Heart Failure With Reduced Ejection FractionPhase 2TITRATIONNCT01922089
Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients
A Phase 2 study testing LCZ696 in people with Heart Failure With Reduced Ejection Fraction, run by Novartis Pharmaceuticals at 105 sites in 11 countries.
Trial summary
The purpose of this study is to assess the safety and tolerability of initiating LCZ696 in heart failure patients with reduced ejection fraction (HF-rEF) using conservative (reaching target dose over 6 weeks) and condensed (reaching target dose over 3 weeks) up-titration regimens. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure With Reduced Ejection Fraction
- What is being tested?
- LCZ696
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 498 participants
- Where
- 105 sitesin 11 countries
- Study dates
- Nov 2013to Aug 2014
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years; CHF with New York Heart Association class II-IV; left ventricular ejection fraction ≤ 35%; on beta blockers
Who cannot join
- Potassium > 5.2 mmol/l; estimated glomerular filtration rate < 30 ml/min/1.73 m2; systolic blood pressure <100 mmHg or > 180 mmHg; history of intolerance to recommended target doses of angiotensin converting enzyme inhibitors or angiotensin receptor blockers
- Other protocol-defined inclusion/exclusion criteria may apply.
Trial locations and contacts
105 sites in 11 countries.
105 sites in 11 countries
Germany25 sites
Novartis Investigative Site
Bad Krozingen, 79189
Novartis Investigative Site
Berlin, 10367
Novartis Investigative Site
Berlin, 10787
Novartis Investigative Site
Berlin, 10789
Novartis Investigative Site
Berlin, 13055
Novartis Investigative Site
Berlin, 13347
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Berlin, 13405
Novartis Investigative Site
Buch, 13125
Novartis Investigative Site
Dietzenbach, 63128
Novartis Investigative Site
Ebersbach, 02730
Novartis Investigative Site
Frankfurt, 60594
Novartis Investigative Site
Göttingen, D-37075
Novartis Investigative Site
Haßloch, 67454
Novartis Investigative Site
Huy / OT Anderbeck, 38836
Novartis Investigative Site
Ingelheim, 55218
Novartis Investigative Site
Kelkheim, 65779
Novartis Investigative Site
Kleve, 47533
Novartis Investigative Site
Leipzig, 04315
Novartis Investigative Site
Mainz, 55116
Novartis Investigative Site
Mainz, 55131
Novartis Investigative Site
Mühlheim, 45468
Novartis Investigative Site
Siegen, 57072
Novartis Investigative Site
Straubing, 94315
Novartis Investigative Site
Würzburg, 97078
United States22 sites
Novartis Investigative Site
Anaheim, California, 92801
Novartis Investigative Site
Anchorage, Alaska, 99508
Novartis Investigative Site
Atlantis, Florida, 33462
Novartis Investigative Site
Aurora, Illinois, 60504
Novartis Investigative Site
Buffalo, New York, 14215
Novartis Investigative Site
Chiefland, Florida, 32626
Novartis Investigative Site
Dallas, Texas, 75231
Novartis Investigative Site
Evansville, Indiana, 47714
Novartis Investigative Site
Gilbert, Arizona, 85297
Novartis Investigative Site
Houston, Texas, 77030
Novartis Investigative Site
Houston, Texas, 77094
Novartis Investigative Site
Laurelton, New York, 11422
Novartis Investigative Site
Livingston, Texas, 77351
Novartis Investigative Site
Marion, Ohio, 43302
Novartis Investigative Site
Minneapolis, Minnesota, 55417
Novartis Investigative Site
Oak Ridge, Tennessee, 37830
Novartis Investigative Site
Peoria, Illinois, 61602
Novartis Investigative Site
Slidell, Louisiana, 70458
Novartis Investigative Site
St Louis, Missouri, 63110
Novartis Investigative Site
Tacoma, Washington, 98405
Novartis Investigative Site
Torrance, California, 90502
Novartis Investigative Site
Tucson, Arizona, 85710
Italy10 sites
Novartis Investigative Site
Albano Laziale, RM, 00041
Novartis Investigative Site
Aosta, AO, 11100
Novartis Investigative Site
Bergamo, BG, 24128
Novartis Investigative Site
Bologna, BO, 40138
Novartis Investigative Site
Cona, FE, 44100
Novartis Investigative Site
Cortona, AR, 52044
Novartis Investigative Site
Roma, RM, 00163
Novartis Investigative Site
San Daniele del Friuli, UD, 33038
Novartis Investigative Site
Sassari, SS, 07100
Novartis Investigative Site
Vittorio Veneto, TV, 31029
Slovakia9 sites
Novartis Investigative Site
Bratislava, Slovakia, 821 07
Novartis Investigative Site
Bratislava, Slovakia, 83301
Novartis Investigative Site
Brezno, Slovak Republic, 977 42
Novartis Investigative Site
Košice, Slovakia, 040 01
Novartis Investigative Site
Lučenec, Slovakia, 98439
Novartis Investigative Site
Nitra, Slovak Republic, 949 01
Novartis Investigative Site
