Odors to Insufflate Life (PREMODEUR)

PREMODEUR. "Odors to Insufflate Life". Implementation of a Controlled Olfactory Sensorial Method to Decrease Apneas in Premature Newborns. Proof of Concept Study. Latin-square Open Study With Blind Evaluation of Primary Outcome.

Apneas concern about 85% of premature newborns (NB) born after less than 34 weeks of pregnancy. They are considered as an important risk factor for subsequent neuropsychological deficiency. Current pharmacological treatments are not very effective, and have side effects (agitation, irritability, sleep disorders, tachycardia). Some studies suggest that in NBs with apneas resisting to drugs, a permanent odorisation with a drop of vanillin on the incubator's pillow might reduce the frequency of apneas. This latin square design study will test a controlled olfactory stimulation method, i.e. an olfactometer which controls the odor duration, intensity, and sequence using three different odors, to reduce apneic episodes measured using 24-registration of heart and respiratory rates.

Study Overview

• Status: Terminated
• Conditions: Premature Newborns With Gestational Age 28 to 33 Weeks
• Intervention / Treatment: Other: Olfactory stimulations

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Bron, France
    • Hôpital Femme Mère Enfant
  • Saint-Étienne, France
    • Chu de Saint-Etienne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 days and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newborns from a single or multiple pregnancy
• Newborns hospitalized in the Lyon East or Saint-Etienne neonatology services, of both sexes, born before 33 weeks of amenorrhea and after at least 6 days of life, without respiratory disease beside premature birth.
• Newborns must present at least 3 bradycardia during 3 days, or presenting apneas at observation.
• Newborns will be randomized if they present at least 3 apnea episodes per 24 hour monitored by RECAN for 3 consecutive days prior to randomization.
• Written informed consents obtained from the newborns parents or legal representatives

Exclusion Criteria:

• Severe congenital malformation
• History of allergic reaction to smell stimulation (cough, sneeze, watery eyes, breathing pauses)
• No social insurance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: S0 - S1 - S2; S0 = no stimulation; washout; S1 = vehicle; washout; S2 = olfactory stimulation	Other: Olfactory stimulations; Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.
Experimental: S0 - S2 - S1; S0 = no stimulation; washout; S2 = olfactory stimulation; washout; S1 = vehicle	Other: Olfactory stimulations; Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.
Experimental: S1 - S0 - S2; S1 = vehicle; washout; S0 = no stimulation; washout; S2 = olfactory stimulation	Other: Olfactory stimulations; Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.
Experimental: S1 - S2 -S0; S1 = vehicle; washout; S2 = olfactory stimulation; washout; S0 = no stimulation	Other: Olfactory stimulations; Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.
Experimental: S2 - S0 - S1; S2 = olfactory stimulation; washout; S0 = no stimulation; washout; S1 = vehicle	Other: Olfactory stimulations; Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.
Experimental: S2 - S1 - S0; S2 = olfactory stimulation; washout; S1 = vehicle; washout S0 = no stimulation	Other: Olfactory stimulations; Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of respiratory pauses between S1 and S2	variation of the number of apnea episodes per 24hours -registered on the continuous heart / respiratory monitoring device, defined as a total cessation of breathing superior to 20 seconds (single apnea) or ≤ 20 seconds with decreased heart rate <80 beats / min) - between olfactory stimulation (S2) and placebo stimulation (S1).	per 24hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
difference of the number of apnea episodes between S1 and S2	difference of the number of apnea episodes between S1 and S2 adjusted on the order of stimulations, gestational age, concomitant treatments likely to interfere with breathing and their dosage	per 24hours
difference of the number of apnea episodes between S0 and S2	difference in the number of apnea episodes between olfactory stimulation (S2) and no stimulation (S0)	per 24hours
adverse events		up to day 8

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: HELENE GAUTHIER MOULINIER, Hospices Civils de Lyon

Publications and helpful links

General Publications

• Duchamp-Viret P, Nguyen HK, Maucort-Boulch D, Remontet L, Guyon A, Franco P, Cividjian A, Thevenet M, Iwaz J, Galletti S, Kassai B, Cornaton E, Plaisant F, Claris O, Gauthier-Moulinier H. Protocol of controlled odorant stimulation for reducing apnoeic episodes in premature newborns: a randomised open-label Latin-square study with independent evaluation of the main endpoint (PREMODEUR). BMJ Open. 2021 Sep 13;11(9):e047141. doi: 10.1136/bmjopen-2020-047141.

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2018
• Primary Completion (Actual): March 28, 2023
• Study Completion (Actual): March 28, 2023

Study Registration Dates

• First Submitted: July 28, 2016
• First Submitted That Met QC Criteria: July 28, 2016
• First Posted (Estimated): August 2, 2016

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: premature newborns; apneas prevention; olfactory stimulation; latin square design
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth
• Other Study ID Numbers: 69HCL16_0078

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No