Disorders of ConsciousnessPhase 1NCT04330547

Use of Analgesic Treatment to Reduce Signs of Pain in Patients With Disorders of Consciousness.

A Phase 1 study testing Analgesic administration in people with Disorders of Consciousness and Severe Brain Injury, run by University of Liege at 1 site in Belgium.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The purpose of this study is to characterize and improve pain and nociception management in patients with disorders of consciousness (DOC). This project is divided into two phases, a first phase to evaluate pain level and a second phase which consist of a clinical trial to evalute pain medication efficacy. Read more about this study

Who is it for?: Ages 16 to 99 years
Conditions the study is for: Disorders of Consciousness, Severe Brain Injury, Post-comatose Non-communicative Patients
What is being tested?: Analgesic administration
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 19 participants
Where: 1 siteBelgium
Study dates: 21 Feb 2018to 28 Apr 2021
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 16 to 99 years
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

Have had an acquired brain injury with a loss of consciousness > 28 days (patients) or have no history of previous brain injury (healthy controls)
Legally authorized surrogate available to provide informed consent.
Diagnosis of vegetative/unresponsive (VS/UWS) or minimally conscious state (MCS) or emergence of the minimally conscious state without communication (eMCS; as defined by the CRS-R, see above).
Medically stable (i.e., no systemic illness or disease).
Patients with NCS-R score during mobilization above or equal to the previously determined cut-off score or NCS-R scores during mobilization equivalent to NCS-R score obtain during nociceptive stimulation will be included in the second phase of the study (i.e. D1 and D2).

Who cannot join

History of developmental, neurologic, or major psychiatric disorder resulting in functional disability.
Contraindication or unwillingness to discontinuing sedating and centrally-active drugs (benzodiazepine, long-acting sedating drugs) within 48 hours of assessment.
Upper limb contusions, fractures or flaccid paralysis.
Uncontrolled epilepsy and already on level 1 drugs

Trial locations and contacts

1 site in 1 country.

Belgium1 site

Centre Hospitalier Universitaire de Liège
Liège, 4000

Other trials in Belgium

About this study

Official title: Use of Analgesic Treatment to Reduce Signs of Pain in Patients With Disorders of Consciousness: a Double-blind Placebo-controlled Clinical Study.

The main aim is to evaluate the use of the Nociception Coma Scale-Revised (NCS-R) and its cut-off score (i.e., 5) as an assessment and management tool to define guidelines for managing pain in patients with DOC. In this double-blind, placebo-controlled clinical study, we will evaluate the use of analgesic treatments in reducing pain in subacute/chronic patients. The project will also allow us to validate the NCS-R cut-off score defined previously.

Read the detailed description

The study will be performed within one week (i.e, 7 days) and consists of two phases:

Phase 1 "Patients selection (D0)": Patients will be assessed by the NCS-R during experimental stimulation (rest, tactile, noxious) and mobilizations (physiotherapy). Patients with potential pain will be included in the phase 2.
Phase 2 "Analgesic administration (D1 and D2)": double-blind placebo-controlled randomized clinical trial on potential responders identified in phase 1. A medical doctor of our team will suggest to the physician in charge to prescribe the dedicated medication. One placebo and one real treatment will be administered on day 1 and 2 by the nurses at least half-hour before the physiotherapy. Randomization between day 1 and 2 will be applied at that time.

For each day of phase 1 and 2, several assessments will be performed: NCS-R, CRS-R and spasticity assessment.

