Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Review Question
2.2. Search Strategy
2.3. Study Selection
2.4. Data Extraction
2.5. Endpoints
2.6. Strategy for Data Synthesis
2.7. Quality Score
3. Results
3.1. Study Characteristics
3.2. IL-4Rα Inhibitor
3.3. Anti-IL-5 mAbs
3.4. Anti-IL-17A mAbs
3.5. Anti-IL-33 mAbs
3.6. Anti-TSLP mAbs
3.7. LABAs
3.8. SGRMs
3.9. MABAs
3.10. DP2 Antagonists
3.11. Selective BTK Inhibitors
3.12. ENaC Inhibitors
3.13. Pan-JAK Inhibitors
3.14. Anti-Fel d 1 mAbs
3.15. Synthetic Amino-Benzothiazoles
3.16. Antifungal Triazoles
3.17. Probiotics
3.18. Risk of Bias
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study and Year | Class of Drug | ClinicalTrials.gov Identifier and/or Company ID | Study Characteristics | Treatment Duration (wks) | Number of Analysed Patients | Drugs, Doses, and Regimen of Administration | Comparator | Route of Administration | Inhaler Device (Brand) | Patients’ Characteristics | Age (Years) | Male (%) | Current Smokers (%) | Post Bronchodilator FEV1 (% Predicted) | Investigated Outcome | Jadad Score |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Moss et al., 2022, LEDA [36,37] | DP2 antagonist | NCT03683576 | Phase IIb, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 24 | 481 | Standard of care treatment + GB001 20 mg, 40 mg, 60 mg QD | Standard of care treatment + PCB | GB001 and PCB: PO | NA | Moderate to severe eosinophilic asthma (pre-bronchodilator FEV1 ≤ 85% predicted and airway reversibility or AHR; peripheral blood eosinophil count ≥ 250 cells/μL) | 51.8 | 35.8 | 0.0 | NA | FEV1, PEF, ACQ, symptoms control, and exacerbations | 3 |
Singh et al., 2022 [30,31] | Anti-IL-5 mAb | NCT03287310 | Phase I, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 1 day | 48 | As-needed SABA and stable low to moderate dose of ICS or ICS/LABA + single dose of depemokimab (GSK3511294) 2 mg, 10 mg, 30 mg, 100, 300 mg | As-needed SABA and stable low-to-moderate dose of ICS or stable low-to-moderate dose of ICS/LABA + PCB | SABA, ICS/LABA, ICS: oral inhalation; depemokimab: SC | NA | Mild to moderate asthma (pre-bronchodilator FEV1≥ 60% predicted, ACT score >19, and blood eosinophil count of ≥200 cells/μL) | 44.0 | 95.8 | 0.0 | 81.0 | FEV1 and eosinophil count | 5 |
Cass et al., 2021 [38,39] | Antifungal triazole | NCT02715570 | Phase I, single centre, two-part randomised, PCB-controlled, single-blind crossover study | 1 day | 9 | Single dose of PC945 5 mg | PCB | Oral inhalation | NA | Mild asthma | 37.7 | 66.7 | NA | NA | FEV1 | 2 |
Chupp et al., 2021, GRANIT [48,49,50] | SGRM | NCT03622112 | Phase IIb, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 12 | 805 | Velsecorat (AZD7594) 50μg, 90 µg, 180 µg, 360 µg, 720 µg QD | FF (100 µg QD); PCB | Oral inhalation | DPI (NA) | Asthma (patients who remain symptomatic on low dose BUD [200 μg BID in Europe and 180 μg BID in US] | 53.2 | 42.0 | NA | NA | FEV1, PEF, ACQ, symptoms control, FENO, rescue medication use, and exacerbations | 3 |
De Gaix et al., 2021 [51,52] | Anti-Fel d 1 mAb cocktail | NCT03838731 | Phase II, single-centre, randomised, PCB-controlled, double-blind parallel-group study | 1 day | 56 | Single dose of REGN1908-1909 600 mg | PCB | SC | NA | Mild asthma with cat allergy | 29.3 | 37.5 | NA | NA | FEV1 | 3 |
