Clinical Trials Register

Summary
EudraCT Number:	2016-001877-34
Sponsor's Protocol Code Number:	HOT-Treated
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-08-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-001877-34

A.3

Full title of the trial

Improving understanding of Heroin Overdose Testing: diamorphine dose-escalation testing in a treated population

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Improving understanding of Heroin Overdose Testing

A.4.1

Sponsor's protocol code number

HOT-Treated

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	South London and Maudsley NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Addictions Department of the Institute of Psychiatry, Psychology & Neuroscience, King's College London
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	NIHR Biomedical Research Centre of King's College London
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	South London and Maudsley NHS Foundation Trust
B.5.2	Functional name of contact point	Professor John Strang
B.5.3	Address:
B.5.3.1	Street Address	4 Windsor Walk, Denmark Hill
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE5 8AF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	4402078480438
B.5.5	Fax number	4402077018454
B.5.6	E-mail	john.strang@kcl.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	King's College London
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Addictions Department of the Institute of Psychiatry, Psychology & Neuroscience, King's College London
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	NIHR Biomedical Research Centre of King's College London
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	King's College London
B.5.2	Functional name of contact point	Professor John Strang
B.5.3	Address:
B.5.3.1	Street Address	4 Windsor Walk, Denmark Hill
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE5 8AF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	4402078480438
B.5.5	Fax number	4402077018454
B.5.6	E-mail	john.strang@kcl.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Diamorphine Hydrochloride BP
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Diamorphine hydrochloride
D.3.9.1	CAS number	1502-95-0
D.3.9.3	Other descriptive name	Heroin
D.3.9.4	EV Substance Code	SUB13557MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Opioid Overdose

E.1.1.1

Medical condition in easily understood language

Heroin Overdose

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Behaviours [F01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10033295
E.1.2	Term	Overdose
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10033299
E.1.2	Term	Overdose effect
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10067695
E.1.2	Term	Acute overdose
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate respiratory depression and hypoxaemic response to intravenous (IV) or intramuscular (IM) higher-than-regular doses of heroin as a marker for overdose

E.2.2

Secondary objectives of the trial

To investigate effect of variations in heroin dose on subjective drug effect and whether these are correlated to physiological changes
To investigate the unique arms movements of injecting (IV) heroin using wearable devices (motion signature)
To monitor variation in breathing patterns (rhythm) using wearable devices (Apple watch or similar)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diamorphine-injecting subjects who have been in treatment for a minimum of one month;
2. Male or female;
3. ≥ 18 years;
4. Capable of providing voluntary written informed consent;
5. A non custodial stable residence and telephone number;
6. Venous access has to be suitable for intravenous drug administration and cannula insertion NB: only intravenous injecting users will be included in this study, however, for trial purposes, intramuscular administration of the IMP will be used if peripheral venous access is not appropriate on the study days;
7. Oxygen saturation reading of ≥92%;
8. Forced expiratory volume in 1 second ratio, predicted % (FEV1%) of >50% (spirometry);
9. Absence of acute respiratory illness for 6 weeks prior to screening or any study day.

