Safety, Tolerability and Efficacy of Nefopam Cream in Burn Patients
Safety, Tolerability and Efficacy of Nefopam Cream in Burn Patients
Burn patients very commonly develop abnormal scars after injury which can be red, raised or
 elevated, painful and very itchy. They can prevent normal movement of hands and other joints
 and lead to ugly deformities which makes physical and psychological recovery very difficult.
 This proposal seeks to test the usefulness of a cream called Nefopam to prevent and treat
 these bad scars after burns and other injury to the skin. Nefopam is a drug that has been
 used as a pain medicine in Europe but has been found to have anti-scarring properties in rats
 and pigs. It has been tested in healthy people and found to be well tolerated and safe. The
 study purposes to make a scratch in the hip skin in 60 adult burn patients at two burn unit
 sites, the University of Alberta and the University of California at Davis, Sacramento CA.
 Burn patients in the study will have a scratch wound in the skin of the each side of the hip,
 part way through the thickness of the skin which is shallow at first but gets deeper. This
 scratch is made with a special guide which precisely controls the length and depth of the
 scratch so that each scratch is the same. Part of the scratch heals without scar and the
 deeper part heals with a red raised scar over a small region less than 2 inches long. One
 side will be treated with the drug and the other with a control or placebo are in a white
 cream that is indistinguishable, where you cannot tell which side contains the drug. Once the
 wound is nearly healed, usually less than 21 days, the cream will be applied twice daily for
 three weeks. Measurements will be done about once per month for four months where the healing
 scratches will be photographed, measurements of the thickness made with ultrasound and
 mexameter for scar color or pigment and redness. Ultrasound is a painless probe that uses
 sound waves to measure scar thickness and mexameter is a painless probe on the surface of the
 scratch to measure color and redness. Both measurements take only minutes to complete.
 Patients will be asked to answer a scar assessment form about on how they feel each scratch
 during the treatment and the research staff will also the complete scar form as well. It is
 the aim of the study to find a cream the works to prevent and reduce scarring after burn
 injury in military or civilian patients. In the future, an useful cream for scarring in burn
 patients may also be helpful for other skin damage which leads to scarring.
Background:

 Fibroproliferative disorders (FPD) are common and serious disorders involving many human
 tissues and are a leading cause of mortality and reported as high a 45% of annual deaths.
 Hypertrophic scar (HTS) and keloids are the dermal equivalent of FPD and impose lower
 mortality but great morbidity, particularly following burn injury. In the US, 1.25 million
 people are treated for burns annually, 50,000 requiring hospitalization. Although the
 mortality rate for burn injury has improved, burn patients experience a prolonged
 hospitalization (mean 26.2 days) and rehabilitation, requiring an average of 12.7 weeks off
 work for patients with thermal injuries >30% of the TBSA. Much of the rehabilitation relates
 to functional and cosmetic limitations imposed by HTS, including a reduction in range of
 motion of the extremities and the intense pruritus and heat intolerance making early return
 to work prohibitive, until remodelling of the HTS has occurred. Although risk factors for HTS
 include sex, age, racial or genetic factors, and wound location, HTS develops after prolonged
 inflammation of slowly healing burn wounds with a very high frequency especially in deep
 dermal wounds independent of other factors in up to 75% of burn patients. Unfortunately, HTS
 and keloid are known to respond poorly to current forms of therapy, including pressure
 garments, topically applied silicone and intralesional steroids, usually slowly over months
 or years, often incompletely. Advances in the immunology of FPD including HTS and keloids,
 reveal many common features, such that novel advances in therapy for these disorders may
 provide far reaching benefits to many patients and military personnel suffering from severe
 scarring after burn injury.

 Drug Information: NEFOPAM HCL has been found safe and effective for the reduction of dermal
 scarring following standardized human dermal wounds of critical depth that produces HTS in
 normal human volunteers. NEFOPAM HCl was first developed as a non-narcotic analgesic drug and
 it is currently marketed primarily in Europe, New Zealand and parts of Asia for oral,
 intramuscular or intravenous use for acute or chronic pain. NEFOPAM HCl has over 30 years of
 human safety data. It is considered generally safe with mild side effects including nausea,
 sweating, dry mouth and tachycardia. NEFOPAM reformulated into a cream and topically
 administered has been shown to reduce the amount of scar tissue formed during wound healing
 in mice and the red Duroc pig model of hypertrophic scarring. Most recently, a phase I safety
 and efficacy study was conducted in human volunteers using a standardized progressively
 deeper dermal wound (0-1.6 mm in depth over 6 cm) made with a sterile jig in each hip, where
 normotrophic (negative control) and HTS (positive control) develop in the superficial and
 deep regions of the scratch. 24 patients have been studied over 104 days where the
 preliminary results demonstrate that NEFOPAM cream has very few adverse side effects, low
 immunogenicity and encouraging antifibrotic effects on the healing wounds.

