Allergic Conjunctivitis, Allergic Rhinitis Due to Tree Pollen, Allergic Rhinoconjunctivitis
Conditions
Keywords
Mountain Cedar, Juniperus Ashei, Pollinosis, Intra-lymphatic
Brief summary
TX-SMILE is an investigator-initiated, multi-center, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy, safety, and tolerability of intra-lymphatic administration of an approved allergenic extract for the immunotherapy treatment of allergic rhinitis and conjunctivitis due to pollen from the conifer Mountain Cedar.
Detailed description
TX-SMILE is an investigator-initiated, multi-center, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy, safety, and tolerability of an alternative injection site and associated adjustments to dosing and treatment regimen for allergen immunotherapy with a commercially-available, FDA-approved allergenic extract for the immunotherapy treatment of allergic rhinitis and conjunctivitis due to pollen from the conifer Mountain Cedar (Juniperus ashei). The purpose of this study is to evaluate the effect of a three-dose treatment series of ultrasonography-guided, intra-lymphatic immunotherapy injections over a two-month period prior to the start of the 2018-2019 Mountain Cedar allergy season in central Texas. Patients will be evaluated for safety and tolerability during the treatment period and for efficacy during the 2018-2019 Texas Mountain Cedar pollen season.
Interventions
BIOLOGICALIntra-lymphatic allergenic extract
Mountain Cedar pollen allergenic extract is an FDA-approved, commercially available product for diagnosis and hypo-sensitization treatment of allergies. The labeled use is deep subcutaneous or percutaneous injection. Hyposensitization treatment is typically a series of 30 - 70 injections over 3 - 5 years into the upper aspect of the arm. This investigation is a proof-of-concept study to evaluate an alternative hyposensitization regimen of 3 injections directly into an inguinal lymph node.
BIOLOGICALIntra-lymphatic placebo
The control group will receive a regimen of 3 injections of diluent (placebo) directly into an inguinal lymph node on the same schedule as the active treatment group.
Sponsors
Christopher Thompson, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Both male and female adult patients with a history of Season Allergic Rhinitis (SAR) with bothersome symptoms due to Mountain Cedar pollinosis confirmed using the Modified Quantitate Test (MQT; defined as a wheal greater than or equal to 3 millimeters larger than the diluent control) 2. Patients must be willing to provide written, informed consent 3. Patients must be willing and able to comply with study procedures 4. Women of childbearing potential must agree to use an acceptable form of contraception during the trial
Exclusion criteria
1. Patients less than 18 years of age 2. Clinically-significant chronic sinusitis, as determined by the investigator 3. History of anaphylaxis during Mountain Cedar skin prick testing 4. Participation in another clinical trial or use of an experimental medication within 30 days of enrollment 5. Medically significant co-morbidities that, in the opinion of the investigator, place the subject at increased risk during the study, including but not limited to: 1. Autoimmune diseases, other than allergic rhinitis (AR), stable allergic asthma, eczema and food sensitivities 2. Pulmonary or respiratory diseases other than stable asthma 3. Cancer other than basal cell carcinoma 4. Coronary artery disease or hypertension treated with beta-blockers 5. Clinically significant impairment of renal or hepatic function 6. Use of concomitant medications that, in the opinion of the investigator, may reduce the effectiveness of rescue treatments for anaphylaxis (e.g. beta-blockers) or alter the immune response to allergen immunotherapy (e.g., immunosuppressants, systemic corticosteroids) 7. Previously completed immunotherapy for Mountain Cedar pollinosis, that in the opinion of the investigator would interfere with the assessment or treatment of the patient 8. Inability to access suitable lymph nodes for intralympahtic injections 9. Plans to leave the area for a significant period of the upcoming Mountain Cedar pollen season 10. Pregnant or lactating females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Daily Total Combined Score (TCS) | Up to 4 months | The TCS is the preferred endpoint for rhinoconjunctivitis as recommended by the European Academy of Allergy and Clinical Immunology. Scoring of the TCS is from 0 to 38 on each day that it is assessed. The TCS is the sum of the symptom scores