Olfactory Disorder
Conditions
Keywords
Anosmia, Hyposmia, Intranasal Steroid Irrigation, Olfactory Neuroplasticity, Olfactory training
Brief summary
The purpose of this research study is to examine the efficacy of a 12-week smell training intervention for participants with olfactory dysfunction following an infection of the upper respiratory tract.
Detailed description
Olfactory dysfunction affects up to fifteen percent of the general population and can cause significant psychosocial distress including decreased appetite, reduced self-hygiene, and mood disturbances. This study aims to study the efficacy of smell training for patients with olfactory dysfunction following a viral upper respiratory tract infection. Eligible participants will complete a 30-day course of budesonide nasal saline irrigation. Participants who do not show improvement in their olfaction based on composite smell and taste tests will be eligible to receive a baseline resting-state fMRI (rs-fMRI) and complete a 12-week smell training intervention program. Smell training involves participants smelling 4 odors (phenyl ethyl alcohol, eucalyptus, lemon, and eugenol) twice a day for 12 weeks. Following completion of smell training, participants will undergo repeat smell and taste tests as well as rs-fMRI to ascertain the efficacy of smell training.
Interventions
BEHAVIORALSmell training
Participants will be provided with 4 vials of essential odors. Participants will sniff each scent for 20-30 seconds, twice daily, for 12 weeks. The participant will take 30 seconds of rest between each scent. All participants will undergo this smell training regimen for 12 weeks.
Sponsors
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective cohort, pre- and post-intervention study
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Age between 18 and 70 * Anosmia or hyposmia (UPSIT \<34 (male), UPSIT \<34 (female); Sniffin' Sticks threshold below 5.5)
Exclusion criteria
* Inability to understand English * Current smoker or history of smoking within the past 6 months * Current nasal polyps * Exposure to head and or/neck radiation * Exposure to chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training. | 12 weeks | Baseline and post-intervention connectivity within and between regions of interest in the olfactory and olfactory related networks using resting state fMRI will be obtained. Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons. p\<0.05 was considered to be significant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment | 30 days | Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation. University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores indicating better sense of smell. Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score \>30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell. |
| Subjective Response to Smell Training Intervention | 12 weeks | Participants subjective sense of smell following intervention is measured using a visual analogue scale from 0 to 100 with 0 representing no sense of smell and 100 representing best possible sense of smell. |
| Comparison of Olfactory Network in Healthy Controls to Study Participants | 1 week | Baseline functional connectivity within and between the olfactory and associated networks of healthy controls will be compared to that of study participants prior to smell intervention treatment as measured by rs-fMRI.Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons . P \< .05 was considered statistically significant. |
| Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training | 12 weeks | Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation. University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores representing better sense of smell. Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score \>30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell. |
| Pre and Post Difference in QOD-NS After Smell Training | 12 weeks | The QOD-NS is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (maximum score of 51), with higher scores reflective of more impaired quality of life. |
Countries
United States
Participant flow
Recruitment details
Adults 18 to 70 years of age with clinically diagnosed or self reported postviral olfactory loss of 3 months or longer were eligible to participate. For the control group, adults with normal smell function were eligible to participate.
Pre-assignment details
PVOD participants first underwent 30-day trial period of budesonide nasal irrigation. If they did not experience improvement in their smell to the normal range as measured by UPSIT and Sniffin'Sticks, they continued budesonide nasal irrigation plus 12-weeks of smell intervention. Resting-state fMRI was obtained before and after smell intervention. For the participants in the Control Group, one time fs-MRI and questionnaire completion only.
Participants by arm
| Arm | Count |
|---|---|
| Budesonide Nasal Irrigation Participants will first undergo a 30-day trial of budesonide nasal saline irrigation. If there is no subsequent improvement in olfaction, participants will undergo a 12-week smell training intervention.
Budesonide nasal irrigation: Eligible participants will be provided with a NeilMed Sinus Rinse Regular Bottle Kit and a one-month supply of USP Grade Sodium Chloride & Sodium Bicarbonate Mixture commercially prepared packets. Participants will need to purchase distilled water or boil tap water for five minutes for use with the saline irrigation. The contents of two capsules (0.5mg budesonide each) will be dissolved into NeilMed Sinus Rinse Regular Bottle along with the saline rinse. Both nasal cavities will be irrigated once daily for 30 days.