 Purpose/ Hypothesis:

 To re-assess the safety, local tolerability and efficacy of NEFOPAM Cream in burn patients
 when applied to bilateral deep dermal wounds using a standardized dermal scratch model of
 hypertrophic scarring.

 Objectives:

 To assess the efficacy of NEFOPAM Cream versus placebo (vehicle) in reducing scar size
 following artificially induced dermal wounds in each lateral hip region of burn patients.

 To determine the efficacy on wound closure of NEFOPAM Cream versus placebo (vehicle) in burn
 patients.

 To assess the satisfaction of burn patients and investigators in the scar rating and
 appearance after topical application of NEFOPAM Cream versus placebo (vehicle).

 To determine the efficacy of NEFOPAM Cream versus placebo on the gene and protein expression
 of fibrotic molecules including type I and type III collagen, β-catenin target gene (AXIN-2),
 TGF- β1, and decorin, quantitative measures of collagen orientation index (COI),
 immunohistochemistry of a-SMA (smooth muscle actin) and β -catenin in scar tissue.

 Research Method/Procedures:

 This study will be a double blind, placebo-controlled, randomized multicenter Phase II study
 in which burn patients will be randomized to receive NEFOPAM Cream or placebo. Qualifying
 subjects will be randomized to receive 2.0 mL of NEFOPAM Cream or placebo (vehicle) on Day -1
 on intact skin in an area on the upper hip not intended for the incision. On Day 0 burn
 patients who are free of adverse events will enter the treatment phase of the study.

 Consenting burn patients requiring skin graft surgery will be scratch-wounded under aseptic
 conditions on the lateral hip of each lower extremity while under local anesthesia or general
 anesthesia for their wound debridement as previously described. To create small standardized
 depth uniform wounds, a jig fitted with a sterile No.11 surgical scalpel blade will be used
 to create a wound that is 6 cm in length and from 0 to approximately 1.6 mm maximum depth
 into the deep dermis of the lateral hip mid-distance between the anterior superior iliac
 spine and the lateral trochanter of the hip. Two identical wounds will be made, one on each
 hip and subjects will be randomized to receive treatment with NEFOPAM Cream or placebo on
 each wound. Wounds will be followed until >90% re-epithelialized before the wounds will be
 cleaned and the cream will be applied twice a day for the next 21 days. The wounds will be
 covered with an occlusive dressing until Day 21 of treatment (Tegaderm ™). Once the treatment
 is completed and the wounds are fully healed, the wound/scar will be left uncovered and
 treated with a moisturizing cream (Glaxal™) if necessary.

 Burn patients randomized to receive active treatment will have one wound treated with NEFOPAM
 Cream (treatment wound site) and the other wound site treated with placebo cream/vehicle
 (control wound site) according to the randomization schedule and dosing instructions. All
 study team members and subjects will be blinded to all treatments.

 Subjects will receive two applications of treatment to each wound per day for 21 days after
 the wounds are 90% healed.

 Wound evaluations will be performed daily through the treatment period. Digital photography
 of the wound/scar will occur following wounding and on Day 6 (+/- 2), Day 13 (+/- 2), Day 20
 (+/- 3), Day 27 (+/- 2), Day 48 (+/- 7) Day 76 (+/-14), Day 104 (+/- 15). Modified VBSA and
 POSAS scale, vascularity and pigmentation via Mexameter® and ultrasound evaluations of the
 scar will commence after the dermal scratch is completed and thereafter when the wound is
 healed (defined as >90% epithelialization of the wound with no exudate - approximately 1-3
 weeks following wounding) and repeated on Day 20 (+/- 3), Day 27 (+/- 2), Day 48 (+/- 7) Day
 76 (+/-14), Day 104 (+/- 15).

 Two punch biopsies will be performed on the maximally thick region of each scar on Day 28 and
 day 104 for immunohistochemistry analysis of a-SMA (smooth muscle actin) and β-catenin,
 collagen orientation, and RT-qPCR analysis of type I and type III collagen, the β-catenin
 target gene (AXIN-2), TGF- β1 and decorin.