Siddiqui et al., 2021, EXHALE [28,29] | Synthetic aminobenzothiazole | NCT04046939 | Phase II, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 12 | 103 | Dexpramipexole (KNS-760704) 37.5 mg, 75 mg, 150 mg BID | PCB | PO | NA | Moderate to severe eosinophilic asthma (FEV1 < 80% predicted and bronchodilator FEV1 reversibility ≥ 12% and ≥200 mL) | 45.3 | 47.6 | 0.0 | NA | FEV1, ACQ, eosinophil count, FENO, and AQLQ | 3 |
Wechsler et al., 2021 [32,33] | Anti-IL-33 mAb | NCT03387852 | Phase II, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 12 | 296 | Progressive withdrawal of background medication with medium-to-high-dose FP/LABA + itepekimab (SAR440340/REGN3500) 300 mg Q2W with or without dupilumab 300 mg Q2W | Progressive withdrawal of background medication with medium-to-high-dose FP/LABA + PCB or dupilumab | FP/LABA: oral inhalation; itepekimab and dupilumab: SC | NA | Moderate to severe asthma (pre-bronchodilator FEV1 ≥ 50% and ≤85% predicted and bronchodilator FEV1 reversibility ≥ 12% and ≥200 mL; ≥1 severe exacerbation within 12 months prior to screening; FEV1 ≥ 20% reduction in response to a provocative concentration of inhaled methacholine of <8 mg/mL within 12 months prior to screening) | 49.1 | 36.0 | 0.0 | NA | FEV1, ACQ, symptoms control, eosinophil count, and FENO | 3 |
Miller et al., 2020 [34,35] | LABA | NCT03257995 | Phase II, multicentre, three-period complete block, randomised, PCB-controlled, double-blind crossover study | 2 | 54 | Background ICS medication and SABA + indacaterol maleate 150 μg QD | Background ICS medication and SABA + indacaterol acetate 150 μg QD; PCB | Oral inhalation | DPI (Breezhaler) | Asthma (pre-bronchodilator FEV1 ≥ 50% and ≤90% predicted normal, increase in FEV1 ≥ 12% and ≥ 200 mL within 30 min after administration of salbutamol 400 μg/albuterol 360 μg or equivalent dose) | 48.0 | 33.3 | 0.0 | 86.0 | FEV1, PEF, and rescue medication use | 3 |
Moermans et al., 2020 [44,45] | Probiotic | NCT03341403 | Phase II/III, single-centre, randomised, PCB-controlled, double-blind parallel-group study | 12 | 46 | Stable asthma treatment + Probiotical® TID (containing Lactobacillus, Bifidobacterium, and Streptococcus thermophilus, 18 billion bacteria per pill) | Stable asthma treatment + PCB | PO | NA | Severe uncontrolled asthma (ACQ score > 1.5) | 18.0–75.0 | NA | NA | NA | ACQ and eosinophil count | 3 |
NA, 2019 [25] | Selective BTK inhibitor | NCT03944707 | Phase II, multicentre, randomised, PCB-controlled, subject- and investigator-blinded parallel-group study | 12 | 76 | BUD/FOR 160/9 μg BID + remibrutinib (LOU064) 100 mg QD | BUD/FOR 160/9 μg BID + PCB | BUD/FOR: oral inhalation; LOU064 and PCB: PO | BUD/FOR: DPI (NA) | Inadequately controlled asthma | 50.7 | 34.2 | NA | NA | FEV1, PEF, ACQ, rescue medication use, and symptoms control | 3 |
NA, 2019 [27] | Pan-JAK inhibitor | NCT04150341 | Phase II, multicentre, randomised, PCB-controlled, double-blind crossover study | 2 | 24 | TD-8236 150 µg, 1500 µg QD | PCB | Oral inhalation | DPI (NA) | Mild asthma with a known response to an allergen challenge (pre-bronchodilator FEV1 ≥ 70% predicted) | 42.0 | 70.8 | NA | NA | FEV1 | 3 |
