Ignite Creation Date:
2024-05-06 @ 9:34 AM
Last Modification Date:
2024-10-26 @ 12:16 PM
Study NCT ID:
NCT03012191
Status:
COMPLETED
Last Update Posted:
2019-07-23
First Post:
2017-01-04
Brief Title:
Gentamicin for RDEB
Sponsor:
University of Southern California
Organization:
University of Southern California
Study Overview
Official Title:
Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa Patients With Nonsense Mutations
Status:
COMPLETED
Status Verified Date:
2019-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Recessive dystrophic epidermolysis bullosa RDEB is an incurable devastating inherited skin disease caused by mutations in the COL7A1 gene that encodes for type VII collagen C7 the major component of anchoring fibrils AFs structures that mediate epidermal-dermal adherence Thirty percent of RDEB patients have nonsense mutations The investigators recently demonstrated in 5 such patients that intradermal and topical gentamicin induced read-through of their nonsense mutations and created robust and sustained new C7 and AFs at the dermal-epidermal junction DEJ of their skin and also stimulated wound closure and reduced new blister formation No untoward side effects occurred Herein the investigators propose evaluating the safety and efficacy of intravenous gentamicin in these patients In theory this intravenous administration has the possibility of treating simultaneously all of the patients skin wounds The investigators also propose optimizing the concentration and manner of delivery of topical gentamicin The unambiguous milestones will be increased C7 and AFs in the patients DEJ improved EB Disease Activity Scores and absence of significant gentamicin side effects
Detailed Description:
Aim 1 Evaluate the Safety and Efficacy of Short Term Intravenous Gentamicin for RDEB Patients
Overview Rationale The rationale for short-term systemic intravenous gentamicin in these patients is outlined in the sections above namely the drug could treat multiple skin sites simultaneously including the esophagus This approach has proven safe and efficacious in other genetic diseases such as CF and DMD22-25 Our HYPOTHESIS is that intravenous gentamicin will like topical and intradermal gentamicin create new C7 and AFs at the patients DEJ improve multiple skin sites simultaneously improve the patients clinical disease and improve his or her quality of life In accordance with the enclosed letters from two experienced pediatricians we believe this therapy will be safe Because C7 and AFs are incredibly stable we further hypothesize that newly induced C7 and AFs will persist for many months in the patients skin Using dosing regimens of gentamicin that have proven to be safe we will 1 determine the percentage increase of C7 expression in the patients skin before and after treatment 2 determine how durable and sustainable the new C7 and AFs are in the patients skin after treatment 3 determine if this treatment is safe in this patient population 4 determine if this treatment improves the patients clinically and improves their quality of life and 5 generate data for a multi-centered Phase III study using a larger number of patients
PatientsIntervention We have already lined up 3 well-characterized adult RDEB patients with nonsense mutations who wish to participate in this study These patients had positive responses to topical and intradermal gentamicin in our clinical trial Table II The patients will receive intravenous gentamicin 75 mgs per kilogram in 100 ml of 5 dextrose in saline for 14 consecutive days a dose proven to not cause ototoxicity or neprhotoxicity28 and to be efficacious in inducing PTC read-through in DMD patients22 The first few infusions will be done in the Infusion Center of the Keck Hospital of USC We will measure gentamicin trough levels 24 hours after infusion and gentamicin peak levels 30 minutes after the infusion during the second day and if needed adjust the gentamicin doses such that the peak level is between 20 and 40 μgml and the trough level 2 μgml If no untoward side effects occur the patients will then have their infusions in their home via a commercial infusion service
Safety Evaluation Patients will be consented enrolled and evaluated on Day 0 and then evaluated on post-treatment days 30 90 and 180 On Day 0 the patients will have a complete medical history review of systems ROS physical examination vital signs and weight They will also have baseline urine analysis complete blood count CBC electrolytes glucose comprehensive metabolic panel CMP and calculated creatinine clearance Pure tone audiometry and a calculated creatinine clearance will be done on Days 0 7 14 and 30 post-treatment Stop criteria will be a decline of 15 dB on pure tone audiometry at 2 consecutive frequencies and a creatinine clearance 60mlmin28 Whenever there is new protein created in a patient there is the possibility that the patients immune system will raise autoantibodies against it This did not occur in our clinical trial with topical and intradermal gentamicin but it behooves us to evaluate this again with intravenous gentamicin and potentially more auto-antigenic protein created Using indirect immunofluorescence and our anti-C7 ELISA we will test the subjects serum for anti-C7 antibodies at each visit