 Subjects may request that the scar be completely excised on or after D104 under local
 anesthetic (1% xylocaine with epinephrine 1:100,000) and repaired using 4(0) monocril suture
 in the subcuticular plain to produce a fine linear scar. Tissue removed from this procedure
 will be used for immunohistochemistry analysis of β-catenin and RT-qPCR analysis of type I
 and type III collagen, the β-catenin target gene (AXIN-2), TGF- β1 and decorin.

 Plan for Data Analysis:

 All calculations and analyses will be performed using SAS version 9.4 or higher resident on
 the HP Unix (HPUX B.11.11 or higher. The continuous data will be summarized via PROC
 UNIVARIATE - mean, standard deviation, median, minimum, and maximum. The Safety Population
 will be used for analysis of adverse events, tolerability reactions, clinical evaluations,
 and laboratory tests. The ITT Population will be used for all other analyses.

 For any assessments that are not performed per hip (e.g. adverse event reporting), results
 will be grouped by treatment (NEFOPAM 3.0% and placebo, placebo alone). For assessments that
 are performed separately on each hip (e.g. tolerability, POSAS scale), results will be
 grouped two ways: (1) By within-subject differences between hips grouped by the 3 treatment
 groups; and (2) By overall group mean value by treatment applied.

 Tolerability is assessed separately for each hip by the investigator using a 5-point scale
 that ranges from 0 (No visible reaction) to 4 (Severe erythema with induration, vesicles or
 pustules and/or erosion/ulceration). While Likert scales are ordinal in nature, parametric
 methods are still robust and appropriate for analysis (43). Thus, for the assessment of
 tolerability, an ANCOVA model will be used to compare the within-subject difference between
 active and placebo hips (or, for placebo-only subjects, between left and right hips) in
 average tolerability. The average tolerability for each subject-hip will be calculated across
 all non-missing scheduled visits.
Inclusion Criteria:

 1. Male or female burn or trauma patients aged ≥18 - ≤65 years with 5-70% TBSA deep
 second or third degree burns who have uninjured skin in both the lateral hip regions
 and have voluntarily signed the Informed Consent Form (ICF).

 2. Subjects with clinically acceptable results at screening for the laboratory tests
 specified in the trial protocol.

 3. Women of childbearing potential, must provide a negative pregnancy serum/urine test at
 time of screening and have to be compliant with an effective form of birth control
 throughout the entire study. Non-childbearing potential means subjects have had a
 history of tubal ligation or a hysterectomy or are post-menopausal with no menses for
 at least 1 year prior to enrolment in the study.

 4. Subjects, who are, in the opinion of the Investigator, able to understand the study,
 co-operate with the study procedures and are willing to return to the clinic for all
 of the required follow-up visits.

 5. Subjects must be able to cooperate with requirements of the study (e.g. able to speak,
 read and write English, and will be expected to be available for adverse event
 monitoring for the duration of the study).

 Exclusion Criteria:

 1. Subjects must not be involved any other intervention trial(s) where the intervention
 could possibly affect wound healing to be eligible for enrolment in the NEFOPAM study.

 2. Subjects who have scarring from previous interventions or evidence of thermal,
 electrical or radiation burn scars, tattoos, birthmarks or moles within 5 cm of the
 treatment site.

 3. Exclusion criteria specific to burn patients in addition to the previously described
 factors would include severe inhalation injury requiring FiO2 >50%, renal failure
 requiring dialysis or hemodynamic instability requiring vasopressor therapy at the
 time of initiation of therapy.

 4. Subjects with a history or family history of abnormal scarring including hypertrophic
 scarring.

 5. Subjects with additional concurrent illnesses or conditions that may have interfered
 with wound healing like neoplastic, immune-mediated, or primary infectious disease
 (e.g. carcinoma, vasculitis, connective tissue disease, immune system disorders,
 rheumatoid arthritis, chronic renal impairment, significant hepatic impairment,
 inadequately or uncontrolled congestive heart failure or diabetes mellitus) or any
 clinically significant medical condition or history of any condition which may impair
 wound healing.

 6. Subjects with a skin disorder that is chronic or currently active and which the
 investigator considers will adversely affect the healing of acute wounds or will
 involve the areas to be examined in this trial (including psoriasis, dermatitis,
 eczema)

 7. Subjects with a body mass index <15 or >35 kg/m2.

 8. A history of radiotherapy to the study scar area.

 9. Subjects who have used nicotine-containing products (including vaping) within one
 month prior to the screening visit.

 10. Subjects who are positive for HIV, hepatitis B or C.

 11. Subjects who have known sensitivities to NEFOPAM Cream, structurally related compounds
 or any of the constituents of NEFOPAM Cream.

 12. Subjects who have known sensitivities to EMLA cream, chlorhexidine or adhesive
 dressings

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