Conditions: Disorders of Consciousness, Severe Brain Injury, Post-comatose Non-communicative Patients, Vegetative State, Minimally Conscious State
Being tested: Analgesic administration, Placebo administration
Keywords: Nociception, Pain, Disorder of Consciousness, Nociception coma scale revised
Medical subject headings: Consciousness Disorders, Brain Injuries, Persistent Vegetative State, Pain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Analgesic administrationDrug
- Level 1 : Paracétamol 1g/Acetaminophène 1g, Ibuprofène 600mg, Diclofénac 50mg.
- Level 2: Tramadol 50mg.
- Level 3: Oxycodone 5mg, Morphine sulfate 10mg.
- Increase of a prior level 3 medication :
1. 1/6 of the total dose of daily level 3 medication (e.g. the patient receives 30mg of oxycodone a day. He will be administered a single dose of 5 mg for the study), defined as a breakthrough dose in the management of chronic pain. To standardize the treatment, the dose of the prior level 3 medication will be converted to oxycodone. Several online tools exist to do the conversion between opioids (e.g. mobile app Orthodose ®).
2. If the oral intake or the gastrostomy use is not possible, the breakthrough dose will be administered by subcutaneous route. The dose will also be 1/6 of the daily dose and will be converted to injectable morphine. Conversion to injectable morphine will be performed with any equivalence tool (such as the mobile app Orthodose ®)
Placebo administrationDrug
Folavit (folic acid, 0.4 mg)

Study groups in NCT04330547
Study group	Role	What they receive
Analgesic administration	Active comparator	The analgesic treatment will be tailored to the patient's medication and will be based on 3 levels (based on Ventafridda et al., 1985): * Level 1 : Non-opioid analgesics * Level 2 : Weak opioids analgesics * Level 3 : Strong opioids analgesics If the patient is already on pain medications, we will add the lowest effective dose of the level above the level of the regular pain medications of the patient. (e.g. if the patient has no analgesic treatment, he will be given a non-opioid analgesic (level 1). If he already has a level 1 treatment, we will go for level 2 medication. If he has level 2 treatment, we will go for level 3. And if the patient is already at level 3, we will increase the dosage by steps (reference: 5mg oxycodone as first choice for level 3 drugs)). Preferably, the medication will be administered by oral intake or gastrostomy feeding tube. If it is not possible, other routes of administration are allowed. Receives: Drug: Analgesic administration
Placebo administration	Placebo comparator	Folavit capsules will be used as a placebo Receives: Drug: Placebo administration

What is being measured

The primary outcome is the main question the study is designed to answer.

Nociception Coma Scale-Revised (NCS-R)
The NCS-R (Chatelle et al., 2012) is used to assess the perception of acute pain in patients with disorders of consciousness. It is composed of 3 subscales (motor, verbal and facial expressions) respectively scoring from 0 (no response) to 3 (highest response level). Here the NCS-R is administered in 4 different conditions: at rest, during tactile stimulation, during experimental nociceptive stimulation (pressure on the bed of the left and right nail) and during mobilization (physiotherapy).
Measured: through study completion, an average of 2 years
Coma Recovery Scale-Revised (CRS-R)
The CRS-R (Giacino et al., 2004) is the gold standard for the behavioural assessment of the level of consciousness and is widely used in patients with chronic disorders of consciousness. The CRS-R is composed of six subscales that assess the following domains: visual, motor, auditory and oro-motor/verbal functions, as well as communication, and arousal. The score ranges from 0 to 23, in which the lowest score indicates coma and the highest score indicates the emergence from the minimally conscious state. The diagnosis is made according to the presence\absence of particular behavioural responses.
Measured: through study completion, an average of 2 years

Secondary outcomes (1)

Modified Ashworth Scale (MAS)
The MAS (Bohannon et al., 1987) is used to assess spasticity (reflex contraction in response to passive stretching). This is a scoring scale from 0 (no increase in muscle tone) to 4 (very strong increase in tone, stiffness), which will depend on the speed of execution of the movement (the faster the limb will be mobilized the more spastic it will be) and which must be performed at least 3 times for each joint.
Measured: through study completion, an average of 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

21 Feb 201828 Apr 2021

First posted1 Apr 2020
Study start21 Feb 2018
Primary completion19 Feb 2019
Study completion28 Apr 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (4)Papers the sponsor has linked to this study.
Other trials for Disorders of ConsciousnessStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Supportive care
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 19 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04330547
Sponsor's protocol ID: 2019-86
Other IDs: 2009-241
Status last verified: Apr 2021
First submitted: 9 Mar 2020
Last updated: 3 May 2021
Results posted: No
FDA-regulated drug: No
FDA-regulated device: No

