Condition category
Genetic Diseases
Date applied
24/02/2016
Date assigned
01/04/2016
Last edited
09/06/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Terguride is a type of drug which blocks the action of a chemical messenger in the brain (neurotransmitter) called serotonin. It has been approved for treating a number of conditions in Japan and was approved for use in the Czech Republic until 2008. This study is being carried out to find out how much terguride is in the urine and blood after a healthy person has taken it, and to look at the effects of food and another drug called itraconazole (an anti-fungal medication) on its concentration. In the body, terguride is broken down (metabolized) by a chemical (enzyme) in the liver called CYP2D6. There has been found to be a lot of variation in the efficiency of this enzyme and the amount produced in different people, which is determined by genes (genotypes). Some people are able to metabolize terguride very quickly (ultrarapid metabolizers, UMs), while others slowly (poor metabolizers, PMs). Between these two extremes are intermediate metabolizers (IMs) and extensive metabolizers (EMs). The aim of this study is to look at the way that terguride is processed by healthy adults with all of these genotypes, the effects of itraconazole on terguride metabolism in those with PM and EM genotypes, and the effects of food on people with EM genotypes.

Who can participate?
Healthy adults of either sex.

What does the study involve?
The study is made up of three different parts. In the first part of the study, all participants are given four single doses of terguride, increasing in strength on study days 1, 3, 5 and 7 (ending in maximum doses of 0.75 mg, 1.5 mg, 2.5 mg and 3.0 mg in PM, IM, EM, and UM patients respectively). In the second part of the study, participants with the genotype PM, and half of the participants with the genotype EM are given doses of terguride (at one dose lower than the best level for them as determined in part one) twice a day over two days. After this, participants also receive itraconazole twice a day for two days (alone) and then a single dose of itraconazole with a single dose of terguride.In the third part of the study, the other half of the participants with the genotype EM are randomly allocated to one of two groups. Participants in both groups receive a single dose of terguride (the best level for them as determined in part one). Those in the first group are given the dose after they have eaten a meal and those in the second group are given the dose when they have not eaten anything. After this, the dosing will be repeated but with the group who had eaten having not eaten and those having not eaten having eaten. In all parts, after receiving each dose, blood and urine samples are taken so that the amount of terguride in the body can be tested. In part the first part of the study, participants all have an ECG (a test where the electrical activity of the heart is measure through sensors placed on the skin) to measure their heart rate.

What are the possible benefits and risks of participating?
There are no direct benefits to those taking part in this study, although participants will undergo a range of tests which could help them to learn more about their general health. Risks of participating involve the chance of developing side-effects to the study drug and the possibility of pain or bruising during blood tests.

Where is the study run from?
Celerion Research Phase I Unit, Belfast (UK)

When is the study starting and how long is it expected to run for?
September 2015 to October 2016

Who is funding the study?
medac GmbH (Germany)

Who is the main contact?
Dr Elena Osswald

Trial website

Contact information

Type

Scientific

Primary contact

Dr Elena Osswald

ORCID ID

Contact details

medac GmbH
Theaterstr. 6
Wedel
22880
Germany

Additional identifiers

EudraCT number

2015-003729-33

ClinicalTrials.gov number

Protocol/serial number

MC-TER.3/PK

Study information

Scientific title

A phase 1, open-label trial to evaluate the effects of single and multiple doses, CYP3A4 inhibition, and food on the pharmacokinetics of terguride in healthy subjects with known CYP2D6 genotypes

Acronym

Study hypothesis

The aim of this study will investigate the CYP2D6 dependency of terguride pharmacokinetics by inclusion of four groups of healthy subjects with known CYP2D6 genotype, i.e. PM, IM, EM, and UM.

Ethics approval

London - Riverside Research Ethics Committee, 04/01/2016, ref: 15/LO/1987

Study design

Single-centre randomized three-part open-label phase 1 study

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Other

Trial type

Other

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet.

Condition

CYP2D6 genotype

Intervention

The study takes place in three parts. Administered doses will depend on genotype and tolerability by the subject. Initial doses in Part 1 are 0.75 mg, 1.5 mg, 2.5 mg and 3.0 mg terguride in PM, IM, EM, and UM subjects, respectively. Doses administered in Part 2 and Part 3 will be based on well-tolerated individual dose, determined in Part 1 of the study.
Total duration of treatment for UM and IM subject is 7 days (drug to be administered every second day).
Total duration of treatment for PM subjects is 18 days (terguride to be administered on 7 days, itraconazole 200 mg BID to be administered on 3 days) with wash-out days in between.
Total duration of treatment for EM subjects is depending on randomisation:
1. 18 days (terguride to be administered on 7 days, itraconazole 200 mg BID to be administered on 3 days) with wash-out days in between or
2. 13 days (terguride to be administered on 6 days) with wash-out days in between.
Follow-up will be performed for all subjects 14 days after the last study drug administration.

