Ignite Creation Date:
2024-05-06 @ 8:21 PM
Last Modification Date:
2024-10-26 @ 3:26 PM
Study NCT ID:
NCT06351995
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-08
First Post:
2024-03-21
Brief Title:
Neostigmine and Glycopyrrolate by Iontophoresis
Sponsor:
James J Peters Veterans Affairs Medical Center
Organization:
James J Peters Veterans Affairs Medical Center
Study Overview
Official Title:
Neostigmine and Glycopyrrolate by Iontophoresis to Induce Bowel Evacuation
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-04
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:
To determine a lower effective dose of neostigmine to induce bowel evacuation by transcutaneous administration by iontophoresis
Detailed Description:
Subjects will progress to receive the standard dose previously reported and employed for these agents NEO 007 mgkg GLY 0014 mgkg by transdermal administration by use of a wired ION system NEO and GLY can be delivered into the systemic circulation by transcutaneous route by ION to induce a safe and predictable bowel evacuation in persons with SCI If digital rectal stimulation was utilized in the screening session this method will be utilized for the remaining sessions as needed at the discretion of the primary investigator In the anesthesiology literature a ratio of NEO to GLY of about 5 to 1 has been employed in clinical situations Participants will be requested not to have bowel care for at least 1 day prior to the study The subject will assume normal bowel evacuation position until a bowel movement occurs Privacy draping and privacy will be provided at the time of bowel evacuation The subjects will be monitored for 120 minutes A minimum of two research personnel will be present during the study visit to record all of data and perform the tasks required
From recent work it is extrapolated that 85 to 90 of participants will have a bowel evacuation to transdermal administration of NEO by ION The pharmacokinetics of only those who have a bowel evacuation to NEO will be used in the calculation to determine the peak plasma concentration PPC and area under the curve AUC of NEO and GLY The PPC and AUC for the non-responders to NEO will be analyzed separately it is speculated that the PPC of NEO for the non-responders will be blunted-that is at least below the mean value of the PPC for NEO administration
The absorption of study agents is to a certain extent subject-specific because of differential absorption through the skin As such each participant is expected to display differing responses shorter or longer times to bowel evacuation or the absence of bowel evacuation as well as the absence or presence of cholinergic increased bowel activity bradycardia bronchoconstriction or anti-cholinergic activity as previously described in the text above The pharmacokinetic data will to a large extent reflect this variability in transdermal drug absorption The data collected will include the presence or absence of bowel evacuation time to bowel evacuation consistency Bristol stool scale and quantity by weight The presencenumber of cholinergic and anti-cholinergic side-effects on a standardized point scale will be determined as well as their severity eg mild moderate or severe Heart rate blood pressure oxygen saturation and pulmonary mechanics airway patency by impulse oscillation system will be recorded at baseline and sequentially at intervals the initiation of ION at 5 10 15 20 30 45 60 90 and 120 minutes
To quantitate the amount of these agents absorbed into the systemic circulation pharmacokinetic studies will be performed for 2 hours after the start of transdermal drug delivery Venous blood 2 ml will be collected into an EDTA tube for both agents at the following time points baseline time zero 5 10 15 20 30 45 60 90 120 180 240 360 and 480 minutes Upon drawing the blood will be placed in an ice bath and spun using a centrifuge within 5 minutes of collection Upon completion of 5 minutes of centrifugation the plasma will be aliquoted into two separate vials with equal volumes and labeled with date and time of draw study information NEO or GLY testing destination and the subjects unique identifier The transfer vials will be inserted into dry ice for at least 10 minutes after which they will be placed into the -80 degrees Celsius freezer Plasma levels of NEO and of GLY will be batched and measured at a later date A file designating the tubes with random numbers associated with the draw times will be created for each subject to conceal the sequence of draw and to attempt the removal of possible bias during the measurement and recording of the concentrations of NEO and GLY NEO and GLY will be measured by mass spectroscopy
To determine the reproducibility of the transdermal absorption of NEO and GLY as well as the potential side-effects subjects will again receive NEO 007 mgkg GLY 0014 mgkg by transdermal administration by use of a wired ION system Additionally digital rectal stimulation will be utilized as needed at the discretion of the primary investigator Pharmacokinetic data and all other measurements and questionnaires that were previously obtained will be acquired once again and compared to Trial 1
The investigators will have obtained pharmacokinetic data on each participant from Study 1 From the data acquired the peak plasma concentration PPC and the area under the curve AUC for NEO will be calculated The hypothesis is that the PPC for NEO will correlate more closely with bowel evacuation than its AUC and the AUC for GLY will correlate more closely with anti-cholinergic symptoms than its PPC but this prediction is just speculation prior to obtaining and analyzing the data If the plasma concentration of each NEO and GLY are solely responsible for determining biological effects eg cholinergic and anti-cholinergic then the investigators would predict that there will be a direct and strong correlation of drug levels with those endpoints However if the biological effects are primary determined by end-organ responsiveness then the correlation between drug concentration and observed endpoints will be tenuous at best If both plasma concentration and end-organ responsiveness play a role in bowel evacuation and cholinergic side-effect then an effect of plasma concentrations will still be evident but not as strong
