Condition category
Injury, Occupational Diseases, Poisoning
Date applied
30/08/2019
Date assigned
06/09/2019
Last edited
06/09/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Several different versions (called formulations) of a skin patch containing two medicines (physostigmine and hyoscine) have been developed. The skin patch releases these medicines enabling them to cross the skin into the bloodstream. The aim of this study was to measure the amount of physostigmine and hyoscine in the blood at different times over a 72 hour period and assess any associated symptoms.

Who can participate?
Study participants were healthy males aged between 18 and 40 years

What does the study involve?
The plan was for each subject to wear three different patch sizes of their allocated formulation in turn for 72 hours, with start dates for each application being separated by at least two weeks.
On each occasion blood samples were taken before and after patch application to measure the amounts of the two medicines (physostigmine and hyoscine). In addition the activity of the enzyme acetylcholinesterase (AchE) was measured in these blood samples. The effects of the patch were assessed by recording the condition of the skin under the patch at set times and any symptoms that were experienced. Heart rate, blood pressure, electrical activity of the heart (ECG), tests of vison and cognitive function were also recorded at set times.

What are the possible benefits and risks of participating?
There were no direct individual benefits for the subjects participating. However, the information collected from these individuals added to the scientific knowledge about the physostigmine and hyoscine patch. All medicinal products have a risk of causing side effects. The most common side effects known about the medicines in the patch are nausea and vomiting due to physostigmine and blurred vison and dry mouth due to hyoscine. All formulations of patches tested were considered well tolerated.

Where is the study run from?
The study was conducted at Simbec Research Limited

When is the study starting and how long is it expected to run for?
The study has been completed.

Who is funding the study?
The study was funded by UK MoD

Who is the main contact?
centralenquiries@dstl.gov.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Medical Advisor

ORCID ID

Contact details

Defence Science and Technology Laboratory
Porton Down
Salisbury
SP4 0JQ
United Kingdom
NA
centralenquiries@dstl.gov.uk

Additional identifiers

EudraCT number

2004-005029-23

ClinicalTrials.gov number

Nil known

Protocol/serial number

RD 209/24055

Study information

Scientific title

A Dose-escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Four Transdermal Patch Formulations (F4-F7) of Hyoscine and Physostigmine in Healthy Male Subjects

Acronym

Study hypothesis

The aim of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple applications of four patch formulations (F4-F7) of hyoscine and physostigmine in healthy male subjects

Ethics approval

Approved, 13/01/2005, South East Wales Local Research Ethics Committees (LREC) (Churchill House, 17 Churchill Way, Cardiff, CF10 2TW; 02920402402), ref: 04/WSE02/179

Study design

Randomised double-blind parallel dose-escalation three-period study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Other

Patient information sheet

No participant information sheet available

Condition

Potential risk of poisoning by nerve agent

Intervention

1. Generic drug name- physostigmine and hyoscine (transdermal patch). Four versions of PHP transdermal patch were tested. These patches contained different amounts of physostigmine and hyoscine in one of two adhesive matrices.
2. Dosage - three different patch sizes of four patch formulations (F4, F5, F6, F7) were tested.
Each subject received one of four formulations of transdermal patches, with six subjects allocated to each formulation.
Each subject received three applications of that formulation (one each of three different patch sizes in order of increasing size)

Data collection - Safety monitoring, blood sampling for pharmacokinetics and pharmacodynamics, patch adhesion and patch application site assessments, ECG and ocular function assessments were performed for up to 96 hours after the application of each patch. Method of measurements:
Hyoscine and Physostigmine: liquid chromatography-tandem mass spectrometry (LC-MS-MS)
Acetylcholinesterase: spectrophotometry

Added 06/09/2019:
Process for randomisation of patients.
A sequential three-digit subject number was assigned once eligibility for the study had been confirmed. Subjects were randomised to receive one of the four formulations (F-4, F-5, F-6, F-7) in Period 1, and to receive the same formulation in Periods 2 and 3. Treatment was allocated according to the randomisation schedule produced by Simbec Research Limited.

