ISRCTN - ISRCTN78730348: A study of the blood levels of physostigmine and hyoscine and associated symptoms following intravenous administration in healthy male and female participants.

Plain English Summary

Background and study aims
The aim of the study was to measure the blood levels of 2 medicines (physostigmine and hyoscine) given by slow intravenous infusion into a vein and the effect of these on the body, including how well the medicine was tolerated. These medicines were given to healthy male and female participants.

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

What does the study involve?
Participants received either of the medicines physostigmine or hyoscine, or an inactive placebo, by slow intravenous infusion into a vein. The medicines were given separately.

Blood samples were taken before and after the start of the slow intravenous infusion to measure the amounts of the two medicines (physostigmine and hyoscine) in blood. In addition, the activity of the enzyme acetylcholinesterase was measured in these blood samples. Blood pressure, heart rate, breathing rate, blood oxygen, electrical activity of the heart (ECG), and pressure in the eye were also recorded at set times.

What are the possible benefits and risks of participating?
There were no direct benefits for the individuals participating in this study. However, the information collected from the study will add to the scientific knowledge about how the human body absorbs and eliminates physostigmine and hyoscine when they have been given intravenously. All medicinal products may cause side effects. The most common side effects known about these two medicines are nausea and vomiting due to physostigmine and blurred vision and dry mouth due to hyoscine.

In this study, the higher doses of physostigmine given intravenously over 4 h in both men and women produced nausea, vomiting, or dizziness in some individuals. The higher doses of hyoscine administered intravenously over 4 h or 10 h in both men and women, produced somnolence (sleepiness), dizziness, dry mouth, and blurred vision in some individuals.

Where is the study run from?
Hammersmith Medicines Research (HMR) (UK)

When is the study starting and how long is it expected to run for?
August 2010 to January 2016

Who is funding the study?
UK Ministry of Defence

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

Trial website

Contact information

Type

Scientific

Primary contact

Dr Medical Advisor

ORCID ID

Contact details

Porton Down
Salisbury
SP4 0JQ
United Kingdom
-
centralenquiries@dstl.gov.uk

Additional identifiers

EudraCT number

2011-002772-16

ClinicalTrials.gov number

Nil known

Protocol/serial number

PHiv101

Study information

Scientific title

A randomised, double-blind, placebo-controlled, crossover, dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of physostigmine salicylate and hyoscine hydrobromide by continuous, intravenous infusion to healthy Caucasian male and female volunteers, given separately and in combination.

Acronym

Study hypothesis

To define the optimal dose ratio of the active ingredients physostigmine salicylate: hyoscine hydrobromide, to achieve maximum potential therapeutic benefit without significant side effects, when given concomitantly by intravenous infusion.

Ethics approval

Approved 09/11/2011, Ministry of Defence Research Ethics Committee (MoDREC) (National Poisons Information Service Birmingham unit, City Hospital, Birmingham, B18 7QH; +44 (0)121 507 4123; no email address provided), ref: 268/PPE/11

Study design

Single centre, randomized, double-blind, placebo-controlled, crossover study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Prevention

Patient information sheet

No participant information sheet available

Condition

Potential risk of poisoning by nerve agent

Intervention

Subject numbers were allocated to treatments according to a randomisation schedule prepared by an independent statistician.

Doses of the study drug physostigmine salicylate and hyoscine hydrobromide administered in the study were:
1. Part A. Various dosages of physostigmine were administered by intravenous infusions, each lasting 4 hours, to groups of healthy men. Each subject received up to 4 single doses: up to 3 doses of physostigmine and up to 1 dose of placebo. Increasing doses of physostigmine were given.
2.1. Part B1. Various dosages of hyoscine were administered by intravenous infusions, each lasting 10 hours, to groups of healthy men. Each subject received up to 4 doses: up to 3 doses of hyoscine and up to 1 dose of placebo. Increasing doses of hyoscine were given.
2.2. Part B2. Multiple period crossover of dosing regimens of hyoscine administered by intravenous infusions, each lasting 4 hours, to healthy men. Each subject received up to 3 single doses: up to 3 doses of hyoscine and up to one dose of placebo.
3. Part C. Two period, crossover comparison of infusions of physostigmine, hyoscine, and placebo in healthy women. Each subject received 2 single doses- either: physostigmine and hyoscine; physostigmine and placebo; hyoscine and placebo; or 2 doses of placebo.

Description of follow up of all treatment arms:
Trial procedures in Parts A, B2, and C (4-h infusion). Vital signs were recorded at -1 days, pre-dose, 1, 2, 4, 8, 12, and 24 h, and at follow up.

Intervention type

Drug

Phase

Phase I

Drug names

Physostigmine salicylate and hyoscine hydrobromide.

