A Open Label Study to Assess the Long-term Safety, Tolerability and Efficacy of Ambrisentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

NCT01894022 | Terminated Phase 3 Results DMC

• 1 other identifier: 116457
• Study Type: interventional
• Target: 19
• Locations: 16 countries
• Sites: 50

Brief Summary

This is an open label, long term extension to Study AMB115811. All subjects may remain in the extension study for a minimum of 18 months. Beyond the 18-month period, subjects may continue in the extension study until one of the following: the product is approved locally for use in inoperable CTEPH patients; development for use in the CTEPH population is discontinued or product is not approved by the local regulatory authorities; or the investigator decides to discontinue the subject or subject decides to discontinue from the study. The primary purpose of this study is to provide clinically relevant information on the long term safety of ambrisentan in subjects with inoperable CTEPH.

Conditions

Hypertension

Keywords

Inoperable chronic thromboembolic pulmonary hypertension, endothelin receptor antagonist

Outcome Measures

Primary Outcomes (12)

• Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

  An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect. Refer to the general AE/SAE module for a list of AEs and SAEs. Participant's final visit in Study AMB115811 was used as the entry visit of this open-label extension study. Safety (Extension) Population: all participants who enrolled and took at least one dose of study treatment during the extension study.

  From entry visit of the extension study up to approximately 16 months

• Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points

  Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC), platelet count, and WBC count are summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in Study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points

  Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in hemoglobin and MCHC is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in Study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points

  Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in hematocrit is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points

  Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in mean corpuscle volume is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points

  Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in red blood cell count and reticulocytes is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern at Any Time Post Entry Visit

  Blood samples were collected post Entry visit of the extension study and up to end of study for evaluation of the clinical chemistry parameters of alanine amino transferase (ALT), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and total bilirubin. The clinical chemistry parameters of potential clinical concern high were defined as follows: ALT, AST, GGT \>=3 times upper limit of normal (ULN); total bilirubin \>=2 times ULN. Participants with both normal and high values were counted once under their worst case (high). Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study.

  Post entry visit of the extension study and up to End of Study (assessed up to approximately 16 months)

• Number of Participants With Creatinine Values of Potential Clinical Concern at Any Time Post Entry Visit

  Blood samples were collected at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study plus any unscheduled lab tests for creatinine. A creatinine value of potential clinical concern high was defined as \>=176.8 micromoles per Liter. Participants with both normal and high values were counted once under their worst case (high). Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study.

  Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study plus any unscheduled lab tests (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points

  Vital signs including SBP and DBP were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in SBP and DBP is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points

  Vital signs including heart rate were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in heart rate is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Change From Study AMB115811 Baseline in Weight at the Indicated Time Points

  Weight was measured at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and at end of study. Change from study AMB115811 Baseline in weight is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

  Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

• Time to First Change in Dose of Open-label Ambrisentan Due to Tolerability Issues in Any Participant

  The time to change in dose of ambrisentan or other targeted PAH (pulmonary arterial hypertension) therapeutic agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events). Dosing data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including time to first change in dose of open-label ambrisentan. This decision was documented in the reporting and analysis plan prior to database lock.

  From the Entry visit of the extension study up to approximately 16 months

Secondary Outcomes (12)

• Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points

  During Study AMB115811: Months 0 (Baseline), 1, 2, 3, 4, Early Withdrawal (EW); During Extension Study: Months 1, 3, 6, 9, 12, 15 and at End of Study (assessed up to approximately 20 months)

• Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points

  During Study AMB115811: Months (M) 0 (Baseline), 1, 2, 3, 4, Early Withdrawal (EW); During Extension (ext) Study: Months 1, 3, 6, 9, 12, 15 and at End of Study (assessed up to approximately 20 months)

• Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points

  During Study AMB115811: Months (M) 0 (Baseline), 1, 2, 3, 4, Early Withdrawal (EW); During Extension (Ext) Study: Months 1, 3, 6, 9, 12, 15 and at End of Study (assessed up to approximately 20 months)

• Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

  From randomization up to End of Study for the extension study (assessed up to approximately 20 months)

• Change From Study AMB115811 Baseline in Quality of Life as Measured by Short Form 36 Health Survey (SF-36)

  Baseline from study AMB115811 up to End of Study for the extension study (assessed up to approximately 20 months)

Study Arms (1)

Ambrisentan Arm

EXPERIMENTAL

All subjects will receive ambrisentan initially at a dose of 5 mg once daily (OD). Based on the investigator's best judgment, the subject may continue on 5 mg OD, or be up-titrated to 10 mg OD. The dose may also be adjusted back to 5 mg OD at investigator discretion.

Drug: Ambrisentan 5 mg

Interventions

Ambrisentan 5 mg DRUG

Round, white, film-coated, immediate-release tablets, containing 5 mg ambrisentan. Subjects will be dosed orally once daily. Subjects may receive 5mg, or 10 mg of ambrisentan OD.

Ambrisentan Arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have been randomized to the protocol for AMB115811 and have met one of the following: Completed the Week 16 visit in AMB115811; Or Prematurely withdrew from AMB115811 for whatever reason (where investigational product \[IP\] has been stopped due to safety or efficacy reasons, the subject may still enter into the open label study regardless of what treatment they are receiving \[other treatments will not be supplied by the sponsor\]. The investigator will decide whether or not the subject will receive the IP
• Subject is able and willing to give written informed consent. As part of the consent, female subjects of childbearing potential will be informed of the risk of teratogenicity and will need to be counseled in a developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia.
• Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the Investigators Brochure and product label for PAH indication.