Efficacy A Clinical Evaluations At baseline Day 0 and at each follow-up visit days 30 90 and 180 the patients will complete a Quality of Life Assessment tool a Pruritus Score tool and a validated epidermolysis bullosa disease activity index EBDASI2930 Patients will keep a daily diary using a self-ROS questionnaire Patients will be telephoned weekly by a USC study member inquiring about any new signs symptoms or ROS changes since the advent of the study At baseline Day 0 we will identify four Test Sites at least 25 cm2 in size to follow sequentially Two will be from areas that at baseline have blisters or erosions and the other two from intact skin areas The two Test Sites with active blisters and erosions will be traced using a transparency sheet and the areas of the lesions calculated on a digitizing tablet Likewise all of the Test Sites will have standardized photographs and the lesional areas calculated by computer-assisted morphometry as previously published29-31 Within the context of their daily diary patients will note the number of new blisters and erosions that occur in the Test Sites A USC study member will telephone the patient each week and inquire about the Test Sites and ask the patient to estimate the percentage area of the Test Site consumed by erosions and blisters Also at each follow-up visit three dermatologists will observe the four Test Sites and count the number of bullae and erosions in each The intact Test Site areas will be scored at each follow-up visit using the following 3-point scale 0 no lesions 1 any active lesions 2 active lesions consuming over 50 of the Test Site area Tracings to evaluate the areas of blisters or open erosions will be done and standardized photographs paired with computer-assisted morphometry to calculate the areas of any lesions will be performed B Evaluations of C7 and AF Expression At each post-treatment time point 8 mm punch biopsies from the four Test Sites will be divided into three parts for i HE histology and quantitation of epidermal-dermal adherence ii the expression of C7 at the DEJ relative to that of normal human skin using anti-C7 antibodies to the NC1 and NC2 domains of C7 and NIH J Image software One major milestone of the study will be the expression of NC2 since this would clearly indicate restoration of full-length C7 and III evaluation of newly created AFs by immuno-EM and AF enumeration by computer-assisted morphometry Performing these evaluations out to 6 months will determine how durable the newly created C7 and AFs are In our recent clinical trial outlined above it was surprising that gentamicin-induced C7 remained at a similar level at 3 months post-treatment as that of 1 month for Patient 3 Please see Figure 1 and Table II
Aim 2 Evaluate the Safety and Efficacy of Higher Dose Topical Gentamicin for RDEB Patients
Overview and Rationale In our gentamicin clinical trial outlined earlier there was significant variation in the production of new C7 and AFs as shown in Table II Patients 2 and 5 only restored C7 to 20 of normal skin in response to gentamicin We only used one concentration of gentamicin 01 ointment and our in vitro studies with RDEB fibroblasts from these same two patients showed that the C7 response to gentamicin was dose-dependent26 In these patients there could have been sub-optimal dosing or sub-optimal access of the gentamicin to the patients dermal fibroblasts and basal keratinocytes In this aim we will use 05 gentamicin ointment rather than 01 and determine if the C7 response is more robust in these two patients Based on our encouraging data shown in Figure 2 we will also treat intact skin and determine if higher dose gentamicin can prophylactically prevent frank skin blisters and erosions from forming
PatientsIntervention We will study two RDEB children tested in our previous trial for this study In addition we also have 2 other children and 2 other adult patients who have contacted us and wish to participate in this study Table III Two of these patients share the same mutations R578X and R2814 as our current patients We will select a total of four Test Sites two with open wounds of at least 3 cm by 3 cm and two areas of intact skin nearby the Test Sites with blisters or erosions and apply 05 gentamicin ointment two times a day under an occlusive dressing of the patients choice for two weeks This dose was used in combination with 15 paromomycin to ulcerative cutaneous leishmaniasis lesions once daily for 20 days in two publications without renal or ototoxicity detected3233 Safety and Efficacy We will essentially assess in these patients the safety and efficacy parameters outlined in Aim 1 at months 1 3 and 6 after topical application Potential renal toxicity and ototoxicity will be monitored by creatinine clearance and pure tone audiometry at day 0 and at each follow up visit