Nové Zámky, Slovakia, 940 01
Novartis Investigative Site
Svidník, Slovak Republic, 08901
Novartis Investigative Site
Trebišov, Slovakia, 075 01
United Kingdom9 sites
Novartis Investigative Site
Bath, BA1 3NG
Novartis Investigative Site
Bradford, BD9 6RJ
Novartis Investigative Site
Coventry, CV2 2DX
Novartis Investigative Site
Dorchester, Dorset, DT1 2JY
Novartis Investigative Site
Gateshead, Tyne and Wear, NE9 6SX
Novartis Investigative Site
Harrow, HA1 3UJ
Novartis Investigative Site
Nuneaton, CV10 7DJ
Novartis Investigative Site
Oldham, Lancashire, OL1 2JH
Novartis Investigative Site
Saint Leonards-on-Sea, East Sussex, TN37 7RD
Hungary8 sites
Novartis Investigative Site
Budapest, 1042
Novartis Investigative Site
Budapest, 1145
Novartis Investigative Site
Budapest, H-1096
Novartis Investigative Site
Debrecen, 4032
Novartis Investigative Site
Mosonmagyaróvár, 9200
Novartis Investigative Site
Nyiregyháza, 4400
Novartis Investigative Site
Pécs, 7623
Novartis Investigative Site
Székesfehérvár, 8000
Spain8 sites
Novartis Investigative Site
A Coruña, Galicia, 15006
Novartis Investigative Site
Almería, Andalusia, 04120
Novartis Investigative Site
Barcelona, Catalonia, 08035
Novartis Investigative Site
Madrid, Madrid, 28007
Novartis Investigative Site
Málaga, Andalusia, 29010
Novartis Investigative Site
Sanlúcar de Barrameda, Andalusia, 11540
Novartis Investigative Site
Seville, Andalusia, 41014
Novartis Investigative Site
Villamartín, Cadiz, 11650
Bulgaria6 sites
Novartis Investigative Site
Gabrovo, Bulgaria, 5300
Novartis Investigative Site
Plovdiv, Bulgaria, 4000
Novartis Investigative Site
Plovdiv, Bulgaria, 4004
Novartis Investigative Site
Smolyan, Bulgaria, 4700
Novartis Investigative Site
Sofia, 1202
Novartis Investigative Site
Sofia, 1407
Turkey (Türkiye)5 sites
Novartis Investigative Site
Haydarpasa/Istanbul, 34668
Novartis Investigative Site
Istanbul, Turkey, 34304
Novartis Investigative Site
Kocaeli, 41380
Novartis Investigative Site
Mersin, 33079
Novartis Investigative Site
Sivas, 58140
Finland2 sites
Novartis Investigative Site
Jyväskylä, 40620
Novartis Investigative Site
Tampere, 33520
About this study
Official title: A Multicenter, Randomized, Double-blind, Parallel Group Study to Assess the Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients Comparing Two Titration Regimens
The purpose of this study is to assess the safety and tolerability of initiating LCZ696 in heart failure patients with reduced ejection fraction (HF-rEF) using conservative (reaching target dose over 6 weeks) and condensed (reaching target dose over 3 weeks) up-titration regimens.
- Being tested
- LCZ696
- Keywords
- Heart failure, reduced ejection fraction, LCZ696, titration, safety, tolerability
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LCZ696Drug
LCZ696 50 mg/100 mg/200 mg bid
| Study group | Role | What they receive |
|---|---|---|
| LCZ696 Condensed | Experimental | Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks Receives: Drug: LCZ696 |
| LCZ696 Conservative | Experimental | Up-titration to LCZ696 200 mg bid over 6 weeks Receives: Drug: LCZ696 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Measured: 12 weeks
Secondary outcomes (2)
Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Treatment success was defined as the number of participants who achieved and maintained LCZ696 200 mg bid without any dose interruption or down-titration over 12 weeks and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Measured: 12 weeks
Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low).
Tolerability was assessed as the number of participants who achieved LCZ696 200 mg bid and maintained this dose for at least 2 weeks before study completion, regardless of previous dose interruption or down-titration and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2013 (estimated)
- Study startNov 2013
- Primary completionAug 2014
- Study completionAug 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Heart Failure With Reduced Ejection FractionStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 498 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01922089
- Sponsor's protocol ID
- CLCZ696B2228
- Other IDs
- 2013-001835-33
- Acronym
- TITRATION
- Status last verified
- Sep 2015
- First submitted
- 12 Aug 2013
- Last updated
- 15 Oct 2015
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Senni M, McMurray JJV, Wachter R, McIntyre HF, Anand IS, Duino V, Sarkar A, Shi V, Charney A. Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. Eur J Heart Fail. 2018 Mar;20(3):491-500. doi: 10.1002/ejhf.1054. Epub 2017 Nov 22.