Part 1 will be conducted as a 4-period dose titration. All subjects will participate in Part 1 of the study which will be composed of 4 groups defined by their CYP2D6 metabolic status (i.e., PM, IM, EM, and UM). On Study Days 1, 3, 5, and 7, single oral ascending doses of terguride will be administered followed by blood and urine sampling for PK and PD assessments. Cardiodynamic sampling will also be conducted following each dosing. Dose escalation will be performed depending on tolerability of the previous dose.

Part 2 will be conducted as a 2-group, 2-period, fixed sequence study. All PM subjects will continue to Part 2 of the study. EM subjects will continue in either Part 2 or Part 3 as per the randomization schedule. In Period 1, multiple oral doses of terguride (at one dose level lower than the well-tolerated single dose level determined in Part 1) will be administered TID for 2 consecutive days (Study Days 10 and 11), with a single dose administered on the morning of Study Day 12. In Period 2, oral doses of itraconazole will be administered twice daily (BID) for 2 consecutive days (Study Days 15 and 16). In the morning of Study Day 17, a single dose of itraconazole will be coadministered with a single oral dose of terguride.

Part 3 will be conducted as a 1-group, 2-period, 2-way crossover study. 12 EM subjects will participate in Part 3. On Study Days 10 (Period 1) and 12 (Period 2) a single oral dose of terguride (at the well-tolerated single dose level determined in Part 1) will be administered under either fasting or fed conditions or vice versa as per the randomization schedule.

Intervention type

Drug

Phase

Phase I

Drug names

Terguride

Primary outcome measures

Maximum concentration (Cmax) and area under the plasma concentration curve (AUC) of terguride is measured using blood analysis and uranlysis:
Part one: Study days 1, 3, 5, and 7
Part two: Study days 12 and 17
Part three: Study days 10 and 12

Secondary outcome measures

1. Cmax and AUC of N’-monodesethyl-terguride, measured using blood analysis and uranlysis:
Part one: Study days 1, 3, 5, and 7
Part two: Study days 12 and 17
Part three: Study days 10 and 12
2. Heart rate-corrected QT interval (QTcF) determined using EEG scanning in part one only, on study days 1, 3, 5, and 7

Overall trial start date

01/09/2015

Overall trial end date

06/05/2016

Reason abandoned

Eligibility

Participant inclusion criteria

1. Medically healthy adults
2. Aged between 18-60 years inclusive at the time of screening
3. Non-smoker
4. Body mass index (BMI) ≥ 18.5 and ≤ 30.0 kg/m2 at screening
5. Known CYP2D6 genotype
6. No clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the PI
7. Appropriate contraception
8. Able to swallow multiple capsules and/or tablets
9. Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol

Participant type

Healthy volunteer

Age group

Adult

Gender

Both

Target number of participants

Up to 36 participants

Participant exclusion criteria

1. Mentally or legally incapacity
2. History or presence of clinically significant medical or psychiatric condition or disease
3. Alcoholism or drug abuse within the past 2 years
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug, itraconazole, metoclopramide (MCP) or related compounds
6. Female subjects who are pregnant or lactating
7. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or antihepatitis C virus (antiHCV) antibodies screen
8. QTcF interval is >450 msec (males) or >470 msec (females) or clinically significant ECG findings at screening
9. Creatinine clearance < 80 mL/min
10. Drugs / herbals known to be significant inducers of CYP enzymes and/or P-gp
11. Diet incompatible with the on-study diet, lactose intolerance
12. Major surgery within 60 days prior to the first dose of study drug and throughout the study
13. Donation of blood or plasma within 90 days prior to the first dose of study drug
14. Donation of bone marrow within the last 6 months prior to the first dose of study drug
15. Participation in another clinical trial within 90 days prior to the first dose of study drug

Recruitment start date

02/02/2016

Recruitment end date

30/04/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Celerion Research Phase I Unit
22-24 Lisburn Road
Belfast
BT9 6AD
United Kingdom

Sponsor information

Organisation

medac GmbH

Sponsor details

Theaterstr. 6
Wedel
22880
Germany

Sponsor type

Industry

Website

Funders

Funder type

Industry

Funder name

medac GmbH

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication of study results in a peer reviewed journal.

Intention to publish date

31/07/2017

Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

09/06/2016: the overall trial end date was changed from 31/10/2016 to 06/05/2016.