Paracetamol (acetaminophen) route in palliative care (PC) patients: Intravenous versus subcutaneous route pharmacokinetics study protocol for a randomized pilot trial = ParaSCIVPallia

Background :Among palliative care patients, the subcutaneous route is often an alternative to the intravenous route, yet pharmacological and clinical data are lacking. Many French palliative teams are now empirically using paracetamol by the subcutaneous route, but there are no data to support this practice. Aim :Compare Design : A randomized, open, crossover study in two palliative care centres. The primary endpoints are AUC0-t, AUC0- ∞ , Cmax, and Vd et t1/2. All adverse events will be reported for a safety analysis. Setting/participants 20 adult palliative care patients with an IV device, having spontaneous pain, not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol in the usual treatment. They also have to meet all eligibility criteria. Conclusion : First pilot study comparing paracetamol intravenous versus subcutaneous route pharmacokinetics.


Abstract
Background :Among palliative care patients, the subcutaneous route is often an alternative to the intravenous route, yet pharmacological and clinical data are lacking. Many French palliative teams are now empirically using paracetamol by the subcutaneous route, but there are no data to support this practice.
Aim :Compare pharmacokinetic parameters between the intravenous and subcutaneous routes for PC patients.
Design : A randomized, open, crossover study in two palliative care centres. The primary endpoints are AUC0-t, AUC0-∞, Cmax, and Vd et t1/2. All adverse events will be reported for a safety analysis.
Setting/participants 20 adult palliative care patients with an IV device, having spontaneous pain, not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol in the usual treatment. They also have to meet all eligibility criteria.
Conclusion : First pilot study comparing paracetamol intravenous versus subcutaneous route pharmacokinetics.

Background
In France, paracetamol (acetaminophen) is the rst treatment, non-opioid, which is use in the current pain management. This treatment is prescribed in different route of administration for patients according to possibility to take it.
In palliative care, many injectable drugs are used by the subcutaneous (SC) route 1,2 to prevent the patient from having a venous track and iterative puncture or for patients with damaged venous access. Many French palliative teams are now empirically using paracetamol by the SC route 3 . A recent French study carried out by Leheup et al., 3 conducted in 160 patients hospitalized in the PC units of three hospitals in France from 2014 to 2017, evaluated the tolerability of SC paracetamol administration by a prospective multicentre observational study. Of the 160 patients, 44 (28%) presented at least one non-serious local adverse event (oedema in 29, erythema in 5, pain in 15, haematoma in 2, pruritus in 1, and localized in ammation in 2). No serious adverse events were observed. Factors associated with the occurrence of local adverse events were younger age, administration in the arm and thorax, and a high number of daily administrations. At minimum, this study shows a good safety of paracetamol using the SC route.
Sometimes, there is no any other alternative drug or route of administration: excessively poor venous access, no possibility of oral intake, or no possibility of mobilizing the patient for using the intrarectal route. Furthermore, the rectal route has an inconstant biodisponibility.
In the face of this, we built a pilot study to compare the pharmacokinetics (PK) of SC and intravenous (IV) routes in the same patient in a palliative care situation, to determine if there is a PK equivalence between Page 4/15 these two modes of administration.

Methods And Designs
The design of this study is based on other PK studies. [4][5][6][7][8] Study Setting This is a comparative, randomized, open, crossover, bicentre clinical trial (Pain and PC Department of University Hospital and Regional PC Unit, Fondation de la Miséricorde, Caen, France) with SC and IV paracetamol injections successively given to each patient.

Eligibility Criteria
Inclusion Criteria Patients having a low opioid less than 2 hours before or a strong opioid less than one hour before the beginning of administration of paracetamol 8-Patients having a fever

9-No possibility of communication Experimental Plan / Intervention
Patients will be screened by investigators according to eligibility criteria. Patients will be randomly assigned (by using an informatic software) to SC before IV route paracetamol injection or IV before SC with a washout period of 24 hours between the injections.

