Trial Outcomes & Findings for Smell in Covid-19 and Efficacy of Nasal Theophylline (NCT NCT04789499)

Results Overview

UPSIT 0-40 with higher scores indicating better results. The response rate defined as the number of participants in each group self-reporting of at least slightly better improvement in the Clinical Global Improvement Scale at 6 weeks post intervention as compared to baseline, devided by the total number of participants in that specific group. The CGI-Improvement Scale has seven response options (from 1 as Very Much Improved to 7 as Very Much Worsened) for answers to the question "Compared to your sense of smell before you started the nasal irrigations, how would you rate your sense of smell now" . Participants reporting 3 as "Minimally Improved", 2 as "Much Improved", or 1 as "Very Much Improved" in the CGI-I will be deemed responders to treatment, and the rate of responders will be compared between the two arms.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

51 participants

Primary outcome timeframe

Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups

Results posted on

2023-05-24

Participant Flow

Participant milestones

Participant milestones
Measure	Theophylline 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
Overall Study STARTED	26	25
Overall Study COMPLETED	22	23
Overall Study NOT COMPLETED	4	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Theophylline n=26 Participants 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=25 Participants 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Total n=51 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=26 Participants	0 Participants n=25 Participants	0 Participants n=51 Participants
Age, Categorical Between 18 and 65 years	25 Participants n=26 Participants	22 Participants n=25 Participants	47 Participants n=51 Participants
Age, Categorical >=65 years	1 Participants n=26 Participants	3 Participants n=25 Participants	4 Participants n=51 Participants
Age, Continuous	42.43 years STANDARD_DEVIATION 11.63 • n=26 Participants	47.08 years STANDARD_DEVIATION 13.89 • n=25 Participants	45.96 years STANDARD_DEVIATION 13.11 • n=51 Participants
Sex: Female, Male Female	19 Participants n=26 Participants	17 Participants n=25 Participants	36 Participants n=51 Participants
Sex: Female, Male Male	7 Participants n=26 Participants	8 Participants n=25 Participants	15 Participants n=51 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United States	26 participants n=26 Participants	25 participants n=25 Participants	51 participants n=51 Participants

PRIMARY outcome

Timeframe: Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups

Population: This outcome measure could be assessed only from the participants that completed CGI-I at 6 weeks post intervention.

UPSIT 0-40 with higher scores indicating better results. The response rate defined as the number of participants in each group self-reporting of at least slightly better improvement in the Clinical Global Improvement Scale at 6 weeks post intervention as compared to baseline, devided by the total number of participants in that specific group. The CGI-Improvement Scale has seven response options (from 1 as Very Much Improved to 7 as Very Much Worsened) for answers to the question "Compared to your sense of smell before you started the nasal irrigations, how would you rate your sense of smell now" . Participants reporting 3 as "Minimally Improved", 2 as "Much Improved", or 1 as "Very Much Improved" in the CGI-I will be deemed responders to treatment, and the rate of responders will be compared between the two arms.

Outcome measures

Outcome measures
Measure	Theophylline n=22 Participants 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=23 Participants 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
UPSIT	59 percentage of participants	43 percentage of participants

SECONDARY outcome

Timeframe: Comparison at 6 weeks post-intervention from baseline

Population: The outcome measure could be assessed only on subjects that completed UPSIT test at 6 weeks post-intervention

UPSIT 0-40 with higher scores indicating better smell. This test is an objective, clinically validated 40-question forced-choice odor identification test where microencapsulated odorants on a strip are released by scratching. Out of a total of 40 points, normosmia is defined as ≥34 for males and ≥35 for females, and an increase in ≥4 points will be deemed a clinically significant improvement in symptoms.

Outcome measures

Outcome measures
Measure	Theophylline n=22 Participants 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=23 Participants 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
University of Pennsylvania Smell Identification Test (UPSIT)	3 score on a scale Interval -1.0 to 7.0	0 score on a scale Interval -2.0 to 6.0

SECONDARY outcome

Timeframe: Comparison at 6 weeks post-intervention from baseline

Population: Since the outcome is measuring the change in QOD, only the data from participant completing QOD at baseline and 6 weeks were included

Questionnaire for Olfactory Dysfunction (QOD) assesses health-related quality of life of participants based on four factors such as eating, mental health, social interactions, or fear of dysfunction.. The survey also includes questions on parosmia, a phenomena of COVID-related OD. The QOD consists of 17 statements that participants score from 0-3, resulting in a total score from 0 to 51. Higher scores reflect better olfactory-specific QOL.

