Asthma
Conditions
Keywords
TD-8236, Asthma, Proof of concept
Brief summary
This will be a randomized, double-blind, placebo-controlled study. The study will use a three-period, six-sequence, complete-block, cross-over study design to characterize two doses of inhaled TD-8236 compared to placebo in subjects with mild asthma and a known response to an allergen. Each of the three periods will be 14 days, followed by a washout period before the next period.
Interventions
DRUGTD-8236
The study drug will be administered by inhalation in the morning for 14 days during each period. A washout period of at least 21 days will exist between subsequent periods.
DRUGPlacebo
The placebo will be administered by inhalation in the morning for 14 days during each period. A washout period of at least 21 days will exist between subsequent periods.
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 to 65 years of age * Willing and able to give informed consent and comply with study requirements * Documented physician-diagnosed asthma for ≥ 4 months prior to Screening * Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening and weighs ≥ 50 kg at Screening. * Women of child bearing potential must have a negative pregnancy test * Males and females must use a highly efficient birth control method * Pre-bronchodilator FEV1 ≥ 70% predicted * Documented allergy to at least one common allergen * Dual responder to inhaled bronchial challenges * Additional inclusion criteria apply
Exclusion criteria
* Positive for hepatitis A, B or C, HIV or tuberculosis * Clinically significant abnormalities of laboratory evaluations * Have abnormal ECG measurements * Any sign of respiratory tract infection within 6 weeks of screening * Have a current bacterial, parasitic, fungal or viral infection * History of life-threatening asthma * Uses or have used tobacco or nicotine-containing products within 6 months prior to screening * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | Day 14 of treatment period: 3 to 8 hours after allergen challenge | Values are reported as a weighted mean derived by calculating the AUC change from baseline over the relative time interval, divided by the time interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | Day 14 of treatment period: 3 to 8 hours after allergen challenge | — |
| Maximum Percentage Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | Day 14 of treatment period: 3 to 8 hours after allergen challenge | — |
| Area Under the Concentration-time Curve Over One 24-hour Dosing Interval (AUC0-24) of TD-8236 in Plasma | Day 14 of treatment period: Pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose | — |
| Area Under the Curve of Percentage Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | Day 14 of treatment period: 3 to 8 hours after allergen challenge | Values are reported as a weighted mean derived by calculating the AUC percentage change from baseline over the relative time interval, divided by the time interval. |
| Time to Maximum Observed Concentration (Tmax) of TD-8236 in Plasma Over a Dosing Interval | Day 14 of treatment period: Pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose | — |
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Day 1 to end of follow-up (up to approximately 98 days) | A TEAE was defined as any adverse event (AE) that begins on or after the date of first dose of study drug up to the date of last dose of study drug plus the number of days in the follow-up period. The severity of TEAEs were also assessed and were classified as mild, moderate or severe per the definitions below: Mild - The AE is noticeable to the participant and/or the investigator, but does not interfere with routine activity. Moderate - The AE interferes with routine activity, but responds to symptomatic therapy or rest. Severe - The AE significantly limits the participant's ability to perform routine activities despite symptomatic therapy. |
| Maximum Observed Plasma Concentration (Cmax) of TD-8236 in Plasma During Dosing Interval | Day 14 of treatment period: Pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose | — |
Countries
United Kingdom
Participant flow
Recruitment details
A total of 24 participants were enrolled at 2 sites in the United Kingdom.
Pre-assignment details
Participants were screened with an allergen challenge test within 35 days prior to first dosing. Participants received increasing concentrations of inhaled allergen until a decrease of ≥20% from preallergen forced expiratory volume (in 1 second) (FEV1) was observed during the 30 minutes following the most recent inhalation, and then monitored for a late asthmatic response (LAR).
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants were randomized to 1 of 6 treatment sequences. Each treatment period was 14 days with a 21 day washout between treatments. All participants were randomized to receive all study drugs. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age, Continuous | 42.0 years STANDARD_DEVIATION 11.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 10 / 24 | 9 / 23 | 9 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 | 0 / 24 |
Outcome results
Primary
Area Under the Curve of Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14
Values are reported as a weighted mean derived by calculating the AUC change from baseline over the relative time interval, divided by the time interval.
