Condition category
Injury, Occupational Diseases, Poisoning
Date applied
30/05/2018
Date assigned
04/06/2018
Last edited
04/06/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Hormones, such as dehydroepiandrosterone (DHEA), play an important role in the body helping to maintain muscle mass and the immune system. The immune system helps the body recover from injury and fight off infection. Immediately after an injury DHEA levels have been shown to drop quickly and if DHEA levels are already low, as seen in older people, this puts them at increased risk of infection and reduces their chance of a full recovery. Research has shown in both young and old men and women that DHEA levels are below normal levels for as long as 3 months after injury. As a result, giving trauma patients DHEA to boost DHEA levels in the blood could improve the immune response and speed up recovery. The aim of this study is to work out what dose of DHEA (50, 100 or 200mg per day) will increase patient’s DHEA levels to those seen in a healthy young adult males. The study will also work out what is the best method of delivering the DHEA into the body, either by an oral tablet that is swallowed or a tablet that is placed under the tongue and dissolves.

Who can participate?
Male and female trauma patients aged 16 – 50, and female hip fracture patients aged 50 or older admitted to University Hospital Birmingham

What does the study involve?
A blood sample is taken within 24 hours of the injury if the patients are admitted within this time frame. This sample is used to assess the acute response of DHEA and immune markers to injury. Participants are randomly allocated to receive doses of DHEA via either oral tablets or sublingual tablets for the 3-day treatment period. The dose is increased if the treatment is seen to be ineffective, i.e. it does not restore serum DHEA to at least 15 nmol/L. Once a sufficient dose to restore DHEA levels has been established the dose is still increased to investigate if higher doses are optimal for enhancing the immune response. Research has demonstrated that complications such as infection commonly occur 1-2 weeks post trauma. Due to these findings, supplementation begins on day 8; DHEA is administered once daily for three days at 08:00. On day 7 after injury ten blood samples are taken at regular intervals across the day. On day 8 these samples are repeated after the first dose of DHEA has been administered. On day 9, 10 and 11 blood samples are taken once daily to assess DHEA levels, immune function and systemic inflammation. Urine samples are collected 24 hours a day from day 7 to day 11 to assess DHEA and other hormones in urine. Follow up is completed on day 12 as this covers a period of 48 hours after the last dose.

What are the possible benefits and risks of participating?
The benefits for participants are small, there will be increased monitoring of their progress throughout the study period. It is unknown how beneficial DHEA supplementation is in trauma patients, but it is unlikely that three doses of DHEA will have any enhanced effect on rate and/or degree of recovery. The main benefit of participating in this study is that this work will help to develop future studies exploring the effects of DHEA supplementation on healing, recovery and rehabilitation in severely injured patients. There is a minimal risk of side effects associated with the doses of DHEA and length of treatment in this study. A few studies have reported rare side effects associated with DHEA including: acne, mood swings, altered liver function, and in extremely rare occasions increased facial hair growth in women. However, these side effects are all related to long-term use of DHEA and it is extremely unlikely the participants will experience any of these side effects after 3 days of treatment. The risks associated with participation in the study are minimal. Blood samples and urine collection are a routine part of hospital medical care. The drawing of a blood sample, where possible, will be taken as an additional sample in routine blood sampling for clinical necessity. It is likely that some study sampling will be performed when there is no clinical need. A mid-line or cannulation will be used in all patients who do not have an A-line in situ to reduce discomfort of multiple samples on day 7 and 8. Nevertheless, the sample will be drawn by medical personnel well trained in this procedure and care will be taken to ensure that any discomfort is kept to a minimum.

Where is the study run from?
Queen Elizabeth Hospital Birmingham (UK)

When is the study starting and how long is it expected to run for?
March 2017 to April 2021

Who is funding the study?
1. AO Foundation (Switzerland)
2. NIHR Surgical Reconstruction and Microbiology Research Centre (SRMRC) (UK)
3. University Hospitals Birmingham Charity (UK)

Who is the main contact?
Amrita Athwal
a.k.athwal@bham.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Miss Amrita Athwal

ORCID ID

Contact details

D3B Team (Drugs
Devices
Diagnostics and Biomarkers)
5th Floor
Open Plan EAST
ITM
Heritage Building
Mindelson Way
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 8459
a.k.athwal@bham.ac.uk

