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NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use.

ABSTRACT: INTRODUCTION:Intranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate efficacy and safety of approved IN naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 mL per dose is non-inferior to 0.8 mg intramuscular injection in patients treated for opioid overdose. METHODS AND ANALYSIS:Sponsor is the Norwegian University of Science and Technology. The study has been developed in collaboration with user representatives. The primary endpoint is the restoration of spontaneous respiration?10 breaths/min based on a sample of 200 opioid overdose cases. Double-dummy design ensures blinding, which will be maintained until the database is locked. ETHICS AND DISSEMINATION:The study was approved by the Norwegian Medicines Agency and Regional Ethics Committees (REC: 2016/2000). It adheres to the Good Clinical Practice guidelines as set out by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.Informed consent will be sought through a differentiated model. This allows for deferred consent after inclusion for patients who have regained the ability to consent. Patients who are unable to consent prior to discharge by emergency services are given written information and can withdraw at a later date in line with user recommendations. Metadata will be published in the Norwegian University of Science and Technology Open repository. Deidentified individual participant data will be made available to recipients conditional of data processor agreement being entered. TRIAL REGISTRATION NUMBERS:EudraCT Registry (2016-004072-22) and Clinicaltrials.gov Registry (NCT03518021).

SUBMITTER: Skulberg AK

PROVIDER: S-EPMC7662429 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use.

Skulberg Arne Kristian AK Tylleskär Ida I Braarud Anne-Cathrine AC Dale Jostein J Heyerdahl Fridtjof F Mellesmo Sindre S Valberg Morten M Dale Ola O

BMJ open 20201112 11

<h4>Introduction</h4>Intranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate effi ...[more]

PMID: 33184084

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Project description:AimsTo measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre-hospital environment.DesignRandomised, controlled, double-dummy, blinded, non-inferiority trial, and conducted at two centres.SettingParticipants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where the overdose occurred.ParticipantsMen and women age above 18 years with miosis, rate of respiration ≤8/min, and Glasgow Coma Score <12/15 were included. Informed consent was obtained through a deferred-consent procedure.Intervention and comparatorA commercially available 1.4 mg/0.1 mL intranasal naloxone was compared with 0.8 mg/2 mL naloxone administered intramuscularly.MeasurementsThe primary end-point was restoration of spontaneous respiration of ≥10 breaths/min within 10 minutes. Secondary outcomes included time to restoration of spontaneous respiration, recurrence of overdose within 12 hours and adverse events.FindingsIn total, 201 participants were analysed in the per-protocol population. Heroin was suspected in 196 cases. With 82% of the participants being men, 105 (97.2%) in the intramuscular group and 74 (79.6%) in the intranasal group returned to adequate spontaneous respiration within 10 minutes after one dose. The estimated risk difference was 17.5% (95% CI, 8.9%-26.1%) in favour of the intramuscular group. The risk of receiving additional naloxone was 19.4% (95% CI, 9.0%-29.7%) higher in the intranasal group. Adverse reactions were evenly distributed, except for drug withdrawal reactions, where the estimated risk difference was 6.8% (95% CI, 0.2%-13%) in favour of the intranasal group in a post hoc analysis.ConclusionIntranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre-hospital environment when compared head-to-head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions.

Project description:ImportancePrevious unblinded clinical trials suggested that the intranasal route of naloxone hydrochloride was inferior to the widely used intramuscular route for the reversal of opioid overdose.ObjectiveTo test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose.Design, setting, and participantsA double-blind, double-dummy randomized clinical trial was conducted at the Uniting Medically Supervised Injecting Centre in Sydney, Australia. Clients of the center were recruited to participate from February 1, 2012, to January 3, 2017. Eligible clients were aged 18 years or older with a history of injecting drug use (n = 197). Intention-to-treat analysis was performed for all participants who received both intranasal and intramuscular modes of treatment (active or placebo).InterventionsClients were randomized to receive 1 of 2 treatments: (1) intranasal administration of naloxone hydrochloride 800 μg per 1 mL and intramuscular administration of placebo 1 mL or (2) intramuscular administration of naloxone hydrochloride 800 μg per 1 mL and intranasal administration of placebo 1 mL.Main outcomes and measuresThe primary outcome measure was the need for a rescue dose of intramuscular naloxone hydrochloride (800 μg) 10 minutes after the initial treatment. Secondary outcome measures included time to adequate respiratory rate greater than or equal to 10 breaths per minute and time to Glasgow Coma Scale score greater than or equal to 13.ResultsA total of 197 clients (173 [87.8%] male; mean [SD] age, 34.0 [7.82] years) completed the trial, of whom 93 (47.2%) were randomized to intramuscular naloxone dose and 104 (52.8%) to intranasal naloxone dose. Clients randomized to intramuscular naloxone administration were less likely to require a rescue dose of naloxone compared with clients randomized to intranasal naloxone administration (8 [8.6%] vs 24 [23.1%]; odds ratio, 0.35; 95% CI, 0.15-0.66; P = .002). A 65% increase in hazard (hazard ratio, 1.65; 95% CI, 1.21-2.25; P = .002) for time to respiratory rate of at least 10 and an 81% increase in hazard (hazard ratio, 1.81; 95% CI, 1.28-2.56; P = .001) for time to Glasgow Coma Scale score of at least 13 were observed for the group receiving intranasal naloxone compared with the group receiving intramuscular naloxone. No major adverse events were reported for either group.Conclusions and relevanceThis trial showed that intranasally administered naloxone in a supervised injecting facility can reverse opioid overdose but not as efficiently as intramuscularly administered naloxone can, findings that largely replicate those of previous unblinded clinical trials. These results suggest that determining the optimal dose and concentration of intranasal naloxone to respond to opioid overdose in real-world conditions is an international priority.Trial registrationanzctr.org.au Identifier: ACTRN12611000852954.

