Trial Outcomes & Findings for Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study) (NCT NCT03273257)

Last Updated: 2021-06-22

Results Overview

Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

14 participants

Primary outcome timeframe

90 days

Results posted on

2021-06-22

Participant Flow

Eligible patients were recruited at 3 expert centers for CTEPH in France, Germany and the UK between August 2018 and May 2020.

Participant milestones

Participant milestones
Measure	Riociguat Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Overall Study STARTED	7	7
Overall Study Started Treatment	7	6
Overall Study Underwent PEA	6	5
Overall Study COMPLETED	3	3
Overall Study NOT COMPLETED	4	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Riociguat Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Overall Study Death	0	1
Overall Study Inability to schedule PEA according to the protocol due to the COVID pandemic	1	1
Overall Study Study terminated	3	2

Baseline Characteristics

Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Riociguat n=7 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=6 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)	Total n=13 Participants Total of all reporting groups
Age, Continuous	66 years n=5 Participants	67 years n=7 Participants	66 years n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Body mass index	31.2 kg/m^2 STANDARD_DEVIATION 3.9 • n=5 Participants	25.4 kg/m^2 STANDARD_DEVIATION 1.7 • n=7 Participants	28.8 kg/m^2 STANDARD_DEVIATION 4.3 • n=5 Participants
PVR at diagnosis	944.0 dyn*sec/cm^5 STANDARD_DEVIATION 92.7 • n=5 Participants	1007.5 dyn*sec/cm^5 STANDARD_DEVIATION 368.2 • n=7 Participants	973.3 dyn*sec/cm^5 STANDARD_DEVIATION 248.8 • n=5 Participants
Mean pulmonary arterial pressure (mPAP) at diagnosis	50.3 mmHg STANDARD_DEVIATION 8.4 • n=5 Participants	53.2 mmHg STANDARD_DEVIATION 4.8 • n=7 Participants	51.5 mmHg STANDARD_DEVIATION 7.0 • n=5 Participants
Received beta blockers between enrollment and PEA	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Received vitamin K antagonists between enrollment and PEA	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Received new/direct oral anticoagulants between enrollment and PEA	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants

PRIMARY outcome

Timeframe: 90 days

Population: All participants who received at least one dose of randomized study drug and underwent PEA before study termination

Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)	-28.4 percentage of baseline PVR Standard Deviation 16.2	-6.9 percentage of baseline PVR Standard Deviation 27.9

SECONDARY outcome

Timeframe: 270 days

Population: All participants who received at least one dose of randomized study drug and completed the study prior to study termination

Pulmonary vascular resistance (PVR) will be assessed at baseline and 6 months post pulmonary endarterectomy (PEA). The change in PVR will be assessed as percentage.

Outcome measures

Outcome measures
Measure	Riociguat n=3 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=3 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)	-68.1 percentage of baseline PVR Standard Deviation 9.8	-83.0 percentage of baseline PVR Standard Deviation 2.2

SECONDARY outcome

Timeframe: 270 days

Population: All participants who underwent PEA before study termination

All deaths occurring post-randomization until the last visit will be included. All PH-related hospitalizations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomization until 6 months after PEA will be included. The worst value for World Health Organization (WHO) functional class after treatment will be used.

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Number of Patients With Either All-cause Death, PH-related Hospitalization, Need for PAH-targeted Therapy or WHO Functional Class Unchanged or Worse Between Randomization and 6 Months Post Pulmonary Endarterectomy (Composite Endpoint)	6 Participants	5 Participants

SECONDARY outcome

Timeframe: intraoperative

Population: All participants who underwent PEA before study termination

Circulatory arrest time will be measured in minutes

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Intraoperative Circulatory Arrest Time	32 minutes Standard Deviation 9	40 minutes Standard Deviation 12

SECONDARY outcome

Timeframe: intraoperative

Population: All participants who underwent PEA before study termination

The occurrence of any of the following complications will be assessed: * Bleeding and/or blood loss \>1 L in 12 hours * Airway bleed with need for extracorporeal membrane oxygenation * Any use of extracorporeal membrane oxygenation for respiratory or hemodynamic support, specified as veno-venous or veno-arterial * Prolonged ventilation \>96 hours * Need for tracheostomy * Need for drainage of pericardial effusion * Neurological complications, ie, stroke, cerebral, subdural bleeding * Reintubation or noninvasive ventilation for reperfusion response * Hemoptysis requiring any intervention * Renal failure requiring dialysis * Wound infections * Pneumonia * Prolonged need for inotropic support (≥ 5 days)

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: intraoperative

Population: All participants who underwent PEA

Classed as easier than normal (1); normal (2); more difficult than normal (3)

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane Easier than normal	1 Participants	1 Participants
Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane Normal	3 Participants	4 Participants
Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane More difficult than normal	2 Participants	0 Participants

SECONDARY outcome

Timeframe: intraoperative

Population: All participants who underwent PEA before study termination

Classed as better than expected (1); as expected (2); worse than expected (3)

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance As expected	6 Participants	5 Participants
Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance Worse than expected	0 Participants	0 Participants
Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance Better than expected	0 Participants	0 Participants

SECONDARY outcome

Timeframe: intraoperative

Population: All participants who underwent PEA before study termination

Classed as more solid than usual (1); normal (2); more friable than usual (3)

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall More solid than usual	0 Participants	0 Participants
Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall Normal	4 Participants	5 Participants
Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall More friable than usual	2 Participants	0 Participants

SECONDARY outcome

Timeframe: 270 days

Population: All participants who underwent PEA before study termination

All deaths occurring during the whole course of the study

Outcome measures

Outcome measures
Measure	Riociguat n=6 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=5 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Number of Patients Who Died During the Course of the Study	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 90 days

Population: All participants who received at least one dose of randomized study drug

Only withdrawals after randomization but before PEA will be included

Outcome measures

Outcome measures
Measure	Riociguat n=7 Participants Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=6 Participants Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Patients Who Withdraw During the Randomized Treatment Phase	1 Participants	1 Participants

Adverse Events

Riociguat

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 5 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Riociguat n=7 participants at risk Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. Riociguat will be initiated at 1 mg. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability. PEA will be performed at the end of medical treatment (Day 90)	Placebo n=6 participants at risk Patients will receive placebo for 3 months followed by pulmonary endarterectomy. Placebo will be given analogue to riociguat with matching tablets. PEA will be performed at the end of medical treatment (Day 90)
Infections and infestations Mediastinitis	14.3% 1/7 • Number of events 1 • From informed consent until study completion (typically 9-12 months) or early termination Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.	0.00% 0/6 • From informed consent until study completion (typically 9-12 months) or early termination Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/7 • From informed consent until study completion (typically 9-12 months) or early termination Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.	16.7% 1/6 • Number of events 1 • From informed consent until study completion (typically 9-12 months) or early termination Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/7 • From informed consent until study completion (typically 9-12 months) or early termination Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.	16.7% 1/6 • Number of events 1 • From informed consent until study completion (typically 9-12 months) or early termination Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug. Events were identified by investigator assessment at each visit, and from study data. All-cause mortality is reported based on all patients enrolled, including one patient who died prior to initiating treatment.

Other adverse events

Additional Information

David Jenkins, MD; Principal Investigator and ICA Board member

Papworth Hospital NHS Foundation Trust

Phone: +44 1223 638000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Both the International CTEPH Association and the financial sponsor can review results communications prior to public release and can embargo communications regarding trial results for up to 180 days from submission for review
Publication restrictions are in place

Restriction type: OTHER