for runny nose, stuff nose, sneezing, itchy nose, gritty/itchy eyes, and watery eyes rated from no symptoms = 0 to severe symptoms = 3 plus the score for use of rescue medications for allergy symptoms 6 points for oral antihistamine, 6 points for eye drops, and 8 points for a nasal corticosteroid. Thus, a lower score represents fewer symptoms and associated need for allergy medication, while a higher score reflects more severe symptoms and the use of medication to treat symptoms. The TCS will be measured during the 2018-2019 Mountain Cedar pollen se |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Peak Pollen Season Days With a Lower Group Average Total Combined Score | Assessed up to 4 months, number of actual peak pollen season days was 27 | Evaluated during the 2018-2019 Texas Mountain Cedar allergy season. The number of days with a lower group average Total Combined Score, comparatively, in each Arm/Group are reported. Scoring of the TCS is from 0 to 38 on each day that it is assessed.The TCS is the sum of the symptom scores for runny nose, stuff nose, sneezing, itchy nose, gritty/itchy eyes, and watery eyes rated from no symptoms = 0 to severe symptoms = 3 plus the score for use of rescue medications for allergy symptoms 6 points for oral antihistamine, 6 points for eye drops, and 8 points for a nasal corticosteroid. Thus, a lower score represents fewer symptoms and associated need for allergy medication, while a higher score reflects more severe symptoms and the use of medication to treat symptoms. |
| Patient Reported Pain or Discomfort Following Intra-lymphatic Injections | Immediately after the ILIT procedure | Patient reported pain will be measured immediately after ILIT procedure using the Numeric Rating Scale 11 (NRS-11 rating scale). The NRS-11 asks patients to rate their pain on a scale from 0 (no pain or discomfort) to 11 (worst possible pain). |
| Patient-reported Treatment Satisfaction at the End of Study | Up to 4 months | Percentage of patients reporting satisfaction with their treatment |
| Total Safety Score (TSS) for Active and Placebo Treatment Groups | 8 weeks | The total safety score is a is based on World Allergy Organization grading for allergic reactions. Following allergen or placebo exposure via intra-lymphatic injection, patients are monitored for local and systemic allergic reactions for up to 60 minutes post-procedure. At each exposure, a score is rated on a scale from none = 0, local reactions only = 1, mild systemic reactions (WAO Grade 1/2) = 2, moderate systemic reaction (WAO Grade 3) = 3, and severe systemic reaction (WAO grade 4) = 4. The total safety score for each group is the sum of the individual scores of each patient across all three treatments (exposures). Thus, the subject may have a score from 0 to 12 with 0 reflecting no allergic reaction to the allergen and 12 reflecting severe allergic reactions, and the TSS for a group is the sum for all patients in the group. The TSS is used to elicit and grade adverse events of interest rather than for statistical analysis. |
| Number of Subjects Who: Experienced Anaphylaxis, Were Treated With Epinephrine, or Experienced Any Other Treatment-emergent SAE Within 60 Minutes of Any of Three Planned ILIT Procedures | 8 weeks | To evaluate the safety of ILIT for Mountain Cedar pollinosis relative to placebo control based on the proportion of subjects receiving allergenic extract versus the proportion of subjects receiving placebo that: 1. experience anaphylaxis, or 2. are treated with epinephrine, or 3. experience any other treatment-emergent, serious adverse event (SAE) within 60 minutes of any of the three planned ILIT procedures. |
| Percentage Change in Allergen-specific Serum IgE | Assessed prior to the first injection and to 4-8 weeks after the end of the 2018-2019 pollen season | Percentage change in allergen-specific serum IgE from baseline to the end-of-study visit between active ILIT and placebo. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Rescue Inhaler Uses by Patients With Asthma | Up to 4 month | Relative use of rescue inhalers by patients with comorbid asthma between active and placebo groups during the 2018-2019 Mountain Cedar pollen season. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intra-lymphatic Allergenic Extract A series of three injections of 0.1 mL (about 2 drops) of the allergenic extract of Mountain Cedar Pollen given every four weeks into a superficial inguinal lymph node through guidance via ultrasonography using a 1-mL hypodermic syringe with a 25-gauge or smaller needle.