E.4

Principal exclusion criteria

1. Dependent use of cocaine or amphetamines requiring specific treatment. This will be assessed at Pre-Study Screen.
2. Active significant medical condition (e.g. hepatic failure or severe hepatic disease) as determined by clinical assessment, medical history and as advised by their treating clinician. This will be assessed by the clinical investigator at Pre-Study Screen, for example:
i. Severe hepatic insufficiency (liver function tests conducted within the last 6 months prior to screening): Patients with clinical features of hepatic failure (e.g. encephalopathy, ascites, jaundice, prolonged bleeding, hypoalbuminaemia and secondary oedema – consistent with Child-Pugh Classification B or C). Patients with liver disease (e.g. HCV, HBV infection) without features of hepatic failure are potentially eligible.
ii. Severe respiratory insufficiency or the inability to reliably perform physiological tests of respiratory function (spirometry).
iii. Pre-existing renal or cardiac issues that the study physician or treating clinician considers inappropriate for the purposes of this trial.
3. In cases where subjects are able to perform spirometry, a FEV1% of ≤50% as confirmed by spirometry at Pre-Study Screen.
4. Oxygen saturation reading of <92% as confirmed by finger pulse oximetry at Pre-Study Screen.
5. Acute illnesses that make participation inappropriate, as assessed by the study physician. Presence of acute respiratory illness within 6 weeks prior to screening or any of the study sessions. This will be assessed during screening and on each study day. If acute illness is present, subject will be asked to return 6 weeks post-acute illness. Acute diarrhoeal conditions caused by antibiotic-induced pseudomembranous colitis or by poisoning will be assessed by the study physician. Assessment at Pre-Study Screen and on each Study Visit.
6. Subjects suffering from acute alcoholism or delirium tremens. This will be assessed at Pre-Study Screen.
7. Subjects who have suffered from head injury or have been with diagnosed phaeochromocytoma. These will be assessed at Pre-Study Screen.
8. Risk of paralytic ileus or biliary colic assessed by the study physician. This will be assessed at Pre-Study Screen.
9. A benzodiazepine prescription that is above the standard therapeutic dose range (e.g. if oral Diazepam above 30mg/daily; BNF, 2016). This will be examined by medical notes at the Pre-Study Screen. A drug test on each Study Visit will be performed to assess whether there is any presence of benzodiazepines that the participant is not prescribed. Concomitant medication check will also be conducted at Pre-Study Screen.
10. Subjects prescribed other contraindicated drugs: monoamine oxidase inhibitors (or within 2 weeks of their discontinuation), 4-quinolone antibacterials, phenothiazines, tricyclic antidepressants, anxiolytics (see above), hypnotics, cisapride, domperidone and metoclopramide, cimetidine and selegiline. This will be assessed at Pre-Study Screen.
11. Alcohol and other drug use on the specific study days. A drug screen (Angelscope) and breathalyser (BACtrack, Xtend®) will be used to confirm additional drug/alcohol use on the study days. A positive drug screen (excluding prescribed drugs) and an excessive blood alcohol content (BAC) (based on the legal driving limit in England & Wales of 0.8g/L) will result in a re-invitation to an alternative study date. This will be assessed on each Study Visit.
12. Current psychiatric diagnosis of major depression with suicidal ideation, psychosis, bipolar disorder, or any psychiatric disorder that would compromise the subject's ability to complete the study. These will be assessed at Pre-Study Screen.
13. At screening and on each study day, if there is a chance that female subjects may be pregnant; subjects will undergo a pregnancy test. A positive pregnancy test will result in an exclusion from the study. In addition, mothers who are lactating, women of childbearing potential who refuse to use adequate contraception and pregnancy tests during the study, or women who are planning to become pregnant during the period of the study will also be excluded. This will be assessed at Pre-Study Screen and on each Study Visit by the clinical investigator.
14. Any other factor that in the opinion of the study physician would make the subject unsafe or unsuitable for the study. This will be addressed at Pre-Study Screen and on each Study Visit by clinical investigator.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoints will be to assess:
• Blood oxygen saturation (SpO2),
• End-tidal carbon dioxide (ETCO2),
• Transcutaneous carbon dioxide (TcCO2), and
• Intercostal parasternal electromyography to measure neural respiratory drive

E.5.1.1

Timepoint(s) of evaluation of this end point

All endpoints will be obtained by measurements taken during the study visits.

E.5.2

Secondary end point(s)

Secondary endpoints will be to assess:
• Pupil size
• Subjective drug effects (using visual analogue scale)
• Staff rating of drug effects (using visual analogue scale)
• Arm movement using the three-axis gyroscope, accelerometer, and magnetometer embedded in the wrist watch (Apple Watch or similar)
• Respiratory pattern (rhythm) using the microphone embedded in the wrist watch (Apple Watch or similar)

E.5.2.1

Timepoint(s) of evaluation of this end point

All endpoints will be obtained by measurements taken during the study visits.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

dose escalation

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Dose escalation

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the study will be defined as the database lock date following the last patient’s last visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Between study visits, subjects will be taking their treatment of diamorphine maintenance as per standard care. Additionally, after the trial end, subjects will be able to continue diamorphine maintenance treatment as per standard care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-09-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-25

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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