Trial Outcomes & Findings for PT027 Compared to PT007 in Patients With Asthma With Mannitol-induced Acute Airway Obstruction (NCT NCT05555290)

This study was conducted from 28 September 2022 to 18 November 2024 at 11 study centers in the United States of America (USA). Participants were enrolled separately to Part 1 and Part 2 of the study. Both parts were conducted independently and no cross-over happened between the parts.

Participants who signed informed consent form (ICF) were enrolled into the study and those who met all eligibility criteria during screening were randomized and treated. All study assessments were performed as per the schedule. A total of 190 participants who provided the ICF were enrolled and screened at Visit 1. Of these, 105 participants met the eligibility criteria at Visit 2 and were randomized and treated in the study; thus, only data for these participants was collectable and analyzable.

PT027 Compared to PT007 in Patients With Asthma With Mannitol-induced Acute Airway Obstruction

The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The primary efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on treatment estimand in the Per Protocol (PP) analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the randomized set (RS). Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The primary efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the modified randomized set (mRS). Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of PT027 after a single dose compared with PT007 in reversal of acute airway obstruction, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The efficacy of PT027 after a single dose compared with PT007 in reversal of acute airway obstruction, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the RS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of PT027 after a single dose compared with PT007 in reversal of acute airway obstruction, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The efficacy of PT027 after a single dose compared with PT007 in reversal of acute airway obstruction, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the mRS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of PT027 compared with PT007 in the sustainability of effect of reversal of acute airway obstruction post-mannitol challenge 1 in participants with asthma on SABA as needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol is observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The efficacy of PT027 compared with PT007 in the sustainability of effect of reversal of acute airway obstruction post-mannitol challenge 1 in participants with asthma on SABA as needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the RS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of PT027 compared with PT007 in the sustainability of effect of reversal of acute airway obstruction post-mannitol challenge 1 in participants with asthma on SABA as needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The efficacy of PT027 compared with PT007 in the sustainability of effect of reversal of acute airway obstruction post-mannitol challenge 1 in participants with asthma on SABA as needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the mRS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of a single dose of PT027 compared with PT007 on post-dose speed of recovery of lung function following a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as needed treatment only was assessed. The time to return in minutes was calculated as the time it took for a participant to return to within 5% of the baseline (- 30 min) FEV1 value, post-mannitol challenge 2. FEV1 baseline is defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of 3.5 min.

The efficacy of a single dose of PT027 compared with PT007 on post-dose speed of recovery of lung function following a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as needed treatment only was assessed. The time to return in minutes was calculated as the time it took for a participant to return to within 5% of the baseline (- 30 min) FEV1 value, post-mannitol challenge 2. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the RS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The efficacy of a single dose of PT027 compared with PT007 on post-dose speed of recovery of lung function following a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as needed treatment only was assessed. The time to return in minutes was calculated as the time it took for a participant to return to within 5% of the baseline (- 30 min) FEV1 value, post-mannitol challenge 2. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the modified per protocol (mPP) analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of 3.5 min.

The efficacy of a single dose of PT027 compared with PT007 on post-dose speed of recovery of lung function following a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as needed treatment only was assessed. The time to return in minutes was calculated as the time it took for a participant to return to within 5% of the baseline (- 30 min) FEV1 value, post-mannitol challenge 2. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the mRS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as-needed treatment only was assessed. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. FEV1 at post-mannitol challenge 2 was the FEV1 result recorded at the end of mannitol challenge 2, i.e. before study intervention treatment, was expected to be at \~490 mins following the mannitol challenge 1. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the mPP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as-needed treatment only was assessed. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. FEV1 at post-mannitol challenge 2 was the FEV1 result recorded at the end of mannitol challenge 2, i.e. before study intervention treatment, was expected to be at \~490 mins following the mannitol challenge 1. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the RS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as-needed treatment only was assessed. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. FEV1 at post-mannitol challenge 2 was the FEV1 result recorded at the end of mannitol challenge 2, i.e. before study intervention treatment, was expected to be at \~490 mins following the mannitol challenge 1. The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the mPP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction induced by mannitol challenges in participants with asthma on SABA as-needed treatment only was assessed. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the acceptable efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. FEV1 at post-mannitol challenge 2 was the FEV1 result recorded at the end of mannitol challenge 2, i.e. before study intervention treatment, was expected to be at \~490 mins following the mannitol challenge 1. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the mRS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction in participants with asthma on SABA as-needed treatment only was assessed. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. The peak fall in FEV1 (in mL) was derived as: FEV1 at 7 hours (at 420 minutes) post-mannitol challenge 1 - FEV1 result recorded at mannitol challenge 2 completion, before initiation of the study intervention (at 430 minutes). The efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction in participants with asthma on SABA as-needed treatment only was assessed. FEV1 baseline was defined as the best FEV1 value (the highest FEV1 of the efforts) taken pre-mannitol challenge at - 30 min for Visit 2 and Visit 3. The peak fall in FEV1 (in mL) was derived as: FEV1 at 7 hours (at 420 minutes) post-mannitol challenge 1 FEV1 result recorded at mannitol challenge 2 completion, before initiation of the study intervention (at 430 minutes). If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the RS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The protective efficacy of prior repetitive doses of PT027 compared with PT007 on lung function fall in response to a recurring trigger of acute airway obstruction in participants with asthma on SABA as-needed treatment only was assessed. FEV1 at post-mannitol challenge 2 was the FEV1 result recorded at the end of mannitol challenge 2, i.e. before study intervention treatment, was expected to be at \~490 mins following the mannitol challenge 1. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the mRS. Superiority was concluded if the 2-sided p-value was \< 0.05.

The safety and tolerability of repeated dosing of PT027 as compared to PT007 in participants with asthma on SABA as-needed treatment only were assessed.