Aim 3 Evaluate the Safety and Efficacy of Intradermal Administration of Gentamicin with a MR2 Micro-needle Roller Device
Overview and Rationale In our current clinical trial outlined above there were excellent C7 responses to intradermal injections of gentamicin solution in several patients Table II Nevertheless these injections were very localized with diffusion of the drug probably less than an inch from the single injection site Recent evidence has shown that a MR2 microneedle roller device can readily deliver lidocaine into the lower epidermis and upper papillary dermis over a wide area of skin with good efficacy safety and excellent patient tolerance34 This may be an opportunity to deliver intradermal gentamicin solution 40 mgml to wide areas of skin in a simple manner that can be done in an outpatient office with minimal logistical issues and avoidance of systemic exposure to the drug Advantages include the possibility of delivering in a pulse fashion significant levels of gentamicin to the papillary dermis over wide areas of skin with minimal discomfort and minimal systemic exposure of gentamicin Avoiding systemic exposure would be valuable for RDEB patients who have ototoxicity or renal compromise poor venous access or cannot tolerate intravenous infusions
Patients Interventions We will enroll two new RDEB patients either adults or children shown in Table III in this proof-of-principle study Skin Test Sites will be areas measuring at least 40 cm2 and we will test one site of intact unwounded skin and one site of skin with lesions blisters or erosions The areas will be cleansed with 4 Hibiclens and then the MR2 Microneedle Roller Device passed over the area in two directions at 90 degrees This device induces tiny micro-wounds in the skin to the depth of the papillary dermis Gentamicin sterile solution 40 mgml will then be liberally applied over the area and the area immediately occluded with a polyrurethane membrane Opsite Another equal sized Test Site of intact skin will be tested without prior intervention with the Microneedle Roller The same gentamicin solution will be applied to the site and immediately occluded with Opsite This will determine if the gentamicin solution can penetrate intact skin
Safety and Efficacy We will measure gentamicin in the serum of these patient 30 minutes after the microneedle delivery to determine if there is any systemic exposure when gentamicin is administered in this manner Efficacy of the gentamicin administration will be assessed identically to those in Aim1 by IF and immuno-EM analysis in conjunction with the patients keeping a daily diary of the treatment sites weekly photographs of Test Sites weekly staff interviews of the patients and physician assessments at patient visits at months 1 3 and 6 after administration of gentamicin Potential renal toxicity and ototoxicity will be monitored by creatinine clearance and pure tone audiometry at day 0 and each follow up visit
Overview Rationale The rationale for short-term systemic intravenous gentamicin in these patients is outlined in the sections above namely the drug could treat multiple skin sites simultaneously including the esophagus This approach has proven safe and efficacious in other genetic diseases such as CF and DMD22-25 Our HYPOTHESIS is that intravenous gentamicin will like topical and intradermal gentamicin create new C7 and AFs at the patients DEJ improve multiple skin sites simultaneously improve the patients clinical disease and improve his or her quality of life In accordance with the enclosed letters from two experienced pediatricians we believe this therapy will be safe Because C7 and AFs are incredibly stable we further hypothesize that newly induced C7 and AFs will persist for many months in the patients skin Using dosing regimens of gentamicin that have proven to be safe we will 1 determine the percentage increase of C7 expression in the patients skin before and after treatment 2 determine how durable and sustainable the new C7 and AFs are in the patients skin after treatment 3 determine if this treatment is safe in this patient population 4 determine if this treatment improves the patients clinically and improves their quality of life and 5 generate data for a multi-centered Phase III study using a larger number of patients
