Dose assessment of melatonin in sepsis trial
| ISRCTN | ISRCTN70688534 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN70688534 |
| EudraCT/CTIS number | 2014-002840-42 |
| ClinicalTrials.gov number | NCT02319265 |
| Secondary identifying numbers | 3/035/14 |
- Submission date
- 01/07/2014
- Registration date
- 29/08/2014
- Last edited
- 26/09/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
Sepsis is a common condition caused by an infection, whereby the bodys immune system goes into overdrive. It can lead to, among other things, widespread inflammation, body swelling and a drop in blood pressure. Low blood pressure can then result in a reduced blood supply to vital organs, such as the brain and the heart. If not treated quickly, sepsis can cause multiple organ failure and death. Sepsis is a major cause of death for patients in intensive care units (ICU). Some 30% of patients currently die from the condition. Melatonin is a hormone naturally produced in the body. It is often referred to as the sleep hormone as it is given as a medicine to help people with insomnia (difficulty sleeping). However, it has proved to be a very versatile molecule; scientists has shown that it may have many health benefits. One of these is its antioxidant effects, mopping up the otherwise cell-damaging free radicals in our bodies. Research has also found that it reduces the inflammatory response to infection. We have recently undertaken a study that showed that, in healthy people, doses of oral melatonin are well tolerated and have no side effects. In this study, we want to find out two things. The first is whether or not oral melatonin is well tolerated in patients with sepsis as well as in healthy people. The second is whether the hormone is safe and how well it treats sepsis in patients compared to a placebo, or dummy, pill. The ultimate aim is to reduce the number of patients that die from sepsis, but for this early study, we hope to be able to identify a substance we can measure in blood which reflects the beneficial effect of melatonin.
Who can participate?
Patients over 16 years of age that have, or are suspected of having, sepsis and showing signs of pneumonia.
What does the study involve?
The study has two stages. In stage 1, two small groups of patients are given one dose of either 50 mg or 100 mg of melatonin. This is done to see whether the doses are well tolerated in sepsis patients. In stage 2, patients are randomly allocated into one of two groups. Patients in group 1 are given melatonin for 72 hours. Patients in group 2 are given a placebo. The effects of the hormone compared to the placebo are then analysed, using a number of measures.
What are the possible benefits and risks of participating?
For those patients given melatonin there is possibility of benefit by reduction of inflammation.
Where is the study run from?
The University of Aberdeen (UK)
When is the study starting and how long is it expected to run for?
October 2014 to June 2017
Who is funding the study?
Chief Scientist Office for Scotland (UK)
Who is the main contact?
Prof. Helen Galley
Contact information
Public
Institute of Medical Sciences
School of Medicine, Medical Sciences and Nutrition
University of Aberdeen
Aberdeen
AB25 2ZD
United Kingdom
| h.f.galley@abdn.ac.uk |
Study information
| Study design | Stage 1: Phase I open-label two-dose cohort study Stage 2: Phase II pilot double blinded randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Dose Assessment of Melatonin in SEpsis triaL: a pilot phase I/II study |
| Study acronym | DAMSEL 2 |
| Study hypothesis | DAMSEL 2 is a pilot Phase I/II study in patients with sepsis. Stage 1 will assess the pharmacokinetics of melatonin and its major metabolite after 2 doses of exogenous melatonin in order to make dosing and dosing interval decisions for Stage 2. Stage 2 is a double blind randomised controlled trial of melatonin in patients with sepsis at the dose and dosing interval decided after Stage 1. Measurements of melatonin and its major metabolite, and an array of biomarkers of inflammation and oxidative stress will be made. |
| Ethics approval(s) | Scotland A REC, 16/12/2014, ref: 14/SS/1078 |
| Condition | Sepsis due to community acquired pneumonia |
| Intervention | Stage 1: Two small groups of patients will receive a single dose of either 50 mg or 100 mg of melatonin. Stage 2: Patients will be randomly allocated into either: Group 1 - these patients will receive melatonin for 72 hours Group 2 - these patients will receive a placebo for 72 hours |
| Intervention type | Other |
| Primary outcome measure | Stage 1: Adminstration of 2 oral melatonin doses with no SUSARs Stage 2: Approval by the DMC of dose and dosing interval decisions The ultimate goal of experimental therapies in sepsis is reduced mortality. However, using mortality as an endpoint in a pilot study such as this is clearly not feasible. A panel of biomarkers will be used which are surrogates of outcome from sepsis. All outcomes other than final outcome will be measured daily during the ICU stay. Final outcome is mortality at 28d. |
