Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use

NCT ID: NCT02307721

Last Updated: 2018-10-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-31
• Study Completion Date: 2015-09-30

Brief Summary

Overdose with potential deadly outcome is a serious problem among opioid abusers, not least in Norway. The annual death toll from overdose is about 250, higher than road traffic accidents. Those who inject heroin or other opioids are considered to have the highest risk for death from overdose. To save lives, immediate treatment with a μ-opioid antidote such as naloxone is required. Usually naloxone is injected into a muscle or a blood vessel. Administration of naloxone via the nose (intranasal) has been suggested as an alternative for use by emergency teams and possibly also bystanders. This is not only an easier way to give naloxone, but would also eliminate the risk for needle stick injuries and blood contamination. In a series of studies on intranasal naloxone at The Norwegian University of Science and Technology, this study explores pharmacokinetics and pharmacodynamics of intranasal and intramuscular naloxone in healthy volunteers under the influence of remifentanil.

Detailed Description

Healthy volunteers will be brought into a state of opioid influence in a well-known, short acting, controlled and safe manner using remifentanil.

Naloxone is a well-known, well-tolerated drug with an excellent safety profile over many decades of use. The current formulation has proven safe and without local or systemic side effects in the studies conducted so far. The excipients in the present nasal formulation are all well known.

This study has two aims. Firstly to investigate what naloxone does to the body under opioid influence, applying a well-tested model with infusion of the potent opioid remifentanil (Target Control Infusion). This will create a state of strong opioid effect for a short time and in a highly controlled fashion, inducing a state of miosis, reduced respiratory rate and reduced sensation to pain, all three strong indicators of opiates. Naloxone will antagonise these effects, and this change can be measured. Choosing intramuscular 0.8 mg naloxone for comparison means that the novel intranasal naloxone formulation will be compared with the well-established and described treatment protocol for opioid overdose in Norway used today.

Secondly the pharmacokinetic profile of intranasal and intramuscular naloxone will be studied. The same measurements as in preparative studies (OPI 12-001 and OPI 13-001) will be taken: Serum naloxone concentration over time to calculate maximum concentration, Time to maximum concentration, Area Under the Curve and Relative bioavailability. There are two main reasons to repeat these measurements. In contrast to the previous studies under the current protocol the participants will be under the influence by strong opioids. This may have significant physiologic effects, and it will be explored whether the pharmacokinetics of the intranasal formulation are changed. The other reason is that in this study pharmacokinetics of naloxone will be compared with the actual dosage and administration routes of naloxone as used by doctors and paramedics in the pre-hospital setting. This has not been done before, in spite of the widespread use of this treatment, The measurements of remifentanil in serum open the possibility to relate pharmacodynamic data directly to an actual serum concentration of the opioid at the same time.

Care will be taken not to include opioid users in this study as naloxone would precipitate acute withdrawal. Also possible drug misusers will be excluded as well as people who have access to remifentanil and infusion equipment in their daily work, although the abuse potential of this highly specialised drug is minimal.

Safety of the formulation will also be studied by measuring vital signs and for the patient to report any nasal discomfort or potential adverse reactions during the study.

By weighing spray device, and intramuscular syringes before and after discharge the reliability of the dose delivered will be confirmed.

Conditions

Drug Overdose

Study Design

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

Study Groups

intranasal naloxone

8 mg/ml naloxone 0,1 mL IN as one puff in one nostril in supine position

Group Type: EXPERIMENTAL

Intranasal naloxone

Intervention Type: DRUG

Administer 0,1 ml 8 mg/ml naloxone intranasally, dose = 0,8 mg naloxone

Remifentanil

Intervention Type: DRUG

Administer remifentanil intravenously by way of Target Control Infusion, Minto model at a target of 2,5 ng/ml. This to achieve a state of safe and predictable opioid influence to assess pharmacodynamic response to naloxone. After treatment of 4 participants protocol amended 22. january 2015 to reduce remifentanil target to 1,25 ng/ml in the next 4. In the last 4 participants the dose will be decided later, but not exceed 2,5 ng/ml.

Aptar Unidose

Intervention Type: DEVICE

This is the spray device chosen, and its function in this setting (spray up side down) will be assessed by weighing the device before and after administration.

