treatment
-----------------
* Drug: Bisphosphocin Nu-3
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between the ages of 18 and 85. Voluntary written consent, given before performance of any clinical investigation-related procedure not part of standard medical care, and with the understanding that consent may be withdrawn at any time without prejudice to future medical care. Non-hospitalized ambulatory subjects suffering from Diabetes mellitus, Type I or II Diabetic foot ulcer(s) with a DUSS Score of 0 to 3 Ulcerated area(s) of not more than two (2) ulcers between 0.5 to 6 cm2 Any female of child bearing age must consent to use medically acceptable birth control for the duration of the study Female subjects must meet at least one of the following additional criteria: Surgically sterile with bilateral tubal ligation or hysterectomy. Post-menopausal for at least one year. If of child-bearing potential, practicing an acceptable method of birth control for the duration of the clinical investigation as judged by the Investigator, such as condoms, foams, jellies, diaphragm, intrauterine device or abstinence. Subjects willing to undergo pre-and post-clinical investigation blood collection, physical exams and laboratory investigations. Exclusion Criteria: A DUSS Score above 3. DUSS Probing to Bone = Yes An ulcer area(s) greater than 6 cm2 or more than two (2) ulcers Any subject that has received systemic or topical antibiotics within the last seven (7) days Any subject on topical antimicrobial treatment for their infected diabetic foot ulcer whose ulcer is responding to treatment Any subject that would be unable to follow the protocol procedures, safely monitor the infection status at home, and return for schedule visits Positive pregnancy test at Screening or Visit 2 Active infection as demonstrated by temperature > 37.5 oC and clinical features of active infection. Known immunosuppression or taking immunosuppressive agents including systemic steroids. History of severe co-morbidity with expected patient survival ≤ 6 months. Pregnancy or lactation Intake of investigational drugs within 28 days prior to enrollment. History of concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol. Likely inability to comply with the protocol or cooperate fully with the investigator and site personnel. Unwillingness or language barrier precluding adequate understanding of the trial procedure or cooperation with trial site personnel. Known or suspected active abuse of alcohol, narcotics or non-prescription drugs. Other planned surgical procedures within 30 days prior to or 30 days post-index procedure. Prior enrollment in this clinical trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bisphosphocin Nu-3<br>Dosage Form: Topical Antimicrobial, Dosage: 1mg/mL, 10 mg/mL, 20 mg/mL, 50 mg/mL, 100 mg/mL Frequency: QD for day 1, 2x daily for 7 days, Duration: 8 days | Drug: Bisphosphocin Nu-3<br> <br> * Other names: Nu-3;|
| Placebo Comparator: Placebo<br>Dosage Form: Diluent, Frequency: QD for day 1, 2x daily for 7 days, Duration: 8 days | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Treatment-emergent Adverse Events as Graded According to the Common Terminology Criteria for Adverse Events v4.02 (CTCAE) | The severity of each adverse event, as judged by the investigator, was graded according to the CTCAE v4.02. Treatment-emergent adverse events are defined as adverse events with onset times after dosing, or pre-existing adverse events that worsened during the study. | up to Day 15 (Visit 5) | 
| Number of Participants With Normal and Abnormal Cultures at Visits 2, 3, 4, and 5 | The microbiological response to bisphosphocin Nu-3 based on aerobic and anaerobic culture and sensitivity was determined by measuring the reduction of pathogenic bacteria following Nu-3 treatment. Each laboratory used their own standards to decide whether the cultures were normal or abnormal. | Days 1, 2, 9, and 15 (Visits 2, 3, 4, and 5, respectively) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Diabetic Ulcer Severity Score (DUSS) | Clinical response to bisphosphocin Nu-3 was determined by visual evaluation of ulcers, based on the Principal Investigator's judgement, following Nu-3 treatment. Ulcers were scored based on the DUSS. The following 4 parameters were scored as either 0 or 1. Palpable pedal pulses: presence, 0; absence, 1. Probing to the bone: no, 0; yes, 1. Location of ulcer: toe, 0; foot, 1. Number of ulcerations: single, 0; multiple, 1. The four parameter scores were summed to calculate a total score ranging from 0 to 4, with a higher score indicating increased severity. Baseline is defined as the last non-missing value obtained prior to receiving study drug. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. | Baseline and Day 15 (Visit 5) | 
| Mean Change From Baseline in the Diabetic Foot Ulcer Wound Infection Score | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the last non-missing value obtained prior to receiving study drug. The Diabetic Foot Ulcer Wound Infection Score is a numerical scoring system comprised of 7 wound parameters. The score for each individual parameter is summed to calculate a total score, ranging from 0 (less severe infection) to 19 (more severe infection). Parameters are as follows: purulent discharge (0, absent; 3, present); non-purulent discharge (serious, sanguineous) (0, absent; 1, mild); other signs and symptoms of inflammation (erythema, induration, tenderness, pain; 0, none; 1, mild; 2, moderate; 3, severe); local warmth (relative to uninfected contralateral foot) (0, same; 1, mildly increased; 2, moderately increased; 3, severely increased). | Baseline; Day 15 (Visit 5) | 
| Mean Change From Baseline in Ulcer Area in the ITT Population | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the last non-missing value obtained prior to receiving study drug. For participants who have more than one ulcer, the measurement of all ulcers were combined for analysis. | Baseline; Day 15 (Visit 5) | 
| Mean Change From Baseline in the Percentage of Area Reduction for Ulcers in the ITT Population | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the last non-missing value obtained prior to receiving study drug. For participants who have more than one ulcer, the measurement of all ulcers were combined for analysis. | Baseline; Day 15 (Visit 5) | 
| Mean Change From Baseline in Ulcer Area in the Per-Protocol Population | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the last non-missing value obtained prior to receiving study drug. For participants who have more than one ulcer, the measurement of all ulcers were combined for analysis. | Baseline; Day 15 (Visit 5) | 
| Mean Change From Baseline in the Percentage of Area Reduction for Ulcers in the Per-Protocol Population | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the last non-missing value obtained prior to receiving study drug. For participants who have more than one ulcer, the measurement of all ulcers were combined for analysis. | Baseline; Day 15 (Visit 5) |