Smell training: Participants who do not have objective improvement in their olfaction after the trial of budesonide irrigation will have a baseline resting-state fMRI (rs-fMRI) and undergo 12 weeks of smell training. Smell training involves the participants smelling 4 vials of essential odors (clove, lemon, eucalyptus, rose) twice a day for 12 weeks. Following smell training, participants will have their smell ability re-evaluated and a second rs-fMRI performed. | 23 |
| Control Group Control participants sex and age matched (±5 years) to participants with PVOD had normal smell as determined by UPSIT and were recruited for baseline neuroimaging. Individuals with MRI contraindications were excluded. | 20 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Olfaction Testing | Lost to Follow-up | 0 | 5 |
| Olfaction Testing | Protocol Violation | 0 | 3 |
Baseline characteristics
| Characteristic | Total | Control Group | Budesonide Nasal Irrigation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 0 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 20 Participants | 15 Participants |
| Age, Continuous | 62 years | 61.5 years | 62 years |
| Duration of smell loss | 12 months | — | 12 months |
| QOD-NS score | 10.55 units on a scale | — | 10.55 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 18 Participants | 21 Participants |
| Region of Enrollment United States | 43 Participants | 20 Participants | 23 Participants |
| Sex: Female, Male Female | 32 Participants | 15 Participants | 17 Participants |
| Sex: Female, Male Male | 11 Participants | 5 Participants | 6 Participants |
| TDI | 18 units on a scale | — | 18 units on a scale |
| UPSIT | 35 units on a scale | — | 19.5 units on a scale |
| VAS sense of smell | 0.1095 units on a scale | — | 0.1095 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 31 |
| other Total, other adverse events | 3 / 20 | 2 / 31 |
| serious Total, serious adverse events | 0 / 20 | 0 / 31 |
Outcome results
Primary
Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training.
Baseline and post-intervention connectivity within and between regions of interest in the olfactory and olfactory related networks using resting state fMRI will be obtained. Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons. p\<0.05 was considered to be significant.
Time frame: 12 weeks
Population: Of the total 23 participants who completed smell training and rs-fMRI, 7 were excluded from analysis because of excessive artifact. Thus, the final study included a total of 16 participants. A set of 164 regions of interest(ROIs) from the CONN toolbox were used, supplemented with 23 ROIs determined by prior studies to be associated with olfactory processing. The CONN toolbox is an open source Matlab/SPM software that integrates pre-processing, display, and analysis of rs-fMRI data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Smell Training | Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training. | 5 Regions of interest |
Secondary
Comparison of Olfactory Network in Healthy Controls to Study Participants
Baseline functional connectivity within and between the olfactory and associated networks of healthy controls will be compared to that of study participants prior to smell intervention treatment as measured by rs-fMRI.Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons . P \< .05 was considered statistically significant.
Time frame: 1 week
Population: A set of 164 regions of interest (ROIs) from the CONN toolbox were used, supplemented with 23 ROIs determined by prior studies to be associated with olfactory processing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Smell Training | Comparison of Olfactory Network in Healthy Controls to Study Participants | 13 Regions of interest |
Secondary
Pre and Post Difference in QOD-NS After Smell Training
The QOD-NS is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (maximum score of 51), with higher scores reflective of more impaired quality of life.
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Smell Training | Pre and Post Difference in QOD-NS After Smell Training | 7.4 units on a scale |
Secondary
Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment
Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation. University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores indicating better sense of smell. Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score \>30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.
Time frame: 30 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Smell Training | Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment | UPSIT | 19.5 units on a scale |
| Smell Training | Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment | TDI | 17.5 units on a scale |
Secondary
Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training
Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation. University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores representing better sense of smell. Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score \>30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Smell Training | Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training | UPSIT | 19 units on a scale |
| Smell Training | Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training | TDI | 18.3 units on a scale |
Secondary
Subjective Response to Smell Training Intervention
Participants subjective sense of smell following intervention is measured using a visual analogue scale from 0 to 100 with 0 representing no sense of smell and 100 representing best possible sense of smell.
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Smell Training | Subjective Response to Smell Training Intervention | 23.8 units on a scale |