TerminatedNCT02138825RISE-IIPUpdated Dec 4, 2017Results posted

Efficacy and Safety of Riociguat in Patients With Symptomatic Pulmonary Hypertension (PH) Associated With Idiopathic Interstitial Pneumonias (IIP)

A Phase 2 interventional study of Riociguat (Adempas, BAY63-2521) and Placebo in Idiopathic Interstitial Pneumonias / Hypertension,Pulmonary, sponsored by Bayer. Terminated at 94 sites in 21 countries. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2017-12-04.

Sponsored by Bayer · Phase 2, Interventional, and Treatment

Why this study was terminated

Study terminated per recommendation of iDMC. On iDMC request, protocol amended to include 4-month safety follow-up for patients after withdrawal of riociguat.

Phase: Phase 2
Study type: Interventional
Enrollment: 147
Allocation: Randomized
Ages: 18 Years to 80 Years
Sex: All

Study summary

To evaluate the efficacy and safety of 26-weeks of treatment with riociguat vs. placebo in patients with symptomatic PH (pulmonary hypertension) associated with IIP (idiopathic interstitial pneumonias).

Read the detailed description

Number of participants with Adverse Events (AEs) will be reported in Adverse Events section.

Conditions studied

Idiopathic Interstitial Pneumonias / Hypertension,Pulmonary

Browse trials for

In context

Pneumonia

2,044 studies on the registry are indexed under Pneumonia; 283 are open to participants now.

This study's enrollment of 147 is above the median of 106 across 1,247 interventional studies indexed under Pneumonia.

Browse Pneumonia studies →

Lead sponsor

Bayer is the lead sponsor of 1,643 studies on the registry; 57 are open to participants now.

Of its 209 completed or terminated interventional studies of FDA-regulated products, 129 (62%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 80 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Men or women aged from ≥18 to ≤80 years
Diagnosed with one of the following (confirmed using a multidisciplinary approach, as per ATS(American Thoracic Society) / ERS(European Respiratory Society) / JRS (Japanese Respiratory Society) / ALAT(Latin American Thoracic Association) guidelines:
- Major IIPs (idiopathic interstitial pneumonias) diagnosis or suspected as one of the following:
- Idiopathic pulmonary fibrosis
- Idiopathic nonspecific interstitial pneumonia
- Respiratory bronchiolitis-interstitial lung disease
- Desquamative interstitial pneumonia
- Cryptogenic organizing pneumonia
- Acute interstitial pneumonia
- Rare IIPs diagnosis by one of the following:
- Idiopathic lymphoid interstitial pneumonia
- Idiopathic pleuroparenchymal fibroelastosis
- Unclassifiable idiopathic interstitial pneumonias
Forced Vital Capacity (FVC) ≥ 45 %
6MWD (6 minutes walking distance) ≥ 150 m to ≤ 450 m {under stable O2(oxygen) supplementation via nasal cannula}
Diagnosis of PH (pulmonary hypertension) confirmed by right heart catheter (RHC) with (mean artery pulmonary artery pressure )mPAP ≥ 25 mmHg and (pulmonary artery wedge pressure)PAWP ≤15 mmHg at rest
Systolic blood pressure (SBP) ≥ 95 mmHg and no signs or symptoms of hypotension
WHO functional class II-IV
Women of childbearing potential can only be included in the study if a pregnancy test is negative. Women of childbearing potential must agree to use adequate contraception when sexually active. 'Adequate contraception' is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration

Exclusion criteria

Known significant left heart disease:
- Pulmonary venous hypertension indicated by baseline pulmonary capillary wedge pressure > 15 mmHg
- Symptomatic coronary artery disease
- Systolic left-ventricular dysfunction with an left ventricular ejection fraction (LVEF) \<45%
Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization
Any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening. Massive hemoptysis being defined as acute bleeding >240 mL in a 24-hour period or recurrent bleeding >100 mL/d over several days
Difference > 15% between the eligibility and the baseline 6MWD test
Forced expiratory volume in one second (FEV1) / Forced Vital Capacity (FVC) \<0.65 after bronchodilator administration
Initiation in cytotoxic, immunosuppressive, cytokine modulating therapy initiated within 3 months prior to screening. Such agents might include. azathioprine, cyclophosphamide, corticosteroids, etanercept, tumor necrosis factor alpha (TNFα) inhibitors and others
Any specific treatment for (pulmonary arterial hypertension) PAH/PH (pulmonary hypertension )within 3 months prior to screening
Concomitant use of the following medication: nitrates or (nitric oxide) NO donors (such as amyl nitrite) in any form, phosphodiesterase 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole),
Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women of childbearing potential not using adequate contraception (as defined in the aforementioned inclusion criterion) and not willing to agree to 4 weekly pregnancy testing from Visit 1(first administration of study drug) onwards until 4 weeks after last study drug intake