Bruns et al., 2019 [46,47] | IL-4Rα inhibitor | NCT03574805 | Phase I, multicentre, randomised, PCB-controlled, single-blind parallel-group study | ≅1.4 | 42 | AZD1402 (PRS-060) 2 mg, 6 mg, 20 mg, 60 mg BID | PCB | Oral inhalation | Nebuliser (InnoSpire Go) | Mild asthma (pre-bronchodilator FEV1 ≥ 70% predicted and FEV1/FVC ≥ 0.7) | 28.4 | 88.1 | 0.0 | NA | FENO | 2 |
NA, 2018 [23] | Anti-IL-33R mAb | NCT03393806 | Phase II, single-centre, randomised, PCB-controlled, double-blind parallel-group study | 12 | 17 | Standard of care treatment + melrilimab (GSK3772847/CNTO7160) 10 mg/kg Q4W | Standard of care treatment + PCB | Melrilimab and PCB: IV | NA | Moderate to severe asthma with allergic fungal airway disease | 56.9 | 70.6 | 0.0 | NA | FEV1, ACQ, eosinophil count, FENO, and AQLQ | 3 |
NA, 2018 [40,41] | Anti-IL-33 mAb | NCT03469934 | Phase II, multicentre, randomised, PCB-controlled, double-blind parallel-group study | ≅18 | 25 | Background medication with high dose ICS/LABA + single dose of etokimab (ANB-020) 300 mg/100 mL | Background medication with high dose ICS/LABA + PCB | ICS/LABA: oral inhalation; etokimab and PCB: IV | NA | Severe eosinophilic asthma | 38.5 | 72.0 | NA | NA | FEV1, eosinophil count, FENO, and exacerbations | 3 |
NA, 2017 [22] | anti-IL-17A mAb | NCT03299686 | Phase II, multicentre, randomised, PCB-controlled, subject- and investigator-blinded parallel-group study | 12 | 118 | Standard care of treatment + CJM112 300 mg QW for 4 wks, then Q2W up to 12 wks | Standard care of treatment + PCB | CJM112 and PCB: SC | NA | Inadequately controlled moderate to severe asthma (FEV1 ≥ 40% and ≤90% predicted; ACQ score ≥ 1.5; total serum IgE <1 50 IU/mL; peripheral blood eosinophils < 300/μL) | 56.6 | 39.8 | NA | NA | FEV1 and ACQ | 3 |
NA, 2017, [24] | Anti-IL-33R mAb | NCT03207243 | Phase IIa, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 16 | 165 | FP/SAL 500/50 μg BID for 2 wks, then switch to FP 500 μg BID for 2 wks, then FP dose reduction by 50% Q2W until discontinuation + melrilimab (GSK3772847/CNTO7160) 10 mg/kg Q4W | FP/SAL (500/50 μg BID) for 2 wks, then switch to FP (500 μg BID) for 2 wks, then FP dose reduction by 50% Q2W until discontinuation + PCB | FP/SAL, FP: oral inhalation; melrilimab and PCB: IV | FP/SAL, FP: DPI (Diskus) | Moderately severe asthma (bronchodilator FEV1 reversibility ≥ 12% and ≥200 mL; ACQ score ≥ 1.0 and <4.0) | 52.9 | 28.5 | 0.0 | NA | FEV1, PEF, ACQ, symptoms control, rescue eosinophil count, FENO, exacerbations and hospitalisations, and SGRQ | 3 |
NA, 2017 [53,54] | Anti-TSLP mAb fragment | NCT03138811 | Phase I, multicentre, randomised, PCB-controlled, double-blind parallel-group study | 12 | 28 | Ecleralimab (CSJ117) 4 mg QD | PCB | Oral inhalation | DPI (PulmoSol) | Mild atopic asthma with an early and late response to a common inhaled allergen challenge | 34.1 | 39.3 | NA | NA | FEV1 | 3 |
NA, 2017 [26] | ENaC inhibitor | NCT03135899 | Phase I, single-centre, randomised, PCB-controlled, double-blind, double-dummy crossover study | 2 days | 37 | BI 443651 100 μg, 400 μg, 1200 μg, thrice 12 h apart | PCB | Oral inhalation | SMI (Respimat) | Mild asthma upon methacholine challenge (pre-bronchodilator FEV1 ≥ 70% predicted; FEV1 ≥ 20% reduction in response to a provocative concentration of inhaled methacholine of ≤1 mg; ACQ score < 1.5) | 37.4 | 91.9 | 0.0 | NA | FEV1 | 3 |
NA, 2017 [42,43] | MABA | NCT03378648 | Phase I/II, single-centre, randomised, PCB-controlled, double-blind parallel-group study | 1 | 48 | CHF6366 40 μg, 80 μg, 160 μg, 240 μg QD | PCB | Oral inhalation | NA | Asthma (bronchodilator FEV1 reversibility ≥ 12% and ≥200 mL) | 38.1 | 64.6 | NA | NA | FEV1 | 3 |
Outcome | Treatment | Drug Class | Delta Effect | Suggested MCID [103] | Beneficial Clinically Relevant Effect |
---|---|---|---|---|---|
Trough FEV1 | Itepekimab 300 mg Q2W | Anti-IL-33 mAb | 140 mL (10–270) | >100 mL | Yes |
Indacaterol maleate 150 μg QD | LABA | 186 mL (129–243) | >100 mL | Yes | |
Peak FEV1 | Itepekimab 300 mg Q2W + dupilumab 300 Q2W | Anti-IL-33 mAb + anti IL-4/IL-13 mAb | 130 mL (10–250) | ≥12% and ≥200 mL | No |
PEF | Indacaterol maleate 150 μg QD | LABA | 33.00 L/min (25.60–40.30) | >5.39% | ? |
Morning PEF | Velsecorat 720 μg QD | SGRM | 16.60 L/min (8.03–25.17) | >5.39% | ? |
Evening PEF | Velsecorat 720 μg QD | SGRM | 11.99 L/min (3.57–20.42) | >5.39% | ? |
ACQ | Itepekimab 300 mg Q2W | Anti-IL-33 mAb | −0.42 points (−0.73–−0.12) | >0.5 points | Borderline |
Itepekimab 300 mg Q2W + dupilumab 300 mg Q2W | Anti-IL-33 mAb + anti IL-4/IL-13 mAb | −0.32 points (−0.63–−0.01) | >0.5 points | No | |
Velsecorat 720 μg QD | SGRM | −0.27 points (−0.43–−0.10) | >0.5 points | No | |
CJM112 300 mg QW | IL-17A mAb | −0.23 points (−0.40–−0.06) * | >0.5 points | No | |
Exacerbations | Velsecorat 720 μg QD | SGRM | 0.11 rate (0.04–0.25) | >−20% rate | Yes |
AQLQ | Itepekimab 300 mg Q2W | Anti-IL-33 mAb | 0.45 points (0.14–0.77) | >0.5 points | Borderline |
Itepekimab 300 mg Q2W + dupilumab 300 mg Q2W | Anti-IL-33 mAb + anti IL-4/IL-13 mAb | 0.43 points (0.11–0.75) | >0.5 points | Borderline |
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Calzetta, L.; Aiello, M.; Frizzelli, A.; Pistocchini, E.; Ritondo, B.L.; Rogliani, P.; Chetta, A. Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma. Biomedicines 2022, 10, 2330. https://doi.org/10.3390/biomedicines10092330
Calzetta L, Aiello M, Frizzelli A, Pistocchini E, Ritondo BL, Rogliani P, Chetta A. Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma. Biomedicines. 2022; 10(9):2330. https://doi.org/10.3390/biomedicines10092330
Chicago/Turabian StyleCalzetta, Luigino, Marina Aiello, Annalisa Frizzelli, Elena Pistocchini, Beatrice Ludovica Ritondo, Paola Rogliani, and Alfredo Chetta. 2022. "Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma" Biomedicines 10, no. 9: 2330. https://doi.org/10.3390/biomedicines10092330
APA StyleCalzetta, L., Aiello, M., Frizzelli, A., Pistocchini, E., Ritondo, B. L., Rogliani, P., & Chetta, A. (2022). Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma. Biomedicines, 10(9), 2330. https://doi.org/10.3390/biomedicines10092330