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NCT03443414

Dose Ranging Study of RPL554 in Chronic Obstructive Pulmonary Disease (COPD) Patients

Completed Phase 2 Results posted Last updated 4 June 2019
What this trial tests

Phase 2 trial testing RPL554 suspension in COPD in 405 participants. Completed in 7 February 2018.

Timeline
1 June 2017
Primary endpoint
23 January 2018
7 February 2018

Quick facts

Lead sponsorVerona Pharma plc
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingdouble
Primary purposetreatment
Enrollment405
Start date1 June 2017
Primary completion23 January 2018
Estimated completion7 February 2018
Sites49 locations across United Kingdom, Germany, Poland, Romania, Bulgaria, Czechia

Drugs / interventions tested

Conditions studied

Sponsor

Verona Pharma plc — full company profile →

Who can join

Adults 40 to 75, any sex, with COPD. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Mean Change From Baseline in Peak FEV1 (Over 3 Hours) at Week 4 Primary · Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).

Spirometry assessments were used to assess pulmonary function including the forced expiratory volume in 1 second (FEV1). Peak FEV1 at Week 4 was defined as the maximum post-dose value among the 30 minutes, 1, 2 and 3 hour assessments collected at Visit 6. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. A mixed model for repeated measures (MMRM) was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The l

GroupValue95% CI
RPL554 0.75 mg0.2030.152 – 0.253
RPL554 1.5 mg0.2090.160 – 0.258
RPL554 3.0 mg0.2570.208 – 0.306
RPL554 6.0 mg0.1960.147 – 0.246
Placebo0.0570.007 – 0.106
Mean Change From Baseline FEV1 to Morning Trough FEV1 at Week 4 Secondary · Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).

Morning trough FEV1 was defined as the last pre-dose value at Visit 6. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. MMRM was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The LS mean change from baseline FEV1 to morning trough FEV1 at Week 4 is presented.

GroupValue95% CI
RPL554 0.75 mg0.007-0.038 – 0.053
RPL554 1.5 mg-0.019-0.063 – 0.025
RPL554 3.0 mg0.040-0.003 – 0.084
RPL554 6.0 mg-0.026-0.071 – 0.018
Placebo-0.028-0.072 – 0.016
Mean Change From Baseline FEV1 to Average FEV1 (Over 12 Hours) at Day 1 and Week 4 Secondary · Baseline (pre-dose, Visit 2), up to 12 hours post-dose at Visit 2 (Day 1) and Visit 6 (Week 4).

Average FEV1 over 12 hours was defined as the area under the curve from 0 to 12 hours post-dose (AUC\[0-12\]) of the FEV1 values collected during the visit under analysis (Day 1 or Week 4), divided by the length of the time interval of interest (in hours). The AUC was calculated using the trapezoidal rule. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. MMRM was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random

Day 1
GroupValue95% CI
RPL554 0.75 mg0.0880.058 – 0.117
RPL554 1.5 mg0.0770.048 – 0.107
RPL554 3.0 mg0.1030.074 – 0.132
RPL554 6.0 mg0.0950.065 – 0.125
Placebo0.008-0.022 – 0.038
Week 4
GroupValue95% CI
RPL554 0.75 mg0.039-0.007 – 0.085
RPL554 1.5 mg0.0520.008 – 0.096
RPL554 3.0 mg0.0850.040 – 0.130
RPL554 6.0 mg0.031-0.014 – 0.076
Placebo-0.033-0.079 – 0.012
Mean Change From Baseline in COPD Symptoms Using the Exacerbations of Chronic Pulmonary Disease Tool Patient-Reported Outcome (EXACT-PRO) Scoring at Week 4 Secondary · Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).

Patients completed an electronic diary (e-diary) once daily which used the 14-item EXACT-PRO instrument to assess COPD symptoms. The EXACT-PRO instrument contains 11 respiratory symptom questions that comprise the derivative Evaluating Respiratory Symptoms (E-RS) instrument that was used to measure the effect of treatment with RPL554 on the severity of COPD symptoms overall. The E-RS tool contains 3 subscales to assess breathlessness, cough/sputum and chest symptoms. In addition to the subscale scores, a total score for the E-RS part was obtained. The raw totals for the E-RS score and for each