Protocol Steps
The study design is described in gure 1 Pre-inclusion: Patients will be screened by investigators according to eligibility criteria. Patients will sign a consent form after receiving oral and written information from a physician investigator involved in this project.
After inclusion, they will be randomly assigned (by using Ennov clinical® software) to SC before IV route paracetamol injection or IV before SC with a washout period of 24 hours between the injections. -Collect all current treatments -Adapt pain management treatment and if the patient has paracetamol in his treatment, the practitioner has to prescribe alternative antalgics -Plan for collection of alternative antalgics from D-1 to D2: hours of administration; dosage.
-Administration of 1000 mg of paracetamol, by the rst route of administration designated by randomization and with infusion pump Volumat® or Volumed® at the rate of 100 ml in 30 min (200 mL/hour).
-Carry out blood quantitative analysis of paracetamol, according to the following parameters and depending on the route done rst: -At each blood test, the patient will undergo a NPRS and an assessment of the tolerance.

D2:
Twenty-four hours after rst administration of paracetamol (washout) The patient will receive paracetamol by the second route of administration according to the randomization in the same timeline as D1.
In any moment, if pain is not well controlled, the investigator practitioner has to prescribe alternative drugs, and all treatment that he will consider necessary to obtain relief. Any adverse events, other unidenti ed effects of trial intervention and any alternative drugs used have to be listed in the electronic Case Report Form (eCRF) of the patient and declared to the promoter, following the procedure described in the protocol.
Ending-Protocol Visit: Every Patient will have an exam on the fourth and the thirtieth day of the protocol for safety monitoring of the subcutaneous route of administration. In case of adverse events, long term monitoring will be proposed and a specialist opinion will be requested if the investigating physician or the promoter deems it necessary.  Outcomes The main objective is to demonstrate a PK equivalence between the two modes of administration. The secondary objectives are to compare the e cacy of the two modes of administration on pain and to explore global and cutaneous tolerance of paracetamol used by the SC route.
The main judgement test will be the blood concentration of paracetamol.
Curves will be established for each patient, and we'll determine and compare for each route of administration and for each patient AUC0-t, AUC0-¥, Cmax, and Vd et t1/2. Data will also permit us to compare PK characteristics between all of the patients.
Secondary evaluation criteria will be the pain evaluation by NPRS throughout the duration of the protocol, and the evaluation of safety by the nurse.

Data Collection Methods
Every participant will be assigned a unique electronic-Case Report Form (eCRF).

Pharmacokinetic Data
Pharmacokinetic sampling procedure.
Assay method.
After centrifugation, serum samples will be immediately used for quanti cation of acetaminophen with the EMIT tox TM Acetaminophen Assay, which is a homogeneous enzyme immunoassay performed in AU 5800 clinical chemistry systems (Beckman Coulter, France). The limit of quanti cation is 0.12 mg/L. Precision is better than 6% for three quality control levels.
Paracetamol concentrations obtained after IV and subcutaneous administration will be analysed using a 1-compartment open model. The apparent rst-order rate constant (ke) and the corresponding apparent elimination half-life (t1/2 = Ln2/ke) will be determined by least squares regression analysis of the terminal phase of the serum concentration-time curve. The apparent rst-order rate constant (ka) and the corresponding apparent resorption half-life (t1/2 = Ln2/ka) will be determined by least squares regression analysis of the resorption phase from the serum concentration-time curve obtained after subcutaneous administration. The maximum observed serum concentration (Cmax) and the time required to reach Cmax (Tmax) will be calculated using the following formula: Tmax = Ln(Ka/Ke) / (Ka-Ke) and Cmax=C0.