Outcome measures

Outcome measures
Measure	Theophylline n=22 Participants 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=23 Participants 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
Change in Questionnaire for Olfactory Dysfunction (QOD) From Baseline to 6 Weeks Post Intervention	0.86 score on a scale Interval -0.57 to 2.85	1.43 score on a scale Interval -0.29 to 3.14

SECONDARY outcome

Timeframe: Baseline assessment

Population: This was a baseline assessment only, so all randomized participants are analyzed.

The SF-36 is a well-established 36-item questionnaire evaluating physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. This test allows us to study the overall quality of life for those suffering from COVID-19 related OD. There is no single overall score for SF-36. The SF 36 generates 8 subscales with scores ranging from 0 (worst) to 100 (best). General health domain scores are reported here.

Outcome measures

Outcome measures
Measure	Theophylline n=26 Participants 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=25 Participants 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
36-Item Short Form Health Survey (SF-36)	75 score on a scale Interval 40.0 to 100.0	80 score on a scale Interval 50.0 to 100.0

SECONDARY outcome

Timeframe: Comparison of response rate at 6 weeks post-intervention from baseline between the 2 study groups

Population: This outcome is assessed only for participants that have ODOR assessed at baseline and at 6 months.

The ODOR is a 28-item QOL instrument with a total score ranging from 0 to 112 points. Higher scores indicate worse QOL with higher degree of dysfunction and limitation. A decrease of 15 or more points is deemed to be a clinically significant improvement in QOL.

Outcome measures

Outcome measures
Measure	Theophylline n=22 Participants 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=23 Participants 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
Olfactory Dysfunction Outcomes Rating (ODOR)	-6.5 score on a scale Interval -11.5 to -1.5	-4.5 score on a scale Interval -10.5 to 2.0

Adverse Events

Theophylline

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Theophylline n=26 participants at risk 400mg theophylline capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.	Placebo n=25 participants at risk 500mg lactose capsule diluted in 240 mL isotonic nasal saline lavage twice daily. Theophylline Powder: Theophylline is a known phosphodiesterase inhibitor in the treatment of asthma. Evidence for post-viral olfactory dysfunction suggests sensory axonal regeneration and olfactory signaling may rely on elevated levels of secondary messengers cAMP and cGMP, a known effect of theophylline. Therefore it is hypothesized to help treat COVID-related smell dysfunction, especially if delivered intranasally. Twice daily nasal irrigation with 400 mg theophylline capsules and USP Grade Sodium Chloride \& Sodium Bicarbonate Mixture (pH balanced, Isotonic \& Preservative \& Iodine Free) commercially prepared packets dissolved in 240 ml of distilled water.
Blood and lymphatic system disorders fluid retension/extremity swelling	0.00% 0/26 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	4.0% 1/25 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
General disorders Parosmia and Headache	3.8% 1/26 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	0.00% 0/25 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
General disorders Lightheadedness	7.7% 2/26 • Number of events 2 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	12.0% 3/25 • Number of events 3 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
Gastrointestinal disorders Nausea	3.8% 1/26 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	4.0% 1/25 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
Gastrointestinal disorders Diarrhea	3.8% 1/26 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	4.0% 1/25 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
General disorders Abdominal pain	3.8% 1/26 • Number of events 1 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	8.0% 2/25 • Number of events 2 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
General disorders Insomnia	11.5% 3/26 • Number of events 3 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	16.0% 4/25 • Number of events 4 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
Nervous system disorders Tremors	7.7% 2/26 • Number of events 2 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	4.0% 1/25 • Number of events 2 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.
Cardiac disorders Tachycardia	7.7% 2/26 • Number of events 2 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.	12.0% 3/25 • Number of events 3 • All participants were monitored for adverse events throughout participation in the study intervention (week 1 through week 6). The definition of adverse events/serious adverse events do not differ from the Clinical Trials definition.

Additional Information

Research Statistician

Washington University in Saint Louis

Phone: 3143621077

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place