E-RS Total Score
GroupValue95% CI
RPL554 0.75 mg-1.07-2.00 – -0.14
RPL554 1.5 mg-1.26-2.16 – -0.35
RPL554 3.0 mg-0.80-1.69 – 0.10
RPL554 6.0 mg-0.92-1.81 – -0.02
Placebo1.190.30 – 2.08
E-RS Breathlessness Score
GroupValue95% CI
RPL554 0.75 mg-0.46-0.92 – -0.01
RPL554 1.5 mg-0.63-1.07 – -0.18
RPL554 3.0 mg-0.48-0.92 – -0.04
RPL554 6.0 mg-0.48-0.92 – -0.04
Placebo0.470.03 – 0.90
E-RS Cough/Sputum Score
GroupValue95% CI
RPL554 0.75 mg-0.22-0.50 – 0.07
RPL554 1.5 mg-0.30-0.58 – -0.03
RPL554 3.0 mg-0.14-0.41 – 0.13
RPL554 6.0 mg-0.21-0.48 – 0.06
Placebo0.360.09 – 0.63
E-RS Chest Symptoms Score
GroupValue95% CI
RPL554 0.75 mg-0.39-0.70 – -0.08
RPL554 1.5 mg-0.32-0.62 – -0.02
RPL554 3.0 mg-0.19-0.48 – 0.11
RPL554 6.0 mg-0.22-0.52 – 0.07
Placebo0.350.05 – 0.64
Mean Change From Baseline in Breathlessness as Assessed Using the St George's Respiratory Questionnaire (SGRQ) at Week 4 Secondary · Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).

Patients completed the COPD specific SGRQ (SGRQ-C) consisting of 14 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range

SGRQ-C Total score
GroupValue95% CI
RPL554 0.75 mg-2.56-5.13 – 0.02
RPL554 1.5 mg-3.18-5.72 – -0.65
RPL554 3.0 mg-2.63-5.24 – -0.01
RPL554 6.0 mg-3.01-5.51 – -0.51
Placebo-0.33-2.90 – 2.23
SGRQ-C Symptoms score
GroupValue95% CI
RPL554 0.75 mg-4.73-7.99 – -1.46
RPL554 1.5 mg-1.89-5.11 – 1.33
RPL554 3.0 mg-2.17-5.50 – 1.17
RPL554 6.0 mg-4.33-7.51 – -1.16
Placebo1.25-2.02 – 4.51
SGRQ-C Activity score
GroupValue95% CI
RPL554 0.75 mg-2.19-5.30 – 0.91
RPL554 1.5 mg-4.28-7.34 – -1.23
RPL554 3.0 mg-2.70-5.85 – 0.46
RPL554 6.0 mg-2.75-5.76 – 0.27
Placebo-2.16-5.25 – 0.94
SGRQ-C Impact score
GroupValue95% CI
RPL554 0.75 mg-1.73-4.91 – 1.46
RPL554 1.5 mg-2.93-6.06 – 0.20
RPL554 3.0 mg-2.96-6.20 – 0.28
RPL554 6.0 mg-2.80-5.89 – 0.29
Placebo0.11-3.07 – 3.28
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Secondary · Up to end of study (approximately 6 weeks)

The number of patients with TEAEs for each the following categories are presented: any TEAE, any drug-related TEAE, any severe TEAE, any serious TEAE, serious drug-related TEAE, any TEAE leading to drug interruption, any TEAE leading to drug discontinuation, and any TEAE leading to death. All AEs which started after the first dose of investigational product.or started prior to first dose and worsened, based on the Investigator assessment of severity, on or after first dose were considered to be treatment-emergent.

Any TEAE
GroupValue95% CI
RPL554 0.75 mg27
RPL554 1.5 mg36
RPL554 3.0 mg29
RPL554 6.0 mg29
Placebo31
Any drug-related TEAE
GroupValue95% CI
RPL554 0.75 mg8
RPL554 1.5 mg11
RPL554 3.0 mg12
RPL554 6.0 mg8
Placebo10
Any severe TEAE
GroupValue95% CI
RPL554 0.75 mg4
RPL554 1.5 mg1
RPL554 3.0 mg2
RPL554 6.0 mg1
Placebo2
Any serious TEAE
GroupValue95% CI
RPL554 0.75 mg2
RPL554 1.5 mg2
RPL554 3.0 mg1
RPL554 6.0 mg1
Placebo1
Any serious drug-related TEAE
GroupValue95% CI
RPL554 0.75 mg1
RPL554 1.5 mg1
RPL554 3.0 mg0
RPL554 6.0 mg0
Placebo0
Any TEAE leading to drug interruption
GroupValue95% CI
RPL554 0.75 mg1
RPL554 1.5 mg0
RPL554 3.0 mg1
RPL554 6.0 mg0
Placebo0
Any TEAE leading to drug discontinuation
GroupValue95% CI
RPL554 0.75 mg6
RPL554 1.5 mg1
RPL554 3.0 mg4
RPL554 6.0 mg2
Placebo2
Any TEAE leading to death
GroupValue95% CI
RPL554 0.75 mg0
RPL554 1.5 mg1
RPL554 3.0 mg0
RPL554 6.0 mg1
Placebo0