Project description:INTRODUCTION:Psoriasis vulgaris is a common skin disease that is characterised by persistent localised erythematous scaly plaques. Yinxieling is a Chinese herbal formula for psoriasis that has been used for more than 20 years in China. To facilitate application, PSORI-CM01 was developed based on the optimisation and simplification of Yinxieling tablets performed in a previous study and in clinical practice. However, the scientific evidence regarding whether PSORI-CM01 is more effective for psoriasis than the original Yinxieling remains insufficient. Therefore, we designed a randomised clinical trial to investigate the effect, safety and cost-effectiveness of PSORI-CM01 granules compared with those of Yinxieling tablets for the treatment of patients with psoriasis. METHODS AND ANALYSIS:This ongoing study is a two-arm parallel, randomised, double-blind, double-dummy clinical trial. Five hundred and fifty-six participants with psoriasis will be recruited and then randomly allocated into two groups in a 1:1 ratio. Participants in PSORI-CM01 group will receive a 5.5?g granule of PSORI-CM01 two times daily and five placebo tablets three times daily for 12 weeks. The participants in the Yinxieling group will receive five Yinxieling tablets three times daily and a placebo granule two times daily for 12 weeks. The primary outcome is the reduction of the Psoriasis Area and Severity Index. The secondary outcomes include relapse rate, Visual Analogue Scale scores, body surface area and the Dermatology Life Quality Index. Cost-effectiveness analysis will be performed from a health and community care provider perspective. ETHICS AND DISSEMINATION:This research protocol had been reviewed and approved by the institutional review boards of three trial centres (Guangdong Provincial Hospital of Chinese Medicine (B2014-026-01), Affiliated Hospital of Tianjin Chinese Medicine Academy (2014-KY-001) and Third Hospital of Hangzhou (B2014-026-01)). The findings will be disseminated to the public through conference presentations and open-access journals. TRIAL REGISTRATION NUMBER:Chinese Clinical Trial Registry (ChiCTR-TRC-14005185); Pre-results.

Project description:IntroductionSepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome.Methods and analysisImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation.Ethics and disseminationThe protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d'éthique de la recherche sur l'être human of Switzerland. The results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04990232.

Project description:BackgroundChildren under 6 years who need magnetic resonance imaging usually require sedation to obtain best quality images, but the optimal sedation protocol remains to be determined. In 2018, we showed a 22% interruption in image acquisition during magnetic resonance imaging when performing a propofol-based sedation using a bolus approach. As non-pharmacological premedication is often insufficient to reduce the anxiety of children related to parental separation, pharmacological premedication may be useful to facilitate the induction of anesthesia. In our institution, effective premedication is obtained oral intake of midazolam, though its administration relies on patients' compliance and could also lead to paradoxical reaction. Dexmedetomidine has a safe profile in the pediatric population and can therefore represent an interesting alternative. The primary objective of this trial is to demonstrate the superiority of intranasal dexmedetomidine compared to oral midazolam as premedication in reducing the occurrence of any event requiring temporary or definitive interruption of the examination to allow anesthesiologist intervention in children undergoing magnetic resonance imaging under propofol sedation.MethodsIn this single-center, prospective, randomized, double-blind, double-dummy, active comparator-controlled, superiority trial, we planned to include 250 patients, aged 6 months to 6 years, undergoing a scheduled magnetic resonance imaging requiring the presence of an anesthesiologist. After informed consent, the patients will be randomized to receive either oral midazolam or intranasal dexmedetomidine as premedication. The data will be analyzed in intention to treat, using Kolmogorov-Smirnov Z, chi-square, Wilcoxon, and Mann-Whitney U tests. A P-value < 0.05 will be considered statistically significant.DiscussionThe MIDEX MRI study will assess the efficacy of intranasal dexmedetomidine compared to oral midazolam to improve the quality of a propofol-based sedation prior to magnetic resonance imaging, without negative repercussion on the postoperative period.Trial registrationClinicalTrial.gov NCT05192629 . Registered on 14 January 2022. Protocol version 2.1.

Dataset Information

NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use.

Publications

NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use.

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