Adverse Events Data
All adverse events will be collected, from consent to the end of patient participation, and reported to the sponsor. Serious adverse reactions (SAR) will be quali ed as expected or unexpected by the sponsor. Expected SAR related to paracetamol are thrombocytopenia, leucopenia, neutropenia, hypersensitivity, hypotension, increased transaminases, malaise, tachycardia, ushing, pruritus and erythema. Other SAR will be considered as unexpected.
A Data Safety Monitoring Board (DSMB) will review the safety independently. The DSMB will include three experts: one pharmacologist, one physician pain specialist, and one dermatologist. The sponsor will request DSMB advice in case of Suspected Unexpected Serious Adverse Reaction or any new safety information. The DSMB is charged with providing advices to the sponsor recommendations that include (a) continuation of the study, (b) continuation with modi cation, and (c) termination of the study.

Data Analysis
The following PK parameters: AUC0-t, AUC0-¥, Cmax, Vd, and T1/2, whose distributions are known to be approximately log-normal, will be described for the 2 modes of administration in the form of geometric means with geometric coe cients of variation. Tmax will be summarized by a median and quartiles.
The parameters AUC0-t, AUC0-¥, Cmax, Vd and T1/2 will then be log-transformed and compared between the 2 modes of administration using a linear regression model taking into account the following effects: treatment sequence (IV -SC or SC -IV), subjects (nested in the treatment sequence), treatment period (period 1 or period 2) and treatment (mode of administration: IV or SC). For each parameter, the difference between the two modes of administration will be tested, based on the P-value associated with the treatment effect. A non-parametric test (Wilcoxon signed-rank test) will be used for Tmax.
The bioequivalence between the 2 modes of administration will be tested for AUC0-t, AUC0-¥ and Cmax, based on the 90% con dence interval of the ratio of the geometric means (SC vs IV). According to the recommendations of the European Medicines Agency, 9 we can conclude bioequivalence if the con dence interval is fully within the range [80%-125%].
Pain scores will be compared between the 2 modes of administration by paired T-tests or Wilcoxon signed-rank tests, depending on the form of the distribution.
Statistical signi cance will be set at P < 0.05. Data will be analysed at the Biostatistics and Clinical Research Unit of Caen University Hospital, with SPSS and R software.

Sample Size
No sample size calculations were performed due to the pilot nature of the study. Furthermore, we could not nd any information in the literature on the variability of PK parameters in a palliative care population.
We therefore relied on the number of subjects included in clinical studies with a similar methodology 4,10-13 and decided to include 20 patients. This number is also in line with the recommendations of the European Medicines Agency 9 which sets at 12 the minimum number of patients to be included in a bioequivalence trial.

Discussion
Many drugs could be administered by SC route in palliative care 1,2 . For antalgic drugs, strong and low opioids are currently used by the subcutaneous route, with an equivalence dose from the IV route calculated according to well-known conversion factors. 14 However, there is no study highlighting the equivalence, e cacy and safety of paracetamol administered subcutaneously. Currently, increasingly more palliative care teams empirically choose to use this method of administration for patients with an impossible venous or oral route. PC practitioners need more evidence-based data, particularly for frail patients. In these situations, it is di cult to extrapolate from studies in other populations.
Our palliative care study evaluated the pharmacokinetic equivalence between SC and IV route. It could help to determine whether the SC route is a good alternative method of administration for paracetamol. The risks of this method of administration in patients are defects of analgesia, technical problems with the central venous catheter, the appearance of skin lesions and the toxicity of paracetamol. These risks will be controlled by the establishment of increased clinical surveillance and the setting up of preventive care (rinsing the venous pathway, prescribing an alternative analgesic treatment, etc.).
Our study is the rst pharmacokinetic analysis of subcutaneous administration of paracetamol. Our principal limit is the sample size that does not allow us to conclude on the criteria of pain relief and tolerance.

Conclusion
The ethics committee/institutional approval show that pharmacokinetic clinical trials can be carried out for PC patients.
If an equivalence between the SC and IV routes for palliative care patients is demonstrated, paracetamol may be used by palliative care teams in a more consensual, secure and scienti cally proven way.
However, more studies will be necessary to con rm the clinical e ciency.