Additional identifiers

EudraCT number

2016-004250-15

ClinicalTrials.gov number

Protocol/serial number

38158

Study information

Scientific title

A prospective, phase II, single centre, cross-sectional, randomised trial investigating dehydroepiandrosterone and its pharmacokinetics in trauma

Acronym

ADaPT

Study hypothesis

Hormones, such as Dehydroepiandrosterone (DHEA), play an important role in the body helping to maintain muscle mass and the immune system. The immune system helps the body recover from injury and fight off infection. Immediately after an injury DHEA levels have been shown to drop quickly and if DHEA levels are already low, as seen in older people, this puts them at increased risk of infection and reduces their chance of a full recovery. Previous research has shown in both young and old men and women that DHEA levels are below normal levels for as long as 3 months after injury. As a result, the trialists believe giving trauma patients DHEA to boost DHEA levels in the blood could improve the immune response and speed up recovery. The aim of this trial is to work out what dose of DHEA (50, 100 or 200mg per day) will increase patient’s DHEA levels to those seen in a healthy young adult males. It will also work out what is the best method of delivering the DHEA into the body either by an oral tablet that is swallowed or a tablet that is placed under the tongue and dissolves.

Ethics approval

West Midlands – Coventry and Warwickshire Research Ethics Committee, ref: 18/WM/0102 - approval pending

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

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

Condition

Specialty: Injuries and Emergencies, Primary sub-specialty: Injuries and emergencies; UKCRC code/ Disease: Injuries and accidents/ Injuries to the hip and thigh, Injuries and accidents/ Injuries to unspecified part of trunk, limb or body region

Intervention

This is an efficacy dose-finding trial with two objectives. Firstly, to establish a dose sufficient to raise DHEA levels to those seen in healthy young adult males. Secondly, to establish an optimal dose for enhancing the immune response post trauma. This trial is investigating 3 doses of DHEA: 50, 100 and 200 mg and 2 methods of delivery (oral and sublingual tablets). The patient population will be generated from male and female patients attending the Major Trauma Centre (MTC) and Critical Care Unit (ITU) at University Hospital Birmingham Foundation Trust (UHBFT) with a traumatic injury and an additional patient group of older (>50 years old) female patients with a hip fracture. Patients will be randomised to receive the doses of DHEA via either oral tablets or sublingual tablets for the 3 day treatment period. This creates six cohorts: oral–male trauma, sublingual-male trauma, oral–female trauma, sublingual–female trauma, oral–hip fracture, sublingual-hip fracture. Up to 15 patients in each cohort will be treated and assessed. Thus, a maximum of 270 patients will receive DHEA supplementation. However, an adaptive design will be used with regular analyses to stop early in any particular cohort of 15 and dose escalate if the treatment is seen to be inactive, i.e. it does not restore serum DHEA to at least 15 nmol/L. Once a sufficient dose to restore DHEA levels has been established the dose will still be escalated to investigate if higher doses are optimal for enhancing the immune response. Due to the nature of the injuries, informed consent is likely to be obtained from professional legal representatives or personal legal representatives in the first instance, consent from the patient will be obtained as soon as they have capacity.

A blood sample will be taken within 24 hours of the injury if the patients are admitted within this time frame. This sample will be used to assess the acute response of DHEA and immune markers to injury. Patients will be randomised before day 7 to receive the dose of DHEA via either oral tablets or sublingual (under the tongue) tablets. Randomisation will occur on the electronic Clinical Research Tool (CREST) system. A 1:1 allocation ratio will be used. Research has demonstrated that post injury complications such as infection commonly occur 1-2 weeks post trauma. Due to these findings, supplementation will begin on day 8; DHEA will be administered once daily for three days at 08:00. On day 7 post injury ten blood samples will be taken at regular intervals across the day to observe the time course of serum DHEA, the sulphated form DHEAS will also be measured. On day 8 these bloods will be repeated after the first dose of DHEA has been administered. On day 9, 10 and 11 blood samples will be taken once daily to assess DHEA levels, immune function and systemic inflammation. Urine samples will be collected 24 hours a day from day 7 to day 11 to assess DHEA and other hormones within urine. Follow up will be completed on day 12 as this will cover a period of 48 hours post the last IMP dose.