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 147 participants (actual)

Study arms

Experimental
Riociguat (Adempas, BAY63-2521)
In the main study treatment phase participants received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase participants were to be treated with Riociguat until commercial access in the indication of pulmonary hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor's global team.
Drug: Riociguat (Adempas, BAY63-2521)
Placebo comparator
Placebo
In the main study treatment phase participants received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase participants were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor's global team.
Drug: Riociguat (Adempas, BAY63-2521) · Drug: Placebo

Interventions

DrugRiociguat (Adempas, BAY63-2521)
Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient's systolic blood pressure and well-being.
DrugPlacebo
Inactive dosed at 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration for 26 weeks

What researchers measure

Primary outcomes

Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26
The 6MWD test is designed to evaluate a patient's exercise capacity while performing an everyday activity.
Time frame: Baseline to 26 weeks

Secondary outcomes

Number of Participants With Clinical Worsening
The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all-cause mortality; need for hospitalization due to worsening cardiopulmonary (CP) status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling); \>15% decrease in the 6MWD test; worsening of WHO functional class.
Time frame: From baseline to week 26

Results

Posted Jun 5, 2017

Limitations and caveats

The study was prematurely terminated following a recommendation from the independent Data Monitoring Committee, as patients receiving Riociguat showed an increased risk of mortality and serious adverse events as compared to patients receiving Placebo

Participant flow

Overall, 229 participants were enrolled into the study centers in 19 countries worldwide, from 04-Jun-2014 (first patient first visit) to 14-Sep-2016 (last patient last visit).

Main Study Treatment

Participant flow — Main Study Treatment
Milestone	Riociguat (Adempas, BAY63-2521)	Placebo
Started	73	74
Completed	33	39
Not completed	40	35
Withdrew: Adverse event	11	3
Withdrew: Death	1	2
Withdrew: Protocol violation	2	2
Withdrew: Sponsor decision	12	18
Withdrew: Study terminated by sponsor	10	9
Withdrew: Withdrawal by subject	3	1
Withdrew: Medical decision	1	0

Long-term Extension

Participant flow — Long-term Extension
Milestone	Riociguat (Adempas, BAY63-2521)	Placebo
Started	32	38
Completed	0	0
Not completed	32	38
Withdrew: Study termination by sponsor	32	38

Safety Follow-up

Participant flow — Safety Follow-up
Milestone	Riociguat (Adempas, BAY63-2521)	Placebo
Started	72	64
Completed	50	47
Not completed	22	17
Withdrew: Adverse event	4	3
Withdrew: Death	11	5
Withdrew: Withdrawal by subject	5	3
Withdrew: Clinic worsening	1	0
Withdrew: Withdrawal by pi	1	0
Withdrew: Logistical difficulties	0	1
Withdrew: Progressive disease	0	2
Withdrew: Too unwell to attend the visit	0	1
Withdrew: Treatment unblinded	0	1
Withdrew: Withdrawn due to lung transplant	0	1

Outcome measures

PrimaryMean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26

The 6MWD test is designed to evaluate a patient's exercise capacity while performing an everyday activity.

Time frame:: Baseline to 26 weeks
Reported as:: Mean · Meter

Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26
Meter	Riociguat (Adempas, BAY63-2521)	Placebo
Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26	3.63 ± 60.80	-15.94 ± 63.70

Statistical analysis

Riociguat (Adempas, BAY63-2521) vs Placebo · ANCOVA · p = 0.2074 · Ls mean difference: 21.48 · 95% CI -8.75 to 51.71

SecondaryNumber of Participants With Clinical Worsening

The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all-cause mortality; need for hospitalization due to worsening cardiopulmonary (CP) status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling); \>15% decrease in the 6MWD test; worsening of WHO functional class.

