Nasal Fentanyl and Buccal Midazolam for Dying Patients

NCT ID: NCT02009306

Last Updated: 2018-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-23
• Study Completion Date: 2018-02-28

Brief Summary

When patients are dying they become unable to take oral medication and if they develop symptoms (e.g. pain or agitation) they need to be given a subcutaneous injection of medication. If they are at home this requires that a District Nurse is called and it can take a long time (sometimes hours) for the Nurse to arrive. This can be a very stressful time for the patient and family.

There are 2 drug preparations which could potentially be given by family members in the home:

Nasal fentanyl (PecFent) Buccal midazolam (Epistatus) If these preparations helped symptoms this would give much quicker symptom control for patients and might mean the District Nurse visit was not needed.

In advance of a community based randomised trial of these modes of administration, it is important to assess the feasibility of such an approach in terms of carer acceptability and patient tolerability as well as determine appropriate sample sizes and sampling methods. There are 2 work packages which would help assess feasibility of a community trial:

1. An open label randomised controlled trial comparing the use of PecFent with or without Epistatus versus standard subcutaneous breakthrough medication for the management of breakthrough pain (with or without agitation) in dying hospice patients who either remain in the hospice or go home.

2. A qualitative interview study to capture the thoughts of relatives of these patients about the use of these preparations.

Detailed Description

This will be an open-label, randomized, controlled feasibility pilot study to evaluate whether using nasal fentanyl (PecFent: 100, 200, 400 or 800 mcg) alone or in combination with buccal midazolam (Epistatus: 2.5, 5 or 10 mg) has the possibility to give better breakthrough symptom control to dying patients when compared with standard subcutaneous medication (Figure 1 A and B).

Each subject and their carers/family members will receive verbal and written information followed by signing of the Informed Consent Forms (ICFs). The study is divided into two arms. In both arms patients will receive standard regular oral or subcutaneous medication for relieving non-breakthrough symptoms. In the standard care arm, patients will receive standard as needed medication (SANM) administered orally, sublingually or subcutaneously for breakthrough symptoms. The experimental arm will consist of two stages: in Stage 1 of the study, PecFent will be given to patients in order to treat breakthrough pain instead of subcutaneous opioids. PecFent will be titrated in order to establish an effective treatment dose to manage pain. SANM administered orally, sublingually or subcutaneously will be used to treat agitation and other symptoms.

After the effective treatment dose of PecFent has been established patients will enter stage 2. Patients will not move to stage 2 if the treatment dose of PecFent is not deemed effective. Stage 2 will test a range of doses of Epistatus in terms of efficacy in treating agitation alone instead of subcutaneous midazolam (or in combination with the effective treatment dose of PecFent for pain and agitation).

SANM will be used to treat other symptoms. Assessment of effectiveness of any as needed medication will be conducted at 30 minutes from administration. If PecFent, Epistatus or a combination of both is ineffective, administration of SANM will be considered. Further opioid cannot be given within one hour but benzodiazepine can be given within 30 minutes as is standard practice in this setting. Thus, patients in the experimental arm will receive symptom relief regardless the efficacy of test drugs.

Conditions

Terminal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PecFent and Epistatus

Medication administered by family / carer for symptoms

Group Type: EXPERIMENTAL

PecFent and Epistatus

Intervention Type: DRUG

PecFent will be supplied by Archimedes Pharma as two strengths of nasal spray solution at 1000 or 4000 mcg/mL fentanyl (as citrate). One spray contains 100 mcg or 400 mcg fentanyl (as citrate). Each bottle contains 1.55 ml ensuring delivery of 8 sprays of 100 or 400 mcg fentanyl (as citrate). PecFent is a commercially available product and packaging will be in accordance with the manufacturing authorisations (EU/1/10/644/001, EU/1/10/644/002, EU/1/10/644/005, EU/1/10/644/003, EU/1/10/644/004, EU/1/10/644/006).

Epistatus will be supplied by Special Products Ltd. as buccal solution, packed in bottles containing solution for up to 4 x 1 ml doses, as per "Specials" licence. A pack also includes 4 x oral syringes used to administer the solution to the buccal cavity on either side of the mouth.

Standard subcutaneous medication

Intervention Type: DRUG

Subcutaneous as needed medication will include:

• Opioids for pain or dyspnoea

• Diamorphine
• Oxycodone
• Fentanyl
• Benzodiazepine and / or anti-psychotic for agitation

• Midazolam
• Levomepromazine
• Haloperidol Anti-emetic for nausea
• Cyclizine
• Metoclopramide
• Haloperidol
• Levomepromazine
• Anti-secretory drug for respiratory secretions
• Glycopyrronium
• Hyoscine butylbromide
• Hyoscine hydrobromide

Standard subcutaneous medication

Standard subcutaneous medication - diamophine and / or midazolam administered by nursing staff

Group Type: ACTIVE_COMPARATOR

Standard subcutaneous medication

Intervention Type: DRUG

Subcutaneous as needed medication will include:

• Opioids for pain or dyspnoea

• Diamorphine
• Oxycodone
• Fentanyl
• Benzodiazepine and / or anti-psychotic for agitation

• Midazolam
• Levomepromazine
• Haloperidol Anti-emetic for nausea
• Cyclizine
• Metoclopramide
• Haloperidol
• Levomepromazine
• Anti-secretory drug for respiratory secretions
• Glycopyrronium
• Hyoscine butylbromide
• Hyoscine hydrobromide

Epistatus Alone

From 28/11/17 following approval from sponsor, ethics committee and MHRA a 3rd observational arm was introduced:

Epistatus administered PRN by family / carer for symptoms

Group Type: EXPERIMENTAL

Standard subcutaneous medication

Intervention Type: DRUG

Subcutaneous as needed medication will include:

• Opioids for pain or dyspnoea

• Diamorphine
• Oxycodone
• Fentanyl
• Benzodiazepine and / or anti-psychotic for agitation

• Midazolam
• Levomepromazine
• Haloperidol Anti-emetic for nausea
• Cyclizine
• Metoclopramide
• Haloperidol
• Levomepromazine
• Anti-secretory drug for respiratory secretions
• Glycopyrronium
• Hyoscine butylbromide
• Hyoscine hydrobromide

Epistatus Alone

Intervention Type: DRUG

Epistatus will be supplied by Special Products Ltd. as buccal solution, packed in bottles containing solution for up to 4 x 1 ml doses, as per "Specials" licence. A pack also includes 4 x oral syringes used to administer the solution to the buccal cavity on either side of the mouth.

Interventions

PecFent and Epistatus

PecFent will be supplied by Archimedes Pharma as two strengths of nasal spray solution at 1000 or 4000 mcg/mL fentanyl (as citrate). One spray contains 100 mcg or 400 mcg fentanyl (as citrate). Each bottle contains 1.55 ml ensuring delivery of 8 sprays of 100 or 400 mcg fentanyl (as citrate). PecFent is a commercially available product and packaging will be in accordance with the manufacturing authorisations (EU/1/10/644/001, EU/1/10/644/002, EU/1/10/644/005, EU/1/10/644/003, EU/1/10/644/004, EU/1/10/644/006).

Epistatus will be supplied by Special Products Ltd. as buccal solution, packed in bottles containing solution for up to 4 x 1 ml doses, as per "Specials" licence. A pack also includes 4 x oral syringes used to administer the solution to the buccal cavity on either side of the mouth.

Intervention Type: DRUG

Standard subcutaneous medication

Subcutaneous as needed medication will include:

• Opioids for pain or dyspnoea

• Diamorphine
• Oxycodone
• Fentanyl
• Benzodiazepine and / or anti-psychotic for agitation

• Midazolam
• Levomepromazine
• Haloperidol Anti-emetic for nausea
• Cyclizine
• Metoclopramide
• Haloperidol
• Levomepromazine
• Anti-secretory drug for respiratory secretions
• Glycopyrronium
• Hyoscine butylbromide
• Hyoscine hydrobromide

Intervention Type: DRUG

Epistatus Alone

Epistatus will be supplied by Special Products Ltd. as buccal solution, packed in bottles containing solution for up to 4 x 1 ml doses, as per "Specials" licence. A pack also includes 4 x oral syringes used to administer the solution to the buccal cavity on either side of the mouth.

Intervention Type: DRUG

Other Intervention Names

Fentanyl and Midazolam; Subcutaneous opioids and midazolam; Midazolam

Eligibility Criteria

Inclusion Criteria

Adult hospice in-patients fitting the following criteria will be approached to see if they are willing to participate in the study:

1. diagnosis of terminal cancer and thought to have an estimated prognosis of between 1 and 2 weeks

2. have capacity to consent to participation

3. patients who, in the last 24 hours, have experienced at least one episode of breakthrough pain FOR ARMS 1 OR 2 (RCT) For Arm 3 must have had 1 episode of agitation necessitating the use of a benzodiazepine in the last 24 hours

4. taking 60mg or more of oral morphine (or its equivalent) per 24 hours FOR ARMS 1 OR 2 (RCT) IF taking less than this dose of opioid could be enrolled in Arm 3 (Epistatus alone - change in protocol implemented 28/11/17

5. have carers or family members who would be: willing to give the study medication to the patient likely to be at the hospice at least 50% of the time so that they are likely to be present to administer medication.

Exclusion Criteria

1. patients / carers / family members who in the opinion of the clinical team would be too distressed by the idea of participation

2. patients with disease of the nasal/buccal mucosa preventing effective absorption of medication

3. families who are unable to administer breakthrough medication e.g. problems with dexterity

4. history of substance abuse - patient or carer / family.

5. people who who might not adequately understand verbal explanations or written information given in English. The pilot is only recruiting 20 patients and Gloucestershire has a only a very small percentage of people who are not English speaking. It has been decided that it is not cost effective to fund translation for this pilot although this information will have to be taken into account when planning a larger study. We will capture information on the numbers of patients that may have been excluded and the languages that might have been needed.

6. Participated in a medicinal trial within the last four months following the guidance from the Association of the British Pharmaceutical Industry.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gloucestershire Hospitals NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Paul Perkins

Consultant in Palliative Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Paul Perkins, MB BCh FRCP (UK)

Role: PRINCIPAL_INVESTIGATOR

Gloucestershire Hospitals NHS Foundation Trust and

Locations

Sue Ryder Leckhampton Court Hospice

Cheltenham, Gloucestershire, United Kingdom

Countries

United Kingdom

References

Perkins P, Parkinson A, Akyea RK, Husbands E. Nasal fentanyl alone plus buccal midazolam: an open-label, randomised, controlled feasibility study in the dying. BMJ Support Palliat Care. 2020 Sep;10(3):300-303. doi: 10.1136/bmjspcare-2019-002029. Epub 2020 May 6.

Reference Type: DERIVED

PMID: 32376759 (View on PubMed)

Other Identifiers

PecEp1

Identifier Type: -

Identifier Source: org_study_id