PatientsIntervention We have already lined up 3 well-characterized adult RDEB patients with nonsense mutations who wish to participate in this study These patients had positive responses to topical and intradermal gentamicin in our clinical trial Table II The patients will receive intravenous gentamicin 75 mgs per kilogram in 100 ml of 5 dextrose in saline for 14 consecutive days a dose proven to not cause ototoxicity or neprhotoxicity28 and to be efficacious in inducing PTC read-through in DMD patients22 The first few infusions will be done in the Infusion Center of the Keck Hospital of USC We will measure gentamicin trough levels 24 hours after infusion and gentamicin peak levels 30 minutes after the infusion during the second day and if needed adjust the gentamicin doses such that the peak level is between 20 and 40 μgml and the trough level 2 μgml If no untoward side effects occur the patients will then have their infusions in their home via a commercial infusion service
Safety Evaluation Patients will be consented enrolled and evaluated on Day 0 and then evaluated on post-treatment days 30 90 and 180 On Day 0 the patients will have a complete medical history review of systems ROS physical examination vital signs and weight They will also have baseline urine analysis complete blood count CBC electrolytes glucose comprehensive metabolic panel CMP and calculated creatinine clearance Pure tone audiometry and a calculated creatinine clearance will be done on Days 0 7 14 and 30 post-treatment Stop criteria will be a decline of 15 dB on pure tone audiometry at 2 consecutive frequencies and a creatinine clearance 60mlmin28 Whenever there is new protein created in a patient there is the possibility that the patients immune system will raise autoantibodies against it This did not occur in our clinical trial with topical and intradermal gentamicin but it behooves us to evaluate this again with intravenous gentamicin and potentially more auto-antigenic protein created Using indirect immunofluorescence and our anti-C7 ELISA we will test the subjects serum for anti-C7 antibodies at each visit
Efficacy A Clinical Evaluations At baseline Day 0 and at each follow-up visit days 30 90 and 180 the patients will complete a Quality of Life Assessment tool a Pruritus Score tool and a validated epidermolysis bullosa disease activity index EBDASI2930 Patients will keep a daily diary using a self-ROS questionnaire Patients will be telephoned weekly by a USC study member inquiring about any new signs symptoms or ROS changes since the advent of the study At baseline Day 0 we will identify four Test Sites at least 25 cm2 in size to follow sequentially Two will be from areas that at baseline have blisters or erosions and the other two from intact skin areas The two Test Sites with active blisters and erosions will be traced using a transparency sheet and the areas of the lesions calculated on a digitizing tablet Likewise all of the Test Sites will have standardized photographs and the lesional areas calculated by computer-assisted morphometry as previously published29-31 Within the context of their daily diary patients will note the number of new blisters and erosions that occur in the Test Sites A USC study member will telephone the patient each week and inquire about the Test Sites and ask the patient to estimate the percentage area of the Test Site consumed by erosions and blisters Also at each follow-up visit three dermatologists will observe the four Test Sites and count the number of bullae and erosions in each The intact Test Site areas will be scored at each follow-up visit using the following 3-point scale 0 no lesions 1 any active lesions 2 active lesions consuming over 50 of the Test Site area Tracings to evaluate the areas of blisters or open erosions will be done and standardized photographs paired with computer-assisted morphometry to calculate the areas of any lesions will be performed B Evaluations of C7 and AF Expression At each post-treatment time point 8 mm punch biopsies from the four Test Sites will be divided into three parts for i HE histology and quantitation of epidermal-dermal adherence ii the expression of C7 at the DEJ relative to that of normal human skin using anti-C7 antibodies to the NC1 and NC2 domains of C7 and NIH J Image software One major milestone of the study will be the expression of NC2 since this would clearly indicate restoration of full-length C7 and III evaluation of newly created AFs by immuno-EM and AF enumeration by computer-assisted morphometry Performing these evaluations out to 6 months will determine how durable the newly created C7 and AFs are In our recent clinical trial outlined above it was surprising that gentamicin-induced C7 remained at a similar level at 3 months post-treatment as that of 1 month for Patient 3 Please see Figure 1 and Table II
Aim 2 Evaluate the Safety and Efficacy of Higher Dose Topical Gentamicin for RDEB Patients