Time frame:: From baseline to week 26
Reported as:: Number · Participants

Number of Participants With Clinical Worsening
Participants	Riociguat (Adempas, BAY63-2521)	Placebo
No clinical event	39	38
>15% decrease in 6MWD	9	17
All-cause mortality	1	0
Hospitalization due to worsening CP status	15	7
Worsening of WHO functional class	9	12

Statistical analysis

Riociguat (Adempas, BAY63-2521) vs Placebo · Mantel Haenszel · p = 0.3437

Post-hocNumber of Deaths Per Study Phase for Riociguat Group

In the main study treatment phase participants received Riociguat until 26 weeks. This phase was followed by a long-term extension (LTE) phase, during which participants continued with Riociguat treatment. At the time of study termination, all treated participants were taken off study drug and started the safety follow-up phase, regardless of whether they were in the main phase or in the LTE.

Time frame:: From start of treatment to end of study
Reported as:: Number · Participants

Number of Deaths Per Study Phase for Riociguat Group
Participants	Riociguat (Adempas, BAY63-2521)
Main study treatment	8
Long-term extension	1
Safety follow-up	3

Post-hocNumber of Deaths Per Study Phase for Placebo Group

In the main study treatment phase participants received Placebo until 26 weeks. This phase was followed by a long-term extension (LTE) phase, during which participants were treated with Riociguat. At the time of study termination, all treated participants were taken off study drug and started the safety follow-up phase, regardless of whether they were in the main phase or in the LTE.

Time frame:: From start of treatment to end of study
Reported as:: Number · Participants

Number of Deaths Per Study Phase for Placebo Group
Participants	Placebo
Main study treatment	3
Long-term extension: received Riociguat	8
Safety follow-up: only treated with Placebo	3
Safety follow-up: received Riociguat in LTE	1

Post-hocNumber of Serious Adverse Events During Safety Follow-up Phase

At the time of study termination, all participants entered safety follow-up phase regardless of whether they were in the main phase or in the LTE. Participants who had the End of Treatment visit prior to the implementation of the 120-day safety follow-up were followed-up for at least 30 days.

Time frame:: From start of safety follow-up phase until end of study
Reported as:: Number · Participants

Number of Serious Adverse Events During Safety Follow-up Phase
Participants	Riociguat up to 2.5 mg Tid	Placebo
Number of Serious Adverse Events During Safety Follow-up Phase	18	14

Adverse events

Collected over Treatment emergent Adverse Events are reported: from start of study treatment up to 7 days after end of treatment.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Riociguat up to 2.5 mg Tid	—	27/73 (37%)	54/73 (74%)
Placebo	—	17/74 (23%)	52/74 (70.3%)
Riociguat-Riociguat Transition	—	12/32 (37.5%)	26/32 (81.3%)
Placebo-Riociguat Transition	—	21/38 (55.3%)	32/38 (84.2%)

Most frequent serious events

Showing 10 of 75

Most frequent serious events
Event	Riociguat up to 2.5 mg Tid	Placebo	Riociguat-Riociguat Transition	Placebo-Riociguat Transition
PneumoniaInfections and infestations	4/73	1/74	0/32	4/38
Respiratory failureRespiratory, thoracic and mediastinal disorders	0/73	1/74	0/32	4/38
Idiopathic pulmonary fibrosisRespiratory, thoracic and mediastinal disorders	4/73	3/74	3/32	1/38
Right ventricular failureCardiac disorders	1/73	2/74	1/32	2/38
Interstitial lung diseaseRespiratory, thoracic and mediastinal disorders	1/73	1/74	0/32	2/38
Pulmonary fibrosisRespiratory, thoracic and mediastinal disorders	1/73	1/74	0/32	2/38
BronchitisInfections and infestations	3/73	0/74	1/32	0/38
Atrial flutterCardiac disorders	0/73	0/74	1/32	0/38
Coronary artery diseaseCardiac disorders	0/73	0/74	1/32	0/38
ColitisGastrointestinal disorders	0/73	0/74	1/32	0/38