Time frame: Day 14 of treatment period: 3 to 8 hours after allergen challenge
Population: Only participants with quantifiable measurements are included here.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Curve of Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -0.53 liters | Standard Error 0.077 |
| TD-8236 150 mcg | Area Under the Curve of Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -0.54 liters | Standard Error 0.077 |
| TD-8236 1500 mcg | Area Under the Curve of Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -0.57 liters | Standard Error 0.079 |
p-value: 0.88195% CI: [-0.14, 0.12]Mixed Models Analysis
p-value: 0.57595% CI: [-0.17, 0.1]Mixed Models Analysis
Secondary
Area Under the Concentration-time Curve Over One 24-hour Dosing Interval (AUC0-24) of TD-8236 in Plasma
Time frame: Day 14 of treatment period: Pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose
Population: Only participants with quantifiable measurements are included here.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve Over One 24-hour Dosing Interval (AUC0-24) of TD-8236 in Plasma | 0.482 h*ng/mL | Geometric Coefficient of Variation 48.8 |
| TD-8236 150 mcg | Area Under the Concentration-time Curve Over One 24-hour Dosing Interval (AUC0-24) of TD-8236 in Plasma | 1.54 h*ng/mL | Geometric Coefficient of Variation 70.6 |
Secondary
Area Under the Curve of Percentage Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14
Values are reported as a weighted mean derived by calculating the AUC percentage change from baseline over the relative time interval, divided by the time interval.
Time frame: Day 14 of treatment period: 3 to 8 hours after allergen challenge
Population: Only participants with quantifiable measurements are included here.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Curve of Percentage Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -16.92 percentage change | Standard Error 2.512 |
| TD-8236 150 mcg | Area Under the Curve of Percentage Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -17.50 percentage change | Standard Error 2.516 |
| TD-8236 1500 mcg | Area Under the Curve of Percentage Change From Baseline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -17.97 percentage change | Standard Error 2.562 |
Secondary
Maximum Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14
Time frame: Day 14 of treatment period: 3 to 8 hours after allergen challenge
Population: Only participants with available data are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -0.83 liters | Standard Error 0.082 |
| TD-8236 150 mcg | Maximum Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -0.86 liters | Standard Error 0.082 |
| TD-8236 1500 mcg | Maximum Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -0.85 liters | Standard Error 0.084 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of TD-8236 in Plasma During Dosing Interval
Time frame: Day 14 of treatment period: Pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose
Population: Only participants with quantifiable measurements are included here.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Observed Plasma Concentration (Cmax) of TD-8236 in Plasma During Dosing Interval | 0.0207 ng/mL | Geometric Coefficient of Variation 46.4 |
| TD-8236 150 mcg | Maximum Observed Plasma Concentration (Cmax) of TD-8236 in Plasma During Dosing Interval | 0.160 ng/mL | Geometric Coefficient of Variation 54.3 |
Secondary
Maximum Percentage Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14
Time frame: Day 14 of treatment period: 3 to 8 hours after allergen challenge
Population: Only participants with available data are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Percentage Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -27.02 percentage change | Standard Error 2.79 |
| TD-8236 150 mcg | Maximum Percentage Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -28.18 percentage change | Standard Error 2.794 |
| TD-8236 1500 mcg | Maximum Percentage Decline in Forced Expiratory Volume (in 1 Second) (FEV1) From 3 to 8 Hours After Inhaled Allergen Challenge at Day 14 | -26.88 percentage change | Standard Error 2.843 |
Secondary
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
A TEAE was defined as any adverse event (AE) that begins on or after the date of first dose of study drug up to the date of last dose of study drug plus the number of days in the follow-up period. The severity of TEAEs were also assessed and were classified as mild, moderate or severe per the definitions below: Mild - The AE is noticeable to the participant and/or the investigator, but does not interfere with routine activity. Moderate - The AE interferes with routine activity, but responds to symptomatic therapy or rest. Severe - The AE significantly limits the participant's ability to perform routine activities despite symptomatic therapy.
Time frame: Day 1 to end of follow-up (up to approximately 98 days)
Population: Only participants with available data are included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any TEAE | 10 Participants |
| Placebo | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Moderate or Severe TEAE | 3 Participants |
| TD-8236 150 mcg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any TEAE | 9 Participants |
| TD-8236 150 mcg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Moderate or Severe TEAE | 3 Participants |
| TD-8236 1500 mcg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Any TEAE | 9 Participants |
| TD-8236 1500 mcg | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Moderate or Severe TEAE | 2 Participants |
Secondary
Time to Maximum Observed Concentration (Tmax) of TD-8236 in Plasma Over a Dosing Interval
Time frame: Day 14 of treatment period: Pre-dose and 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose
Population: Only participants with quantifiable measurements are included here.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Maximum Observed Concentration (Tmax) of TD-8236 in Plasma Over a Dosing Interval | 0.950 hours |
| TD-8236 150 mcg | Time to Maximum Observed Concentration (Tmax) of TD-8236 in Plasma Over a Dosing Interval | 0.550 hours |