Overview and Rationale In our gentamicin clinical trial outlined earlier there was significant variation in the production of new C7 and AFs as shown in Table II Patients 2 and 5 only restored C7 to 20 of normal skin in response to gentamicin We only used one concentration of gentamicin 01 ointment and our in vitro studies with RDEB fibroblasts from these same two patients showed that the C7 response to gentamicin was dose-dependent26 In these patients there could have been sub-optimal dosing or sub-optimal access of the gentamicin to the patients dermal fibroblasts and basal keratinocytes In this aim we will use 05 gentamicin ointment rather than 01 and determine if the C7 response is more robust in these two patients Based on our encouraging data shown in Figure 2 we will also treat intact skin and determine if higher dose gentamicin can prophylactically prevent frank skin blisters and erosions from forming
PatientsIntervention We will study two RDEB children tested in our previous trial for this study In addition we also have 2 other children and 2 other adult patients who have contacted us and wish to participate in this study Table III Two of these patients share the same mutations R578X and R2814 as our current patients We will select a total of four Test Sites two with open wounds of at least 3 cm by 3 cm and two areas of intact skin nearby the Test Sites with blisters or erosions and apply 05 gentamicin ointment two times a day under an occlusive dressing of the patients choice for two weeks This dose was used in combination with 15 paromomycin to ulcerative cutaneous leishmaniasis lesions once daily for 20 days in two publications without renal or ototoxicity detected3233 Safety and Efficacy We will essentially assess in these patients the safety and efficacy parameters outlined in Aim 1 at months 1 3 and 6 after topical application Potential renal toxicity and ototoxicity will be monitored by creatinine clearance and pure tone audiometry at day 0 and at each follow up visit
Aim 3 Evaluate the Safety and Efficacy of Intradermal Administration of Gentamicin with a MR2 Micro-needle Roller Device
Overview and Rationale In our current clinical trial outlined above there were excellent C7 responses to intradermal injections of gentamicin solution in several patients Table II Nevertheless these injections were very localized with diffusion of the drug probably less than an inch from the single injection site Recent evidence has shown that a MR2 microneedle roller device can readily deliver lidocaine into the lower epidermis and upper papillary dermis over a wide area of skin with good efficacy safety and excellent patient tolerance34 This may be an opportunity to deliver intradermal gentamicin solution 40 mgml to wide areas of skin in a simple manner that can be done in an outpatient office with minimal logistical issues and avoidance of systemic exposure to the drug Advantages include the possibility of delivering in a pulse fashion significant levels of gentamicin to the papillary dermis over wide areas of skin with minimal discomfort and minimal systemic exposure of gentamicin Avoiding systemic exposure would be valuable for RDEB patients who have ototoxicity or renal compromise poor venous access or cannot tolerate intravenous infusions
Patients Interventions We will enroll two new RDEB patients either adults or children shown in Table III in this proof-of-principle study Skin Test Sites will be areas measuring at least 40 cm2 and we will test one site of intact unwounded skin and one site of skin with lesions blisters or erosions The areas will be cleansed with 4 Hibiclens and then the MR2 Microneedle Roller Device passed over the area in two directions at 90 degrees This device induces tiny micro-wounds in the skin to the depth of the papillary dermis Gentamicin sterile solution 40 mgml will then be liberally applied over the area and the area immediately occluded with a polyrurethane membrane Opsite Another equal sized Test Site of intact skin will be tested without prior intervention with the Microneedle Roller The same gentamicin solution will be applied to the site and immediately occluded with Opsite This will determine if the gentamicin solution can penetrate intact skin
Safety and Efficacy We will measure gentamicin in the serum of these patient 30 minutes after the microneedle delivery to determine if there is any systemic exposure when gentamicin is administered in this manner Efficacy of the gentamicin administration will be assessed identically to those in Aim1 by IF and immuno-EM analysis in conjunction with the patients keeping a daily diary of the treatment sites weekly photographs of Test Sites weekly staff interviews of the patients and physician assessments at patient visits at months 1 3 and 6 after administration of gentamicin Potential renal toxicity and ototoxicity will be monitored by creatinine clearance and pure tone audiometry at day 0 and each follow up visit
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None