Determination of a Lower Effective Dose of NEO to Induce Bowel Evacuation Because 85-90 of participants are anticipated to have a bowel evacuation from NEO administration at the dose previously employed standard dose NEO 007 mgkg the dose administered is most probably well above the lowest effective dose to achieve the biological desired effect ceiling effect If the lowest effective dose can be determined side-effects from NEO administration will be reduced As such to identify the upper limit of the lowest effective dose the dose of NEO will be titrated down until the effect on the primary end organ is lost-that is until bowel evacuation no longer occurs after drug administration in at least 50 of the participants Thus to determine if a lower dose of NEO will still result in bowel evacuation participants will have the dose of NEO reduced by 25 with the dose of GLY also reduced by 25 The total volume of the drugs applied to the patch will be kept constant In these dose reduction experiments pharmacokinetic data eg AUC and PPC will be obtained on each participant for each reduction in dose of NEO All other measurements and questionnaires that were obtained in Study 1 will be performed
From recent work it is extrapolated that 85 to 90 of participants will have a bowel evacuation to transdermal administration of NEO by ION The pharmacokinetics of only those who have a bowel evacuation to NEO will be used in the calculation to determine the peak plasma concentration PPC and area under the curve AUC of NEO and GLY The PPC and AUC for the non-responders to NEO will be analyzed separately it is speculated that the PPC of NEO for the non-responders will be blunted-that is at least below the mean value of the PPC for NEO administration
The absorption of study agents is to a certain extent subject-specific because of differential absorption through the skin As such each participant is expected to display differing responses shorter or longer times to bowel evacuation or the absence of bowel evacuation as well as the absence or presence of cholinergic increased bowel activity bradycardia bronchoconstriction or anti-cholinergic activity as previously described in the text above The pharmacokinetic data will to a large extent reflect this variability in transdermal drug absorption The data collected will include the presence or absence of bowel evacuation time to bowel evacuation consistency Bristol stool scale and quantity by weight The presencenumber of cholinergic and anti-cholinergic side-effects on a standardized point scale will be determined as well as their severity eg mild moderate or severe Heart rate blood pressure oxygen saturation and pulmonary mechanics airway patency by impulse oscillation system will be recorded at baseline and sequentially at intervals the initiation of ION at 5 10 15 20 30 45 60 90 and 120 minutes
To quantitate the amount of these agents absorbed into the systemic circulation pharmacokinetic studies will be performed for 2 hours after the start of transdermal drug delivery Venous blood 2 ml will be collected into an EDTA tube for both agents at the following time points baseline time zero 5 10 15 20 30 45 60 90 120 180 240 360 and 480 minutes Upon drawing the blood will be placed in an ice bath and spun using a centrifuge within 5 minutes of collection Upon completion of 5 minutes of centrifugation the plasma will be aliquoted into two separate vials with equal volumes and labeled with date and time of draw study information NEO or GLY testing destination and the subjects unique identifier The transfer vials will be inserted into dry ice for at least 10 minutes after which they will be placed into the -80 degrees Celsius freezer Plasma levels of NEO and of GLY will be batched and measured at a later date A file designating the tubes with random numbers associated with the draw times will be created for each subject to conceal the sequence of draw and to attempt the removal of possible bias during the measurement and recording of the concentrations of NEO and GLY NEO and GLY will be measured by mass spectroscopy
To determine the reproducibility of the transdermal absorption of NEO and GLY as well as the potential side-effects subjects will again receive NEO 007 mgkg GLY 0014 mgkg by transdermal administration by use of a wired ION system Additionally digital rectal stimulation will be utilized as needed at the discretion of the primary investigator Pharmacokinetic data and all other measurements and questionnaires that were previously obtained will be acquired once again and compared to Trial 1
The investigators will have obtained pharmacokinetic data on each participant from Study 1 From the data acquired the peak plasma concentration PPC and the area under the curve AUC for NEO will be calculated The hypothesis is that the PPC for NEO will correlate more closely with bowel evacuation than its AUC and the AUC for GLY will correlate more closely with anti-cholinergic symptoms than its PPC but this prediction is just speculation prior to obtaining and analyzing the data If the plasma concentration of each NEO and GLY are solely responsible for determining biological effects eg cholinergic and anti-cholinergic then the investigators would predict that there will be a direct and strong correlation of drug levels with those endpoints However if the biological effects are primary determined by end-organ responsiveness then the correlation between drug concentration and observed endpoints will be tenuous at best If both plasma concentration and end-organ responsiveness play a role in bowel evacuation and cholinergic side-effect then an effect of plasma concentrations will still be evident but not as strong
Determination of a Lower Effective Dose of NEO to Induce Bowel Evacuation Because 85-90 of participants are anticipated to have a bowel evacuation from NEO administration at the dose previously employed standard dose NEO 007 mgkg the dose administered is most probably well above the lowest effective dose to achieve the biological desired effect ceiling effect If the lowest effective dose can be determined side-effects from NEO administration will be reduced As such to identify the upper limit of the lowest effective dose the dose of NEO will be titrated down until the effect on the primary end organ is lost-that is until bowel evacuation no longer occurs after drug administration in at least 50 of the participants Thus to determine if a lower dose of NEO will still result in bowel evacuation participants will have the dose of NEO reduced by 25 with the dose of GLY also reduced by 25 The total volume of the drugs applied to the patch will be kept constant In these dose reduction experiments pharmacokinetic data eg AUC and PPC will be obtained on each participant for each reduction in dose of NEO All other measurements and questionnaires that were obtained in Study 1 will be performed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None