Intra-lymphatic allergenic extract: Mountain Cedar pollen allergenic extract is an FDA-approved, commercially available product for diagnosis and hypo-sensitization treatment of allergies. The labeled use is deep subcutaneous or percutaneous injection. Hyposensitization treatment is typically a series of 30 - 70 injections over 3 - 5 years into the upper aspect of the arm. This investigation is a proof-of-concept study to evaluate an alternative hyposensitization regimen of 3 injections directly into an inguinal lymph node. | 11 |
| Intra-lymphatic Placebo Diluent as placebo control (sterile saline solution containing 0.4% phenol as a preservative and matched concentration of glycerin) given as a series of three injections of 0.1 mL (about 2 drops) every four weeks into a superficial inguinal lymph node through guidance via ultrasonography using a 1-mL hypodermic syringe with a 25-gauge or smaller needle.
Intra-lymphatic placebo: The control group will receive a regimen of 3 injections of diluent (placebo) directly into an inguinal lymph node on the same schedule as the active treatment group. | 10 |
| Total | 21 |
Baseline characteristics
| Characteristic | Intra-lymphatic Allergenic Extract | Intra-lymphatic Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 10 Participants | 21 Participants |
| Age, Continuous | 34 years | 32 years | 33 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 0 Participants | 0 Participants | 0 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 | 8 Participants | 7 Participants | 15 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 11 participants | 10 participants | 21 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 5 / 11 | 1 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 |
Outcome results
Primary
Average Daily Total Combined Score (TCS)
The TCS is the preferred endpoint for rhinoconjunctivitis as recommended by the European Academy of Allergy and Clinical Immunology. Scoring of the TCS is from 0 to 38 on each day that it is assessed. The TCS is the sum of the symptom scores for runny nose, stuff nose, sneezing, itchy nose, gritty/itchy eyes, and watery eyes rated from no symptoms = 0 to severe symptoms = 3 plus the score for use of rescue medications for allergy symptoms 6 points for oral antihistamine, 6 points for eye drops, and 8 points for a nasal corticosteroid. Thus, a lower score represents fewer symptoms and associated need for allergy medication, while a higher score reflects more severe symptoms and the use of medication to treat symptoms. The TCS will be measured during the 2018-2019 Mountain Cedar pollen se
Time frame: Up to 4 months
Population: Safety analysis included all participants who received at least one dose of study intervention. Efficacy analyses were on the per protocol dataset, which included participants who received three study treatment injections and completed at least 50% of expected electronic diary responses during the allergy season, with no major protocol violations. aLL enrolled patients met the criteria for inclusion in both the safety and per protocol analysis populations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intra-lymphatic Allergenic Extract | Average Daily Total Combined Score (TCS) | 10.1 units on a scale | Standard Deviation 3.3 |
| Intra-lymphatic Placebo | Average Daily Total Combined Score (TCS) | 13.0 units on a scale | Standard Deviation 7.8 |
p-value: 0.004Kruskal-Wallis
Secondary
Number of Peak Pollen Season Days With a Lower Group Average Total Combined Score
Evaluated during the 2018-2019 Texas Mountain Cedar allergy season. The number of days with a lower group average Total Combined Score, comparatively, in each Arm/Group are reported. Scoring of the TCS is from 0 to 38 on each day that it is assessed.The TCS is the sum of the symptom scores for runny nose, stuff nose, sneezing, itchy nose, gritty/itchy eyes, and watery eyes rated from no symptoms = 0 to severe symptoms = 3 plus the score for use of rescue medications for allergy symptoms 6 points for oral antihistamine, 6 points for eye drops, and 8 points for a nasal corticosteroid. Thus, a lower score represents fewer symptoms and associated need for allergy medication, while a higher score reflects more severe symptoms and the use of medication to treat symptoms.