Intramuscular naloxone

0,4 mg/ml Naloxone B Braun 2 ML in deltoid muscle

Group Type: ACTIVE_COMPARATOR

Intramuscular naloxone

Intervention Type: DRUG

Administer 2 mL, dose intramuscular naloxone 0,8 mg

Remifentanil

Intervention Type: DRUG

Administer remifentanil intravenously by way of Target Control Infusion, Minto model at a target of 2,5 ng/ml. This to achieve a state of safe and predictable opioid influence to assess pharmacodynamic response to naloxone. After treatment of 4 participants protocol amended 22. january 2015 to reduce remifentanil target to 1,25 ng/ml in the next 4. In the last 4 participants the dose will be decided later, but not exceed 2,5 ng/ml.

Interventions

Intranasal naloxone

Administer 0,1 ml 8 mg/ml naloxone intranasally, dose = 0,8 mg naloxone

Intervention Type: DRUG

Intramuscular naloxone

Administer 2 mL, dose intramuscular naloxone 0,8 mg

Intervention Type: DRUG

Remifentanil

Administer remifentanil intravenously by way of Target Control Infusion, Minto model at a target of 2,5 ng/ml. This to achieve a state of safe and predictable opioid influence to assess pharmacodynamic response to naloxone. After treatment of 4 participants protocol amended 22. january 2015 to reduce remifentanil target to 1,25 ng/ml in the next 4. In the last 4 participants the dose will be decided later, but not exceed 2,5 ng/ml.

Intervention Type: DRUG

Aptar Unidose

This is the spray device chosen, and its function in this setting (spray up side down) will be assessed by weighing the device before and after administration.

Intervention Type: DEVICE

Other Intervention Names

Naloxone B Braun 0,4 mg/ml

Eligibility Criteria

Inclusion Criteria

• American Society of Anesthesiologists (ASA) class I
• ECG without pathologic abnormalities
• BMI range of 18,5 - 24,9 kg/m2.
• lab values within reference values at St Olav's Hospital for the relevant haematological and biochemical test for inclusion:

• Haemoglobin (male: 13.4-17.0 g/dL, female 11.7 - 15.3 g/dL)
• Creatinine (male: 60-105 micromole/L, female 45 - 90 micromole/L)
• Aspartate aminotransferases (ASAT) (male: 15-45 U/L, female: 15-35 U/L)
• Alanine transaminase (ALAT) (male: 10-70 U/L, female: 10-45 U/L)
• Gamma glutamyl transpeptidase (GT) (male: 10-80 U/L, female: 10-45 U/L)
• For women in reproductive age: serum HCG (normal under 3 ye/L)
• Signed informed consent and expected cooperation of the subjects for the treatment

Exclusion Criteria

• Taking any medications including herbal medicines the last week prior to treatment visits
• Current or history of drug and/or alcohol abuse (To assess problematic drug or alcohol use we use the CAGE AID screening tool)
• History of contact with police or authorities in relation to alcohol or drug offences
• History of prolonged use of opioid analgesics
• History of prior drug allergy
• Having any local nasal disease or nasal surgery for the last 2 months or recent cold for the last week
• Pregnant women (HCG over 3 ye/L at inclusion)
• Women in reproductive age not using high efficacy contraceptives (Oral contraceptives, Patch (Evra), Implants, Vaginal ring, Hormonal IUD, Copper intra-uterine device (IUD), Sterilization) throughout the study period until their last visit.
• Breastfeeding women
• Participants with access to remifentanil or other potent opioids in their daily workplace.
• Hypersensitivity to naloxone or remifentanil hydrochloride and/or to any of its excipients.
• Any reason why, in the opinion of the investigator, the patient should not participate.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

St. Olavs Hospital

OTHER

Sponsor Role: collaborator

Norwegian University of Science and Technology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Toril A Nagelhus Hernes, phd prof

Role: STUDY_DIRECTOR

Norwegian University of Science and Technology

Locations

Department of Circulation and Medical Imaging

Trondheim, , Norway

Countries

Norway

References

Skulberg AK, Tylleskar I, Nilsen T, Skarra S, Salvesen O, Sand T, Loftsson T, Dale O. Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers. Eur J Clin Pharmacol. 2018 Jul;74(7):873-883. doi: 10.1007/s00228-018-2443-3. Epub 2018 Mar 22.

Reference Type: RESULT

PMID: 29568976 (View on PubMed)

Other Identifiers

2014-001465-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

OPI-14-001

Identifier Type: -

Identifier Source: org_study_id