| Secondary outcome measures | 1. Tissue specific injury markers, cytokines, adhesion molecules and chemokines: IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, pentraxin-3, RANTES, MCP-1, MIP1alpha NGAL, SP-D, MMP-9, VCAM-1, P-selectin and TIMP-1. 2. Key clinical parameters including: heart rate, mean arterial pressure, temperature, acute physiologial and chronic health evaluation (APACHE) II score, length of ICU stay, ICU- and 28 day- all cause mortality, daily sequential organ failure score, time on vasopressor support 3. Time on the ventilator and ventilator settings such as positive end expiratory pressure, peak inspiratory pressure and minute volume 4. Ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FIO2 ratio) All outcomes other than final outcome will be measured daily during the ICU stay. Final outcome is mortality at 28d. |
| Overall study start date | 01/10/2014 |
| Overall study end date | 28/02/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 10 + 40 |
| Total final enrolment | 10 |
| Participant inclusion criteria | Patients who are within 24h of fulfilling the criteria for sepsis with clinical suspicion of community acquired pneumonia and the presence of chest X-ray changes consistent with pneumonia will be recruited. The criteria for sepsis are clinical suspicion or evidence of acute infection plus systemic inflammatory response syndrome, defined by two or more of the following: 1. Core temperature <36 or >38°C 2. Tachycardia: heart rate > 90 beats/min 3. Tachypnoea: respiratory rate > 20 breaths/min or ventilated 4. Leucocyte count >12 x 10^9/L or <4 x 10^9/L |
| Participant exclusion criteria | 1. Anyone <16 years old 2. Life expectancy <24h 3. Metastatic cancer or immunosuppression 4. Taking steroids (>20mg/d prednisolone or equivalent, used regularly for >2 weeks prior to ICU admission) 5. Premenopausal females without a negative pregnancy test or a history of surgical sterilization. 6. Patients receiving fluvoxamine or nifedipine 7. Consent refusal |
| Recruitment start date | 08/01/2018 |
| Recruitment end date | 30/04/2021 |
Locations
Countries of recruitment
- Scotland
- United Kingdom
Study participating centre
Aberdeen
AB25 2ZN
United Kingdom
Sponsor information
University/education
Research Governance Office
Foresterhill House Annexe
Foresterhill
Aberdeen
AB25 2ZB
Scotland
United Kingdom
"ROR" |
https://ror.org/016476m91 |
|---|
Funders
Funder type
Government
Government organisation / Local government
- Alternative name(s)
- CSO
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/03/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The protocol is not published and is not available online. Requests to access it will not be unreasonably refused. Planned publication of the study results in a high-impact peer reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Helen Galley. Type of data: pharmacokinetic data (biochemical analysis of melatonin and major metabolite in serum). When the data will become available: after publication. For how long: no restriction. By what access criteria data will be shared including with whom: bona fide researchers in the field of melatonin. For what types of analyses: to support other trials of melatonin. By what mechanism: email request with detailed description of reason/purpose. Whether consent from participants was obtained: yes. Comments on data anonymisation: all data completely anonymous. Any ethical or legal restrictions, any other comments: acknowledgement/citation of source of data. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 6.0 | 28/01/2020 | 20/09/2022 | No | No |
| Results article | 31/08/2022 | 20/09/2022 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
26/09/2022: Total final enrolment added.
20/09/2022: Publication reference added and protocol (not peer reviewed) uploaded.
03/12/2020: The recruitment end date was changed from 01/12/2020 to 30/04/2021.
17/06/2020: The public contact details have been made publicly visible.
23/04/2020: Due to current public health guidance, recruitment for this study has been paused.
11/03/2020: The overall end date was changed from 01/03/2021 to 28/02/2022.
12/12/2019: The EudraCT number was added.
30/07/2019: ClinicalTrials.gov number added.
04/07/2018: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/07/2017 to 08/01/2018.
2. The recruitment end date was changed from 30/06/2019 to 01/12/2020.
3. The overall trial end date was changed from 01/06/2017 to 01/03/2021.
4. Publication and dissemination plan and IPD sharing statement added.
24/04/2017: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/06/2016 to 01/07/2017.
2. The recruitment end date was changed from 31/05/2018 to 30/06/2019.
19/02/2016: The overall trial end date was changed from 30/09/2016 to 01/06/2017.