Time frame: Assessed up to 4 months, number of actual peak pollen season days was 27
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intra-lymphatic Allergenic Extract | Number of Peak Pollen Season Days With a Lower Group Average Total Combined Score | 20 days |
| Intra-lymphatic Placebo | Number of Peak Pollen Season Days With a Lower Group Average Total Combined Score | 7 days |
Comparison: The secondary efficacy endpoint was the percentage of days during peak pollen season for which the average total combined score was lower in the immunotherapy group than in the placebo group.p-value: <0.05Clopper-Pearson binomial exact test
Secondary
Number of Subjects Who: Experienced Anaphylaxis, Were Treated With Epinephrine, or Experienced Any Other Treatment-emergent SAE Within 60 Minutes of Any of Three Planned ILIT Procedures
To evaluate the safety of ILIT for Mountain Cedar pollinosis relative to placebo control based on the proportion of subjects receiving allergenic extract versus the proportion of subjects receiving placebo that: 1. experience anaphylaxis, or 2. are treated with epinephrine, or 3. experience any other treatment-emergent, serious adverse event (SAE) within 60 minutes of any of the three planned ILIT procedures.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intra-lymphatic Allergenic Extract | Number of Subjects Who: Experienced Anaphylaxis, Were Treated With Epinephrine, or Experienced Any Other Treatment-emergent SAE Within 60 Minutes of Any of Three Planned ILIT Procedures | 0 Participants |
| Intra-lymphatic Placebo | Number of Subjects Who: Experienced Anaphylaxis, Were Treated With Epinephrine, or Experienced Any Other Treatment-emergent SAE Within 60 Minutes of Any of Three Planned ILIT Procedures | 0 Participants |
Secondary
Patient Reported Pain or Discomfort Following Intra-lymphatic Injections
Patient reported pain will be measured immediately after ILIT procedure using the Numeric Rating Scale 11 (NRS-11 rating scale). The NRS-11 asks patients to rate their pain on a scale from 0 (no pain or discomfort) to 11 (worst possible pain).
Time frame: Immediately after the ILIT procedure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intra-lymphatic Allergenic Extract | Patient Reported Pain or Discomfort Following Intra-lymphatic Injections | 0.5 units on a scale | Standard Deviation 0.5 |
| Intra-lymphatic Placebo | Patient Reported Pain or Discomfort Following Intra-lymphatic Injections | 0.5 units on a scale | Standard Deviation 0.5 |
Secondary
Patient-reported Treatment Satisfaction at the End of Study
Percentage of patients reporting satisfaction with their treatment
Time frame: Up to 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intra-lymphatic Allergenic Extract | Patient-reported Treatment Satisfaction at the End of Study | 91 percentage of participants |
| Intra-lymphatic Placebo | Patient-reported Treatment Satisfaction at the End of Study | 90 percentage of participants |
p-value: 0.23Wilcoxon (Mann-Whitney)
Secondary
Percentage Change in Allergen-specific Serum IgE
Percentage change in allergen-specific serum IgE from baseline to the end-of-study visit between active ILIT and placebo.
Time frame: Assessed prior to the first injection and to 4-8 weeks after the end of the 2018-2019 pollen season
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intra-lymphatic Allergenic Extract | Percentage Change in Allergen-specific Serum IgE | 148 percentage change in serum IgE | Standard Deviation 214 |
| Intra-lymphatic Placebo | Percentage Change in Allergen-specific Serum IgE | 201 percentage change in serum IgE | Standard Deviation 231 |
Secondary
Total Safety Score (TSS) for Active and Placebo Treatment Groups
The total safety score is a is based on World Allergy Organization grading for allergic reactions. Following allergen or placebo exposure via intra-lymphatic injection, patients are monitored for local and systemic allergic reactions for up to 60 minutes post-procedure. At each exposure, a score is rated on a scale from none = 0, local reactions only = 1, mild systemic reactions (WAO Grade 1/2) = 2, moderate systemic reaction (WAO Grade 3) = 3, and severe systemic reaction (WAO grade 4) = 4. The total safety score for each group is the sum of the individual scores of each patient across all three treatments (exposures). Thus, the subject may have a score from 0 to 12 with 0 reflecting no allergic reaction to the allergen and 12 reflecting severe allergic reactions, and the TSS for a group is the sum for all patients in the group. The TSS is used to elicit and grade adverse events of interest rather than for statistical analysis.
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intra-lymphatic Allergenic Extract | Total Safety Score (TSS) for Active and Placebo Treatment Groups | 3 score on a scale |
| Intra-lymphatic Placebo | Total Safety Score (TSS) for Active and Placebo Treatment Groups | 1 score on a scale |
Other Pre-specified
Total Number of Rescue Inhaler Uses by Patients With Asthma
Relative use of rescue inhalers by patients with comorbid asthma between active and placebo groups during the 2018-2019 Mountain Cedar pollen season.
Time frame: Up to 4 month
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intra-lymphatic Allergenic Extract | Total Number of Rescue Inhaler Uses by Patients With Asthma | 0 Rescue Inhaler Uses |
| Intra-lymphatic Placebo | Total Number of Rescue Inhaler Uses by Patients With Asthma | 0 Rescue Inhaler Uses |