Primary outcome measure

1. Definition of the optimal dose ratio of the active ingredients physostigmine salicylate: hyoscine hydrobromide, to achieve maximum potential therapeutic benefit without significant side effects when given concomitantly by intravenous infusion, measured by vital signs recorded at -1 days, pre-dose, 1, 2, 4, 8, 12, and 24 h, and at follow up
2. Hyoscine blood levels measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS) at pre-dose, 15 and 30 min, and 1, 2, 2.5, 3, 3.5, 3.83, 5, 6, 7, 8, 9, 10, and 12 h
3. Physostigmine blood levels measured using liquid chromatography with tandem mass spectrometry at pre-dose, 15 and 30 min, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, and 8 h

Secondary outcome measures

1. To assess the pharmacokinetics (PK) and pharmacodynamics of increasing dosing regimens of physostigmine/hyoscine administered by intravenous infusion in healthy men and women measured using:
1.1. Hyoscine blood levels measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS) at pre-dose, 15 and 30 min, and 1, 2, 2.5, 3, 3.5, 3.83, 5, 6, 7, 8, 9, 10, and 12 h
1.2. Physostigmine blood levels measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS) at pre-dose, 15 and 30 min, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, and 8 h
1.3. Red blood cell acetylcholinesterase blood levels measured using colorimetrical assay at -1 days, pre-dose, 1, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h

Overall trial start date

20/08/2010

Overall trial end date

20/01/2016

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Parts A and B: caucasian man. Part C: caucasian woman. Women of childbearing potential agreed to use adequate contraception and had a negative serum pregnancy test at screening and before each dose of Investigational Medicinal Product (IMP). Women were considered to be of non-childbearing potential if they were surgically sterile (had undergone removal of both ovaries and/or uterus, or had undergone bilateral tubal ligation at least 6 months before the trial).
2. Aged 18–40 years
3. Body mass index (BMI) in the range 18.9–29.0
4. Weight ≥60 kg
5. Normal vision (spherical error between +1.00 D and –1.00 D, and cylindrical error less than or equal to 1.00 D)
6. Part B, C: normal intraocular pressure and anterior chamber angle assessment
7. Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial.
8. Willingness to give written consent to participate after reading the Informed Consent Form, and having had the opportunity to discuss the trial with the investigator or his delegate
9. Willingness to give written consent to have data entered into The Overvolunteering Prevention System

Participant type

Healthy volunteer

Age group

Adult

Gender

Both

Target number of participants

It was planned that 32 subjects would participate in parts A-C of the trial. Parts A, B1 and B2: 8 men in each part (subtotal = 24) Part C: 8 women.

Participant exclusion criteria

1. Pregnant or lactating
2. Pre-menopausal, sexually active, and not using a reliable method of contraception
3. Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could have interfered with the objectives of the trial or the safety of the volunteer
4. Presence of acute or chronic illness or history of chronic illness sufficient to have invalidated the volunteer’s participation in the trial or have made it unnecessarily hazardous
5. Impaired endocrine, thyroid, hepatic, respiratory, or renal function (including mechanical obstruction of the urinary system), diabetes mellitus, coronary heart disease or arrhythmias, or history of any psychotic mental illness
6. Current or past history of asthma (within the last 10 years)
7. History or family history of glaucoma
8. Dibucaine number <70
9. Presence or history of severe adverse reaction to any drug
10. Use of a prescription medicine (except hormonal contraceptives in females) during the 28 days before the first dose of IMP or use of a non-prescription medicine (including herbal supplements), with the exception of paracetamol (≤2000 mg/day), during the 7 days before the first dose of IMP
11. Consumption of food and drink containing grapefruit (or grapefruit-related citrus fruit, such as Seville oranges and pomelos) during the 7 days before the first dose of IMP
12. Participation in another clinical trial of a new chemical entity or a prescription medicine within the previous 3 months
13. Parts A-3 and B2-2 only: have received the same IMP in a previous part of this trial. Subjects who had previously taken physostigmine in Part A, could do Part B2-2 only, and subjects who had previously taken hyoscine in Part B1 or B2, could do Part A-3 only
14. Parts A-1, A-2, B1, B2-1, and C: participation in a previous part of this trial
15. Presence or history of drug or alcohol abuse, or intake of more than 21 units of alcohol weekly (for men) or 14 units of alcohol weekly (for women)
16. Use of tobacco or nicotine-containing products during the 6 months before the first dose of IMP
17. Blood pressure and heart rate in a seated position at the screening examination outside the ranges 90–140 mmHg systolic, 40–90 mmHg diastolic; heart rate 40-100 beats/min
18. QTcB interval >450 msec at screening (an average of 3 readings after 10 min rest)
19. Possibility that the volunteer would not cooperate with the requirements of the protocol
20. Evidence of drug abuse on urine testing
21. Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 1 or 2
22. Loss of more than 450 ml blood during the 3 months before the trial, e.g. as a blood donor
23. Objection by General Practitioner to volunteer entering trial

Recruitment start date

09/11/2011

Recruitment end date

20/11/2014

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Hammersmith Medicines Research (HMR)
Cumberland Avenue Park Royal
London
NW10 7EW
United Kingdom

Sponsor information

Organisation

Defence Science and Technology Laboratory (Dstl)

Sponsor details