You may not qualify if:

• Subject meeting any of the following criteria must not receive ambrisentan, however may still be followed-up as part of the study and be treated according to best clinical practice as decided by the investigator:
• Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients
• Female subjects who are pregnant or breastfeeding or no-longer agree to comply with using effective contraception as defined in the protocol.
• Subjects with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>= 3x Upper limit of normal (ULN)
• Subjects with bilirubin \>= 2xULN (\>35% direct bilirubin)
• Subjects with severe renal impairment (estimated creatinine clearance \<30 millilitre per minute (mL/min) assessed within the previous 45 days) at the point of transition from Study AMB115811
• Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without cirrhosis) at the point of transition from study AMB115811
• Subject with clinically significant fluid retention in the opinion of the investigator
• Subject with clinically significant anemia in the opinion of the investigator
• Subjects who are to enter another clinical trial or be treated with another investigational product after exiting Study AMB115811.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (50)

GSK Investigational Site

Boston, Massachusetts, 02118, United States

Location

GSK Investigational Site

Dallas, Texas, 75390-8550, United States

Location

GSK Investigational Site

Rosario, Santa Fe Province, S2000ODA, Argentina

Location

GSK Investigational Site

Buenos Aires, C1181ACH, Argentina

Location

GSK Investigational Site

Corrientes, W3400AMZ, Argentina

Location

GSK Investigational Site

Santa Fe, S3000AZG, Argentina

Location

GSK Investigational Site

Graz, A-8036, Austria

Location

GSK Investigational Site

Innsbruck, A-6020, Austria

Location

GSK Investigational Site

Vienna, 1090, Austria

Location

GSK Investigational Site

Edmonton, Alberta, T6G 2G3, Canada

Location

GSK Investigational Site

London, Ontario, N6A 5W9, Canada

Location

GSK Investigational Site

Wuhan, Hubei, 430022, China

Location

GSK Investigational Site

Xi'an, Shaanxi, 710061, China

Location

GSK Investigational Site

Beijing, 100020, China

Location

GSK Investigational Site

Beijing, 100037, China

Location

GSK Investigational Site

Beijing, 100038, China

Location

GSK Investigational Site

Shanghai, 200433, China

Location

GSK Investigational Site

Prague, 128 08, Czechia

Location

GSK Investigational Site

Heidelberg, Baden-Wurttemberg, 69126, Germany

Location

GSK Investigational Site

Regensburg, Bavaria, 93053, Germany

Location

GSK Investigational Site

Würzburg, Bavaria, 97074, Germany

Location

GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

Location

GSK Investigational Site

Homburg, Saarland, 66421, Germany

Location

GSK Investigational Site

Dresden, Saxony, 01307, Germany

Location

GSK Investigational Site

Leipzig, Saxony, 04103, Germany

Location

GSK Investigational Site

Ashkelon, 78360, Israel

Location

GSK Investigational Site

Zrifin, 70300, Israel

Location

GSK Investigational Site

Aichi, 466-8560, Japan

Location

GSK Investigational Site

Fukuoka, 812-8582, Japan

Location

GSK Investigational Site

Hokkaido, 060-8648, Japan

Location

GSK Investigational Site

Hyōgo, 650-0017, Japan

Location

GSK Investigational Site

Miyagi, 980-8574, Japan

Location

GSK Investigational Site

Tochigi, 329-0498, Japan

Location

GSK Investigational Site

Tokyo, 113-8655, Japan

Location

GSK Investigational Site

Tokyo, 181-8611, Japan

Location

GSK Investigational Site

Monterrey NL, Nuevo León, 64718, Mexico

Location

GSK Investigational Site

Amsterdam, 1081 HV, Netherlands

Location

GSK Investigational Site

Kemerovo, 650002, Russia

Location

GSK Investigational Site

Tomsk, 634012, Russia

Location

GSK Investigational Site

Riyadh, Saudi Arabia

Location

GSK Investigational Site

Seoul, 110-744, South Korea

Location

GSK Investigational Site

Seoul, 120-752, South Korea

Location

GSK Investigational Site

Seoul, 135-710, South Korea

Location

GSK Investigational Site

Barcelona, 08036, Spain

Location

GSK Investigational Site

Madrid, 28041, Spain

Location

GSK Investigational Site

Majadahonda (Madrid), 28222, Spain

Location

GSK Investigational Site

Seville, 41013, Spain

Location

GSK Investigational Site

Cambridge, CB23 3RE, United Kingdom

Location

GSK Investigational Site

Clydebank, G81 4DY, United Kingdom

Location

GSK Investigational Site

London, NW3 2QH, United Kingdom

Location

MeSH Terms

Conditions

Hypertension

Interventions

ambrisentan

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 3, 2013
• First Posted: July 9, 2013
• Study Start: January 23, 2014
• Primary Completion: November 18, 2015
• Study Completion: November 18, 2015
• Last Updated: September 11, 2017
• Results First Posted: June 8, 2017

Record last verified: 2017-08

Locations

SA (1); AU (3); CZ (1); IL (2); GB (3); NL (1); AR (4); US (2); ES (4); DE (7); CA (2); JP (8); RU (2); KR (3); ME (1); CN (6)