Adverse events — posted to ClinicalTrials.gov

Time frame: TEAEs were collected from the first dose of investigational product up to 2 weeks after the end of the study (Visit 6) (approximately 6 weeks).. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

RPL554 0.75 mg
Serious: 2/81 (2%)
Deaths: 0/81
RPL554 1.5 mg
Serious: 2/81 (2%)
Deaths: 1/81
RPL554 3.0 mg
Serious: 1/82 (1%)
Deaths: 0/82
RPL554 6.0 mg
Serious: 1/80 (1%)
Deaths: 1/80
Placebo
Serious: 1/79 (1%)
Deaths: 0/79

Serious adverse events (9 terms)

ReactionSystemRPL554 0.75 mgRPL554 1.5 mgRPL554 3.0 mgRPL554 6.0 mgPlacebo
DeathGeneral disorders
Angina pectorisCardiac disorders
Mitral valve incompetenceCardiac disorders
Obstructive pancreatitisGastrointestinal disorders
Oesophageal varices haemorrhageGastrointestinal disorders
Hepatic cirrhosisHepatobiliary disorders
Hepatic encephalopathyNervous system disorders
Completed suicidePsychiatric disorders
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
Other adverse events (17 terms — click to expand)

ReactionSystemRPL554 0.75 mgRPL554 1.5 mgRPL554 3.0 mgRPL554 6.0 mgPlacebo
NasopharyngitisInfections and infestations
HeadacheNervous system disorders
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
CoughRespiratory, thoracic and mediastinal disorders
DyspneaRespiratory, thoracic and mediastinal disorders
HypertensionVascular disorders
Productive coughRespiratory, thoracic and mediastinal disorders
NauseaGastrointestinal disorders
RhinitisInfections and infestations
DizzinessNervous system disorders
Supraventricular extrasystolesCardiac disorders
Ventricular extrasystolesCardiac disorders
Atrial fibrillationCardiac disorders
Dry mouthGastrointestinal disorders
DiarrheaGastrointestinal disorders
Electrocardiogram QT prolongedInvestigations
ArthralgiaMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Death, Angina pectoris, Mitral valve incompetence, Obstructive pancreatitis, Oesophageal varices haemorrhage, Hepatic cirrhosis, Hepatic encephalopathy, Completed suicide.

Data from ClinicalTrials.gov NCT03443414 adverse events section.

Sponsor's own description

The study investigates the effect of 4 weeks of twice daily treatment of four different doses of RPL554 (a phosphodiesterase \[PDE\]3/4 inhibitor) or placebo in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Patients will be equally allocated to one of the five treatment options.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases.
    Li H, Zuo J, Tang W. · · 2018 · cited 355× · PMID 30386231 · DOI 10.3389/fphar.2018.01048
  2. An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022.
    Crocetti L, Floresta G, Cilibrizzi A, Giovannoni MP. · · 2022 · cited 85× · PMID 35956914 · DOI 10.3390/molecules27154964
  3. Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease.
    Rodrigues SO, Cunha CMCD, Soares GMV, Silva PL, et al · · 2021 · cited 61× · PMID 34681202 · DOI 10.3390/ph14100979
  4. A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD.
    Singh D, Martinez FJ, Watz H, Bengtsson T, et al · · 2020 · cited 51× · PMID 32041601 · DOI 10.1186/s12931-020-1307-4
  5. Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD.
    Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, et al · · 2023 · cited 21× · PMID 37533771 · DOI 10.2147/copd.s413436
  6. Symptom Improvement Following Treatment with the Inhaled Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine in Patients with Moderate to Severe COPD - A Detailed Analysis.
    Watz H, Rickard K, Rheault T, Bengtsson T, et al · · 2020 · cited 16× · PMID 32982212 · DOI 10.2147/copd.s263025
  7. Revefenacin: A Once-Daily, Long-Acting Bronchodilator For Nebulized Treatment Of COPD.
    Donohue JF, Mahler DA, Sethi S. · · 2019 · cited 5× · PMID 31908443 · DOI 10.2147/copd.s157654
  8. Advancing Obstructive Airway Disease Treatment: Dual PDE3/4 Inhibition as a Therapeutic Strategy.
    Sherpa RT, Koziol-White CJ, Panettieri RA. · · 2025 · cited 1× · PMID 40358183 · DOI 10.3390/cells14090659

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