Most frequent other events

Showing 10 of 49

Most frequent other events
Event	Riociguat up to 2.5 mg Tid	Placebo	Riociguat-Riociguat Transition	Placebo-Riociguat Transition
DyspnoeaRespiratory, thoracic and mediastinal disorders	8/73	7/74	6/32	11/38
Oedema peripheralGeneral disorders	15/73	7/74	5/32	5/38
HypotensionVascular disorders	4/73	1/74	3/32	7/38
DizzinessNervous system disorders	7/73	8/74	5/32	5/38
DiarrhoeaGastrointestinal disorders	11/73	7/74	4/32	5/38
NauseaGastrointestinal disorders	10/73	9/74	4/32	5/38
CoughRespiratory, thoracic and mediastinal disorders	8/73	10/74	2/32	2/38
HeadacheNervous system disorders	8/73	9/74	2/32	2/38
VomitingGastrointestinal disorders	8/73	2/74	3/32	4/38
HypokalaemiaMetabolism and nutrition disorders	0/73	2/74	0/32	4/38

Baseline characteristics

Age, Customized
Age, Customized(Participants)	Riociguat (Adempas, BAY63-2521)	Placebo	Total
<65 years	20	17	37
>=65 - <75 years	35	45	80
>=75 years	18	12	30

Sex: Female, Male
Sex: Female, Male(Participants)	Riociguat (Adempas, BAY63-2521)	Placebo	Total
Female	23	29	52
Male	50	45	95

Pulmonary hypertension (PH) subtype (Nice Clinical Classification)
Pulmonary hypertension (PH) subtype (Nice Clinical Classification)(Participants)	Riociguat (Adempas, BAY63-2521)	Placebo	Total
PH owing to respiratory disease and /or hypoxia	73	74	147
Other	0	0	0

Classification of Idiopathic Interstitial Pneumonia
Classification of Idiopathic Interstitial Pneumonia(Participants)	Riociguat (Adempas, BAY63-2521)	Placebo	Total
Idiopathic pulmonary fibrosis	54	49	103
Idiopathic nonspecific interstitial pneumonia	9	14	23
Resp. bronchiolitis-interstitial lung disease	1	0	1
Cryptogenic organizing pneumonia	0	1	1
Acute interstitial pneumonia	0	1	1
Idiopathic lymphoid interstitial pneumonia	0	2	2
Unclassifiable idiopathic interstitial pneumonias	9	7	16

World Health Organization (WHO) functional class
World Health Organization (WHO) functional class(Participants)	Riociguat (Adempas, BAY63-2521)	Placebo	Total
Class II	16	22	38
Class III	50	45	95
Class IV	7	7	14

6 minute walking distance (6MWD) category
6 minute walking distance (6MWD) category(Participants)	Riociguat (Adempas, BAY63-2521)	Placebo	Total
< 320 m	43	32	75
>= 320 m and <380m	12	28	40
>= 380 m	18	14	32

Study locations

94 sites

University of California, Los Angeles
Los Angeles, California 90024, United States
San Francisco, California 94143, United States
Aurora, Colorado 80045, United States
Miami, Florida 33136, United States
Orlando, Florida 32803, United States
Via Christi Clinic
Wichita, Kansas 67208, United States
Louisville, Kentucky 40202, United States
Columbia University Medical Center
New York, New York 10032, United States
Durham, North Carolina 27710, United States
Cincinnati, Ohio 45219, United States
Cleveland, Ohio 44195, United States
Columbus, Ohio 43221, United States
Portland, Oregon 97213, United States
Pittsburgh, Pennsylvania 15213, United States
Nashville, Tennessee 37232-5735, United States
Dallas, Texas 75235-3858, United States
Falls Church, Virginia 22042, United States
Mar del Plata, Buenos Aires, Argentina
Buenos Aires, Ciudad Auton. de Buenos Aires 1426, Argentina
Buenos Aires, Ciudad Auton. de Buenos Aires C1280AEB, Argentina
Godoy Cruz, Mendoza 5501, Argentina
San Miguel de Tucumán, Tucuman 4000, Argentina
Camperdown, New South Wales 2050, Australia
Darlinghurst, New South Wales 2010, Australia
Sydney, New South Wales 2751, Australia
Chermside, Queensland 4032, Australia
Adelaide, South Australia 5000, Australia
Prahran, Victoria 3181, Australia
Murdoch, Western Australia 6150, Australia
Leuven, 3000, Belgium
Vancouver, British Columbia V5Z 1M9, Canada
Ottawa, Ontario K1Y 4W7, Canada
Toronto, Ontario M5G 2N2, Canada
Quebec, G1V 4G5, Canada
Bogotá, Distrito Capital de Bogotá, Colombia
Floridablanca-Bucaramanga, Santander, Colombia
Cali, Valle del Cauca, Colombia
Bogotá, Colombia
Santafe de Bogotá, Colombia
Aarhus N, 8200, Denmark
Bron, 69500, France
Lille Cedex, 59037, France
Marseille, 13915, France
Paris Cedex 15, 75908, France
München, Bayern 80539, Germany
München, Bayern 81377, Germany
Würzburg, Bayern 97074, Germany
Gießen, Hessen 35392, Germany
Hannover, Niedersachsen 30625, Germany
Essen, Nordrhein-Westfalen 45239, Germany
Dresden, Sachsen 01307, Germany
Grosshansdorf, 22927, Germany
Athens, 11527, Greece
Haidari, 12462, Greece
Ioannina, 45500, Greece
Thessaloniki, 570 10, Greece
Haifa, 3436212, Israel
Jerusalem, 91120, Israel
Petah Tikva, 4941492, Israel
Ramat Gan, 5262000, Israel
Forlì-Cesena, Emilia-Romagna 47121, Italy
Roma, Lazio 00133, Italy
Monza-Brianza, Lombardia 20900, Italy
Palermo, Sicilia 90127, Italy
Siena, Toscana 53100, Italy
Seto, Aichi 489-8642, Japan
Yokohama, Kanagawa 236-0051, Japan
Sakai, Osaka 591-8555, Japan
Shibuya-ku, Tokyo 151-8528, Japan
Chiba, 260-8677, Japan
Auckland, 1051, New Zealand
Christchurch, 8011, New Zealand
Coimbra, 3000-075, Portugal
Porto, 4200, Portugal
Vila Nova de Gaia, 4434-502, Portugal
Moscow, 105077, Russian Federation
Moscow, 107564, Russian Federation
St. Petersburg, 197022, Russian Federation
Vladimir, 600023, Russian Federation
Riyadh, 11211, Saudi Arabia
Riyadh, 11461, Saudi Arabia
Riyadh, 11525, Saudi Arabia
Barcelona, 08003, Spain
Barcelona, 08036, Spain
Valencia, 46014, Spain
Bern, 3010, Switzerland
Genève, 1205, Switzerland
Zürich, 8091, Switzerland
Denizli, 20070, Turkey
Izmir, 35100, Turkey
Cambridge, Cambridgeshire CB23 3RE, United Kingdom
Clydebank, West Dunbartonshire G81 4DY, United Kingdom
London, SW3 6NP, United Kingdom
Newcastle, NE7 7DN, United Kingdom

References and documents

Publications

Nathan SD, Behr J, Collard HR, Cottin V, Hoeper MM, Martinez FJ, Corte TJ, Keogh AM, Leuchte H, Mogulkoc N, Ulrich S, Wuyts WA, Yao Z, Boateng F, Wells AU. Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study. Lancet Respir Med. 2019 Sep;7(9):780-790. doi: 10.1016/S2213-2600(19)30250-4. Epub 2019 Aug 12. PubMed 31416769 ↗

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 4, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02138825
Lead sponsor: Bayer
Responsible party: Sponsor
First posted: May 15, 2014
Start date: Jun 4, 2014
Primary completion: May 5, 2016
Completion: Sep 14, 2016
Results posted: Jun 5, 2017
Last update: Dec 4, 2017

Study contacts

Bayer Study Director

study director · Bayer

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in Oct 2017. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Pneumonia→

Other studies from this sponsor

Bayer

Start the discussion