The Preterm Infants’ Paracetamol Study

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Brief Title

The Preterm Infants' Paracetamol Study

Official Title

The Preterm Infants' Paracetamol Study

Brief Summary

      Present randomized, controlled, double-blind trial investigates the efficacy and safety of
      early (<24 h) intravenous paracetamol therapy for pain medication in very small premature
      infants. This phase 2 drug study focuses on the efficacy and safety of short-term use. The
      pharmacokinetics and pharmacodynamics of paracetamol, as well as the long-term effects, are
      studied.

      This study recruits preterm infants born less than 32 weeks gestational age and treated at
      the neonatal intensive care unit of Oulu University Hospital. The informed consent is asked
      from all parents. The first drug dose is given before 24 hours of age. Masked study drug is
      paracetamol infusion solution 10 mg/mL or placebo, 0.45% saline solution. The loading dose is
      20 mg/kg, and the maintenance dose 7.5 mg/kg every 6 hours for 4 days. The exact date of the
      closure of ductus is studied by repeated echocardiographic examinations. The symptoms of pain
      are screened by a pain scale of preterm infants (NIAPAS). Patients are monitored for signs of
      possible side effects. After discharge from hospital, patients are examined at follow-up
      clinic for the first year every 3 months and at 2 years of age.
    

Detailed Description

      1 Hypotheses and aims: The aim of the present study is to evaluate the safety and efficacy of
      intravenous paracetamol in pain medication for small preterm infants in a randomized,
      controlled, double-blind trial. The primary outcome of the pain medication arm is the need
      for morphine medication (doses). The secondary outcomes are paracetamol serum concentrations,
      the side effects of paracetamol (possible hepatic dysfunction), neonatal and long-term
      morbidity, and mortality.

      The primary outcome in the phase 2 ductus study-arm was diminishing of the ductal caliber at
      5 days postnatal age. This study arm has been finalized and the results were published on
      2016 (Härkin et al).

      Hypotheses:

      I. Hypothesis. Early, intravenous paracetamol is effective and safe therapy in the relief of
      pain and discomfort of a preterm infant.

      II. Hypothesis. Paracetamol levels of a preterm infant remain in safety limits with study
      dosages.

      III. Hypothesis. Early, intravenous paracetamol does not increase long-term morbidity in
      preterm infants.

      Objectives:

        1. Aim: to evaluate in a randomized, controlled, double-blind trial, the efficacy and
           safety of the early (<24 h), intravenous paracetamol in pain treatment of a preterm
           infant.

        2. Aim: to evaluate the safety of the early (<24 h), intravenous paracetamol in preterm
           infants requiring intensive care.

        3. Aim: to study pharmacokinetics and pharmacodynamics of paracetamol in a preterm infants

        4. Aim: to evaluate the long-term effects of the early (<24 h), intravenous paracetamol in
           preterm infants requiring intensive care.

      2 Study permissions: The research plan is registered to the investigational diary of the
      Department of Pediatrics, Oulu University Hospital (diary number 100-2013). For the present
      trial, the permissions from The Northern Ostrobothnia Hospital district's Ethical Board and
      Oulu University Hospital's administrative officials have been applied and granted. The study
      permission has been applied and granted from Fimea, the Finnish Medicines Agency. The
      amendment of the research plan was approved on 30.4.2018. This project has been assigned to
      EudraCT network (European Clinical Trials Database), Eudra CT number 2013-008142-33, and the
      international ClinicalTrials.gov registry, identification number NCT01938261.

      Written informed consent is asked by the primary investigators of the study from all study
      patients' parents. The present clinical trial is managed by the principles of Good Clinical
      Practice, GCP (Fimea, act 2/2012, Clinical drug trials). The essential changes of the
      research plan are announced to Fimea according to the Drug legislation act 87a, using the
      European commission internet site (http://ec.europa.eu/health/documents/eudralex/vol-10/).

      3 Sample size: The sample size calculation for the pain medication trial was checked after
      the first randomization. According to our previous study (Härmä et al, 2016), non-exposed
      premature infants received approximately 5 doses of morphine (SD 12) during their stay in the
      NICU. In order to treat infants without opioids, the clinical difference was approximated to
      be 6 doses. Therefore, with 20% power and 0.05 alpha-error, 126 infants (63/group) were
      required.

      4 Study patients and exclusion criteria: This study will recruit all the intubated premature
      infants born less than 32 weeks of gestational age managed in Oulu University Hospital's
      neonatal intensive care unit. The deadline for recruitment and administration of the first
      dose of the study drug is postnatal age of 24 hours. The study exclusion criteria are severe
      structural, or chromosomal abnormality, and other severe clinical situation, which
      essentially affects the small premature infants' conventional early-stage treatment, e.g.
      severe asphyxia or persistent pulmonary hypertension (PPHN).

      5 Randomization and blinding: As the informed consent is given, the study patient receives a
      trial number from the list made prior to the entry of the study. The trial number will match
      with an envelope where has been drawn a leaflet with the patient's study medication group
      written on it. Placebo, 0.45 % saline, is similar to paracetamol, both being clear liquids,
      so the staff will remain unaware which drug the patient receives. The study medication will
      be kept and prepared at the ward 55 in a separate office, in a locked cabinet. The study drug
      will be prepared by the study nurse, or by a nurse who does not participate in the study
      patients' treatment in any way.

      6 Intervention: Masked study drug is 10 mg/ml paracetamol solution (Paracetamol Kabi
      Pharmacia®). Placebo is 0.45% saline solution, which does not enhance the potential small
      preterm infants' early-stage hypernatremia or hyperglycemia. Both are visually similar, clear
      solutions. Loading dose, 20 mg/kg, is followed by a maintenance dose 7.5 mg/kg every 6 hours,
      for four days. According to the earlier phase 1 studies, this dose is considered to be safe
      for small preterm infant. The drug is administered as a 15-minute infusion. No other
      paracetamol preparations are allowed to be given simultaneously with the study drug. After
      the intervention, the use of paracetamol should be restricted as far as it is possible. If
      the patient's clinical condition requires starting of paracetamol medication, there should be
      at least two days absence of paracetamol after the last dose of study medication. Half-life
      of intravenous paracetamol in neonates is about 4.5 hours. No other restrictions on the
      patient's therapy are set. After the study intervention, the patient is treated by the
      attending physicians' clinical judgment. Whenever necessary, the patient will be given the
      normal dose of morphine, 0.1 mg/kg.

      6.1 Monitoring of the pain symptoms: The pain or discomfort of the patients will be screened
      using NIAPAS scoring before and after the study drug administration. According to the NIAPAS
      guidelines, values >5 indicate the need for evaluation for pain relief, either with using the
      non-medical pain relief methods, or increasing the pain medication dose. All the study
      patients will receive necessary pain medication during the study which would be morphine ad
      0.1 mg/kg single doses, or morphine infusion. All morphine doses given during and after the
      intervention are recorded and calculated as the cumulative dosage.

      7 Paracetamol safety: Using the study drug dosage, no signs of liver or renal failure have
      been described before. In addition, in the recent retrospective analysis among the study unit
      patient population, none of the preterm infants who received paracetamol showed any clinical
      or laboratory signs of either complication. No increased levels of liver transaminases,
      bilirubin or creatinine were detected.

      In paracetamol intoxication, the hepatic failure is caused by a paracetamol metabolite, not
      paracetamol itself. Thus, the symptoms of intoxication are not immediately evident. The
      hepatic tissue damage can be prevented administering the paracetamol antidote as soon as
      possible. Even a suspicion of a possible intoxication in an otherwise symptom-free patient is
      to be taken seriously. This situation should be cautiously clarified, and, if necessary, the
      antidote started vigorously.

      The signs and symptoms of paracetamol intoxication include:

        -  During the first 24 hours, nausea, vomiting, loss of appetite, fatigue, and perspiration
           may be manifested.

        -  24-48 h after the overdose, the signs of it may be seen in the laboratory examinations:
           bilirubin and hepatic transaminase levels increase, and the prothrombin time lengthens
           (INR increases; this may happen without hepatic failure if the synthesis of vitamin K
           dependent coagulation factors is inhibited). Diuresis may be diminished due to possible
           dehydration (vomiting), renal failure, and the antidiuretic action of paracetamol.

        -  2-5 days later, the liver and renal tissue damage develops. In the patients with hepatic
           failure, metabolic acidosis is usually seen.

      Early acetyl cysteine therapy (<16 h after the overdose) may inhibit the hepatic failure, but
      even when started later, the tissue damage may be restricted. If necessary, the Poison
      Information Centre is consulted about the individualized instructions for treatment. The
      initial treatment includes intravenous fluid therapy in order to correct the acidosis, and
      the goal for the diuresis would be >1.5 ml/kg/h. The intravenously administered study
      medication cannot cause any harmful effects to the patients' relatives, the hospital staff,
      or the environment.

      8 Monitoring, reporting and follow-up of the possible side effects: All study patients will
      be monitored for signs of possible side effects, especially the signs of hepatic or renal
      dysfunction. During the first postnatal days, serum bilirubin levels and diuresis will be
      followed. If a patient had prolonged or otherwise pronounced jaundice, the abdominal
      ultrasound would be performed. Any evidence of hepatic or renal dysfunction would be an
      indication to withdraw the study medication, and to measure the hepatic transaminases and
      creatinine concentrations. Symptomatic hepatic or renal failure is defined as an emergency
      when the blinding code could be opened and the study discontinued.

      All harmful events and suspected side effects are individually evaluated for possible
      association to the study drug. The associations are classified: certain - likely - unlikely -
      not possible. The harmful events that are classified significant (SUSAR) are listed by the
      responsible investigator. Of the serious and unexpected harmful events, death or mortal
      danger are announced to Fimea within seven days after the incidence and the others within 15
      days. The list of the harmful events is delivered to Fimea every year.

      9 Pharmacokinetics: From those study patients with an arterial cannula, a single 1 ml blood
      sample at 48 hours postnatal age will be collected to evaluate paracetamol serum
      concentrations and the biological effects of prematurity. Of all the routine blood samples,
      any remaining droplets are retained for paracetamol concentration measurements.

      10 Data collection: The study data will be collected using Centricity Critical Care Clinisoft
      software (GE Healthcare). All the data is confidential. All the study personnel are involved
      with confidentiality. The computed data is collected into the hospital's intranet station O.
      Study papers are mapped, and kept in the room of the responsible investigator. The Office of
      the Data Protection Ombudsman has been informed about the study register. The study results
      will be published in international, peer-reviewed medical literature, and in medical theses.

      11 Quality control: An external study monitor, observing the quality of the methods used and
      the fulfillment of the study patients' rights, has been named.

      12 Long-term follow-up: For the first year after discharge from hospital, the patients will
      be examined every three months at the follow-up clinic. Patients will be examined the
      clinical status, basic laboratory parameters, and if necessary, radiographic studies.

      13 Statistical analyses: The intention-to-treat principle is applied in all analyzes. P-value
      <.05 will be considered significant. Statistical analyzes will be made using the IBM SPSS
      software.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Ductus diameter mm/kg

Secondary Outcome

 Number of patients who received any treatment for persistent ductus arteriosus

Condition

Persistent Ductus Arteriosus

Intervention

paracetamol

Study Arms / Comparison Groups

 Paracetamol effect on ductus
Description:  The first drug dose is given before 24 hours of age. Masked study drug is paracetamol infusion solution 10 mg/mL (PERFALGAN ®) or placebo, 0.45% saline solution. The loading dose is 20 mg/kg and the maintenance dose 7.5 mg kg every 6 hours for 4 days.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

120

Start Date

August 2013

Completion Date

September 2023

Primary Completion Date

September 2022

Eligibility Criteria

        Inclusion Criteria:

          -  preterm infants born < 32 weeks gestational age

        Exclusion Criteria:

          -  congenital malformation

          -  lethal disease

          -  chromosomal abnormality

          -  persistent pulmonary hypertension of a newborn
      

Gender

All

Ages

N/A - 24 Hours

Accepts Healthy Volunteers

No

Contacts

Antti Harma, M.D., +358 8 3155810, [email protected]

Location Countries

Finland

Location Countries

Finland

Administrative Informations


NCT ID

NCT01938261

Organization ID

100-2013

Secondary IDs

2013-001842-33

Responsible Party

Principal Investigator

Study Sponsor

University of Oulu


Study Sponsor

Antti Harma, M.D., Principal Investigator, Oulu University Hospital


Verification Date

November 2020