Intervention type

Drug

Phase

Not Applicable

Drug names

Dehydroepiandrosterone

Primary outcome measure

Serum DHEA after DHEA supplementation; assessed by mass spectrometry of blood samples collected at:
- 2-4 hours post dose, 4-8 hours post dose and 10 hours post dose on day 8
- 2-4 hours post dose on day 9
- 2-4 hours post dose on day 10
- 24 hours post last dose on day 11
- 48 hours post last dose on day 12

Secondary outcome measures

1. Neutrophil function such as superoxide production and phagocytosis measured using blood samples collected at the following timepoints:
- Within 24 hours of trauma (Day 0, if possible)
- 08:00 on days 7-12
2. Pro and anti-inflammatory cytokines measured using blood samples collected at the following timepoints:
- Within 24 hours of trauma (Day 0, if possible)
- 08:00 on days 7-12
3. Tolerance, measured by gastric residual volumes (GRV) collected at 08:00 on the days where a nasogastric or nasojejunal tube is in situ

Overall trial start date

01/03/2017

Overall trial end date

01/04/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Trauma patients:
1. 16 - 50 years of age
2. Severe trauma injury (Injury severity score (ISS) ≥16 and ≤50)
3. Admitted to University Hospital Birmingham within 6 days of trauma
4. Anticipated to be an inpatient for the 11 day trial period

Hip fracture patients:
1. 50 years or age and older
2. Female
3. Neck of Femur fracture
4. Admitted to University Hospital Birmingham within 6 days of fracture
5. Anticipated to be an inpatient for the 11 day trial period

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 270; UK Sample Size: 270

Participant exclusion criteria

Trauma patients:
1. Ages <16 or >51 years of age
2. ISS <16 or >50
3. Isolated brain injury
4. Unlikely to survive the study period
5. Previous or known hormone sensitive malignancy
6. Known Prostatic hypertrophy (M)
7. Female patients taking Hormone Replacement Therapy medication
8. Intake of any drugs that is likely to influence the metabolism of steroids, in particular inducers and inhibitors of the drug-metabolising enzyme CYP3A4 in the last 3 months
9. Pre-existing liver impairment or chronic liver failure
10. Previous or current malignancy or invasive cancer diagnosed within the past 3 years except for adequately treated basal cell and squamous cell carcinoma of the skin and in situ carcinoma of the uterine cervix
11. Prescribed antipsychotic medication
12. Pregnant and/or breastfeeding females
13. Known hypersensitivity to the active substance or excipient
14. Known thromboembolic events in the last 12 months and any pre-disposition to thrombosis e.g. factor V leiden

Hip fracture patients:
1. <50 years of age
2. Unlikely to survive the study period
3. Previous or known hormone sensitive malignancy
4. Intake of any drugs that is likely to influence the metabolism of steroids, in particular inducers and inhibitors of the drug-metabolising enzyme CYP3A4 in the last 3 months
5. Known pre-existing liver impairment or chronic liver failure
6. Previous or current malignancy or invasive cancer diagnosed within the past 3 years except for adequately treated basal cell and squamous cell carcinoma of the skin and in situ carcinoma of the uterine cervix
7. Prescribed antipsychotic medication
8. Pregnant and/or breastfeeding
9. Known hypersensitivity to the active substance or excipient
10. Patients on Hormone Replacement Therapy medication
11. Known thromboembolic events in the last 12 months and any pre-disposition to thrombosis e.g. factor V leiden

Recruitment start date

01/10/2018

Recruitment end date

01/04/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Queen Elizabeth Hospital Birmingham
Mindelsohn Way Edgbaston
Birmingham
B15 2WB
United Kingdom

Sponsor information

Organisation

University Hospitals Birmingham NHS Foundation Trust

Sponsor details

c/o Dr Chris Counsell
Trust HQ
PO Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 4185
chris.counsell@uhb.nhs.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

AO Foundation

Alternative name(s)

AO

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

Switzerland

Funder name

NIHR Surgical Reconstruction and Microbiology Research Centre (SRMRC)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

University Hospitals Birmingham Charity

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal approximately one year after overall trial end date. Additional documents are not publically available.

IPD sharing statement
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Intention to publish date

Participant level data

Other

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes