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Medication administered by family / carer for symptoms

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

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

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.

PecFent and Epistatus

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

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.

Epistatus Alone

Paul Perkins, MB BCh FRCP (UK)

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.

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.

Nasal Fentanyl and Buccal Midazolam for Dying Patients

Can Nasal Fentanyl and Buccal Midazolam Give Better Symptom Control for Dying Patients When Compared With Standard Subcutaneous Medication? Pilot Randomised Controlled Trial and Qualitative Interview Study.

Happy for researchers to contact us once data has been analysed and published

Data will be captured by patient and/or carer and/or staff with regard to time from need for breakthrough medication (recognition of symptom) to adequate symptom control ('comfortable').

Data will be captured by patient and/or carer and/or staff with regard to time from need for breakthrough medication (recognition of symptom) to administration of drug.

Data will be captured by patient and/or carer and/or staff with regard to need for additional oral or subcutaneous medication

Data will be captured by patient and/or carer and/or staff with regard to symptoms recurring.

The modified Palliative care Outcome Scale Symptom list (POS-S) (patient /carer/ staff versions) at approximately the same time daily (depending on when family / carers are likely to be present).

For this study the Palliative care Outcome Scale Symptom list (known as POS-S) has been modified by removing the question on 'Any other symptoms' and with the addition of the anxiety question from the Integrated Palliative care Outcome Scale (IPOS).

Visual analogue scales for pain and agitation completed by patient (where possible), relatives and staff at baseline (Time X), time 0 (dose), 5, 10, 15, 20, 25 and 30 minutes (post-dose calculated from time 0) for 1 breakthrough episode per day

Adverse event information will be collected by research staff.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Nasal Fentanyl and Buccal Midazolam for Dying Patients	NCT02009306	Terminal Cancer	PecFent and Epi... Standard subcut... Epistatus Alone	18 Years -	Gloucestershire Hospitals NHS Foundation Trust
Nasal Fentanyl and Buccal Midazolam for Dying Patients	NCT02009306	Terminal Cancer	PecFent and Epi... Standard subcut... Epistatus Alone	18 Years -	Gloucestershire Hospitals NHS Foundation Trust

Spots Global Cancer Trial Database for epistatus alone