Publications

Ventafridda V, Saita L, Ripamonti C, De Conno F. WHO guidelines for the use of analgesics in cancer pain. Int J Tissue React. 1985;7(1):93-6.
PubMed 2409039
Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004 Dec;85(12):2020-9. doi: 10.1016/j.apmr.2004.02.033.
PubMed 15605342
Bohannon RW, Larkin PA, Smith MB, Horton MG. Relationship between static muscle strength deficits and spasticity in stroke patients with hemiparesis. Phys Ther. 1987 Jul;67(7):1068-71. doi: 10.1093/ptj/67.7.1068.
PubMed 3602099
Chatelle C, Majerus S, Whyte J, Laureys S, Schnakers C. A sensitive scale to assess nociceptive pain in patients with disorders of consciousness. J Neurol Neurosurg Psychiatry. 2012 Dec;83(12):1233-7. doi: 10.1136/jnnp-2012-302987. Epub 2012 Aug 20.
PubMed 22906615

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 3 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Use of Analgesic Treatment to Reduce Signs of Pain in Patients With Disorders of Consciousness: a Double-blind Placebo-controlled Clinical Study.
ClinicalTrials.gov ID: NCT04330547
Acronym / sponsor ID: 2019-86
Conditions: Disorders of Consciousness, Severe Brain Injury, Post-comatose Non-communicative Patients, Vegetative State, Minimally Conscious State
Keywords: Nociception, Pain, Disorder of Consciousness, Nociception coma scale revised
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 19 participants (actual)
Lead sponsor: University of LiegeUniversity, hospital or other
Study start: 21 Feb 2018 (actual)
Primary completion: 19 Feb 2019 (actual)
Study completion: 28 Apr 2021 (actual)
First posted: 1 Apr 2020 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

The study will be performed within one week (i.e, 7 days) and consists of two phases:

Phase 1 "Patients selection (D0)": Patients will be assessed by the NCS-R during experimental stimulation (rest, tactile, noxious) and mobilizations (physiotherapy). Patients with potential pain will be included in the phase 2.
Phase 2 "Analgesic administration (D1 and D2)": double-blind placebo-controlled randomized clinical trial on potential responders identified in phase 1. A medical doctor of our team will suggest to the physician in charge to prescribe the dedicated medication. One placebo and one real treatment will be administered on day 1 and 2 by the nurses at least half-hour before the physiotherapy. Randomization between day 1 and 2 will be applied at that time.

For each day of phase 1 and 2, several assessments will be performed: NCS-R, CRS-R and spasticity assessment.

Study design

Primary purpose: Supportive care
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Analgesic administration	Active comparator	Drug: Analgesic administrationThe analgesic treatment will be tailored to the patient's medication and will be based on 3 levels (based on Ventafridda et al., 1985): * Level 1 : Non-opioid analgesics * Level 2 : Weak opioids analgesics * Level 3 : Strong opioids analgesics If the patient is already on pain medications, we will add the lowest effective dose of the level above the level of the regular pain medications of the patient. (e.g. if the patient has no analgesic treatment, he will be given a non-opioid analgesic (level 1). If he already has a level 1 treatment, we will go for level 2 medication. If he has level 2 treatment, we will go for level 3. And if the patient is already at level 3, we will increase the dosage by steps (reference: 5mg oxycodone as first choice for level 3 drugs)). Preferably, the medication will be administered by oral intake or gastrostomy feeding tube. If it is not possible, other routes of administration are allowed.
Placebo administration	Placebo comparator	Drug: Placebo administrationFolavit capsules will be used as a placebo

Who may qualify

Ages: 16 to 99 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (5 listed)

Have had an acquired brain injury with a loss of consciousness > 28 days (patients) or have no history of previous brain injury (healthy controls)
Legally authorized surrogate available to provide informed consent.
Diagnosis of vegetative/unresponsive (VS/UWS) or minimally conscious state (MCS) or emergence of the minimally conscious state without communication (eMCS; as defined by the CRS-R, see above).
Medically stable (i.e., no systemic illness or disease).
Patients with NCS-R score during mobilization above or equal to the previously determined cut-off score or NCS-R scores during mobilization equivalent to NCS-R score obtain during nociceptive stimulation will be included in the second phase of the study (i.e. D1 and D2).