Intervention type

Drug

Phase

Phase I

Drug names

Physostigmine, hyoscine

Primary outcome measure

Safety and tolerability of physostigmine/hyoscine combination measured using safety monitoring, blood sampling for pharmacokinetics and pharmacodynamics, patch adhesion and patch application site assessments, ECG and ocular function assessments were performed for up to 96 hours after the application of each patch

Secondary outcome measures

None

Overall trial start date

16/03/2004

Overall trial end date

30/05/2006

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Subjects had to meet all of the following criteria:
1. Ability to give written informed consent prior to study participation
2. Healthy Caucasian male subjects aged between 18 and 40 years (inclusive)
3. Body Mass Index (BMI) within the range of  21 and  30 kg/m2
4. Vital signs within the following ranges:
4.1 Pulse rate 40-90 bpm
4.2 Systolic blood pressure 90-140 mmHg
4.3 Diastolic blood pressure 50-90 mmHg
5. Ability to communicate well with the Investigator and to comply with the requirements of the study

Participant type

Healthy volunteer

Age group

Adult

Gender

Male

Target number of participants

24 healthy male subjects

Participant exclusion criteria

1. Presence of any clinically significant medical condition as determined by the Investigator
2. Any surgical or medical condition which might have significantly altered the absorption, distribution, metabolism or excretion of any drug. (e.g. renal or liver disease, respiratory, immunological, endocrine or neurological disorders)
3. Any ECG abnormality other than sinus bradycardia or respiratory sinus arrhythmia
4. Known or suspected hypersensitivity or idiosyncratic reaction related to any of the study products
5. Any history of contact dermatitis
6. Plasma cholinesterase genotype homozygous for A or S variant
7. Any skin disorder, broken skin, scars, tattoos at the sites of patch application (i.e. on both arms)
8. Glaucoma or a history of glaucoma in first degree relatives (i.e. parents, siblings or offspring)
9. Presence of Anterior Chamber Narrow Angle (Van Herrick Grade 1 and 2)
10. Intra-ocular pressure exceeding 20 mm Hg
11. Uncorrected vision in both eyes of worse than 6/9 on the Snellen Scale
12. Required glasses or contact lenses for distance vision
13. Peripheral visual fields outside of age corrected normal parameters
14. History of asthma (within the previous 10 years), exercise induced bronchospasm or relevant seasonal bronchospasm
15. Lung function of less than 80% of predicted spirometry criteria
16. History or evidence of drug abuse (opiates, methadone, cocaine, amphetamines, methamphetamines, cannabinoids, barbiturates)
17. Positive test for HIV, hepatitis B or hepatitis C
18. History or evidence of alcohol abuse defined as an intake of more than 28 units per week (4 units per day), where 1 unit corresponds to 250 ml beer, 20 ml spirits/liqueur or one glass (100 ml) of wine
19. Positive urine test for alcohol
20. Participation in another clinical study within three months prior to Screening
21. Use of any prescription medication within 21 days prior to Baseline
22. Use of non-prescription medication within 7 days prior to Baseline (apart from paracetamol)
23. Donation of blood or blood products for a period of 3 months prior to or the intention to donate blood or blood products within 3 months after completion of the study

Recruitment start date

13/01/2005

Recruitment end date

08/04/2005

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Simbec Research Limited
Merthyr Tydfil
Merthyr Tydfil
CF48 4DR
United Kingdom

Sponsor information

Organisation

Defence Science and Technology Laboratory (Dstl)

Sponsor details

Porton Down
Salisbury
SP4 OJQ
United Kingdom
NA
centralenquiries@dstl.gov.uk

Sponsor type

Government

Website

Funders

Funder type

Government

Funder name

Study conducted on behalf of UK Ministry of defence

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

At present our publication plans are not confirmed as the PHP development program is ongoing.
If a specific date is required, we suggest a year after the clinical trial summary is accepted by ISRCTN.

IPD sharing statement
The datasets generated during and/or analysed during the current study are not expected to be made available as subject consent for their release was not obtained.

Intention to publish date

30/08/2020

Participant level data

Not expected to be available

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

06/09/2019: A paragraph was added to the interventions. 30/08/2019: Trial’s existence confirmed by MHRA