PubMed 29164797Senni M, McMurray JJ, Wachter R, McIntyre HF, Reyes A, Majercak I, Andreka P, Shehova-Yankova N, Anand I, Yilmaz MB, Gogia H, Martinez-Selles M, Fischer S, Zilahi Z, Cosmi F, Gelev V, Galve E, Gomez-Doblas JJ, Nociar J, Radomska M, Sokolova B, Volterrani M, Sarkar A, Reimund B, Chen F, Charney A. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016 Sep;18(9):1193-202. doi: 10.1002/ejhf.548. Epub 2016 May 12.
PubMed 27170530
Study at a glance
From the registry record, last updated by the sponsor on 15 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Randomized, Double-blind, Parallel Group Study to Assess the Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients Comparing Two Titration Regimens
- ClinicalTrials.gov ID
- NCT01922089
- Acronym / sponsor ID
- TITRATION / CLCZ696B2228
- Keywords
- Heart failure, reduced ejection fraction, LCZ696, titration, safety, tolerability
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 498 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Nov 2013
- Primary completion
- Aug 2014 (actual)
- Study completion
- Aug 2014 (actual)
- First posted
- 14 Aug 2013 (estimated)
- Results
- Posted 15 Oct 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to assess the safety and tolerability of initiating LCZ696 in heart failure patients with reduced ejection fraction (HF-rEF) using conservative (reaching target dose over 6 weeks) and condensed (reaching target dose over 3 weeks) up-titration regimens.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LCZ696 Condensed | Experimental | Drug: LCZ696Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks |
| LCZ696 Conservative | Experimental | Drug: LCZ696Up-titration to LCZ696 200 mg bid over 6 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Age ≥ 18 years; CHF with New York Heart Association class II-IV; left ventricular ejection fraction ≤ 35%; on beta blockers
Key exclusion criteria (2 listed)
- Potassium > 5.2 mmol/l; estimated glomerular filtration rate < 30 ml/min/1.73 m2; systolic blood pressure <100 mmHg or > 180 mmHg; history of intolerance to recommended target doses of angiotensin converting enzyme inhibitors or angiotensin receptor blockers
- Other protocol-defined inclusion/exclusion criteria may apply.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LCZ696LCZ696 50 mg/100 mg/200 mg bid | Drug | LCZ696 Condensed, LCZ696 Conservative |
Primary outcome
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Time frame: 12 weeks
Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
2 secondary outcomes
Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Time frame: 12 weeks
Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low).
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Oct 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29164797Senni M, McMurray JJV, Wachter R, McIntyre HF, Anand IS, Duino V, Sarkar A, Shi V, Charney A. Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. Eur J Heart Fail. 2018 Mar;20(3):491-500. doi: 10.1002/ejhf.1054. Epub 2017 Nov 22.
- Derived from this study: PubMed 27170530Senni M, McMurray JJ, Wachter R, McIntyre HF, Reyes A, Majercak I, Andreka P, Shehova-Yankova N, Anand I, Yilmaz MB, Gogia H, Martinez-Selles M, Fischer S, Zilahi Z, Cosmi F, Gelev V, Galve E, Gomez-Doblas JJ, Nociar J, Radomska M, Sokolova B, Volterrani M, Sarkar A, Reimund B, Chen F, Charney A. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016 Sep;18(9):1193-202. doi: 10.1002/ejhf.548. Epub 2016 May 12.
Related trials for Heart Failure With Reduced Ejection Fraction
Active, not recruiting
Assessment of Combined CCM and ICD Device in HFrEF
Heart Failure, Heart Failure With Reduced Ejection Fraction
RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
Recruiting
Endovascular Ablation of the Right Greater Splanchnic Nerve in Subjects With Reduced Ejection Fraction
Heart Failure With Reduced Ejection Fraction (HFrEF)
Not yet recruiting
RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF
Heart Failure and Reduced Ejection Fraction, Heart Failure Chronic
RecruitingPhase 3
Study With Omecamtiv Mecarbil (CK-1827452) to Treat Chronic Heart Failure With Severely Reduced Ejection Fraction
Heart Failure, Heart Failure With Reduced Ejection Fraction
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
105 sites in 11 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing LCZ696 in people with Heart Failure With Reduced Ejection Fraction, run by Novartis Pharmaceuticals at 105 sites in 11 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 105 sites in Germany, United States, Italy, Slovakia, United Kingdom and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Oct 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01922089, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2015; AzTrials last refreshed its copy on 8 Nov 2026.