Key exclusion criteria (4 listed)

History of developmental, neurologic, or major psychiatric disorder resulting in functional disability.
Contraindication or unwillingness to discontinuing sedating and centrally-active drugs (benzodiazepine, long-acting sedating drugs) within 48 hours of assessment.
Upper limb contusions, fractures or flaccid paralysis.
Uncontrolled epilepsy and already on level 1 drugs

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Analgesic administration* Level 1 : Paracétamol 1g/Acetaminophène 1g, Ibuprofène 600mg, Diclofénac 50mg. * Level 2: Tramadol 50mg. * Level 3: Oxycodone 5mg, Morphine sulfate 10mg. * Increase of a prior level 3 medication : 1. 1/6 of the total dose of daily level 3 medication (e.g. the patient receives 30mg of oxycodone a day. He will be administered a single dose of 5 mg for the study), defined as a breakthrough dose in the management of chronic pain. To standardize the treatment, the dose of the prior level 3 medication will be converted to oxycodone. Several online tools exist to do the conversion between opioids (e.g. mobile app Orthodose ®). 2. If the oral intake or the gastrostomy use is not possible, the breakthrough dose will be administered by subcutaneous route. The dose will also be 1/6 of the daily dose and will be converted to injectable morphine. Conversion to injectable morphine will be performed with any equivalence tool (such as the mobile app Orthodose ®)	Drug	Analgesic administration
Placebo administrationFolavit (folic acid, 0.4 mg)	Drug	Placebo administration

Primary outcome

Nociception Coma Scale-Revised (NCS-R)
Time frame: through study completion, an average of 2 years
The NCS-R (Chatelle et al., 2012) is used to assess the perception of acute pain in patients with disorders of consciousness. It is composed of 3 subscales (motor, verbal and facial expressions) respectively scoring from 0 (no response) to 3 (highest response level). Here the NCS-R is administered in 4 different conditions: at rest, during tactile stimulation, during experimental nociceptive stimulation (pressure on the bed of the left and right nail) and during mobilization (physiotherapy).
Coma Recovery Scale-Revised (CRS-R)
Time frame: through study completion, an average of 2 years
The CRS-R (Giacino et al., 2004) is the gold standard for the behavioural assessment of the level of consciousness and is widely used in patients with chronic disorders of consciousness. The CRS-R is composed of six subscales that assess the following domains: visual, motor, auditory and oro-motor/verbal functions, as well as communication, and arousal. The score ranges from 0 to 23, in which the lowest score indicates coma and the highest score indicates the emergence from the minimally conscious state. The diagnosis is made according to the presence\absence of particular behavioural responses.

1 secondary outcome

Modified Ashworth Scale (MAS)
Time frame: through study completion, an average of 2 years

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 3 May 2021.
Background: PubMed 2409039Ventafridda V, Saita L, Ripamonti C, De Conno F. WHO guidelines for the use of analgesics in cancer pain. Int J Tissue React. 1985;7(1):93-6.
Background: PubMed 15605342Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004 Dec;85(12):2020-9. doi: 10.1016/j.apmr.2004.02.033.
Background: PubMed 3602099Bohannon RW, Larkin PA, Smith MB, Horton MG. Relationship between static muscle strength deficits and spasticity in stroke patients with hemiparesis. Phys Ther. 1987 Jul;67(7):1068-71. doi: 10.1093/ptj/67.7.1068.
Background: PubMed 22906615Chatelle C, Majerus S, Whyte J, Laureys S, Schnakers C. A sensitive scale to assess nociceptive pain in patients with disorders of consciousness. J Neurol Neurosurg Psychiatry. 2012 Dec;83(12):1233-7. doi: 10.1136/jnnp-2012-302987. Epub 2012 Aug 20.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Steven Laureys, M.D., P.h.D study director

Centre du Cerveau, Coma Science Group (GIGA Consciousness)

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Analgesic administration in people with Disorders of Consciousness and Severe Brain Injury, run by University of Liege at 1 site in Belgium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Nociception Coma Scale-Revised (NCS-R) (time frame: through study completion, an average of 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04330547, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2021.