Liver TransplantationPhase 4HEPHAISTOSNCT01551212

Efficacy of Everolimus in Combination With Tacrolimus in Liver Transplant Recipients

A Phase 4 study testing Everolimus, Tacrolimus and Corticosteroids in people with Liver Transplantation, run by Novartis Pharmaceuticals at 15 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This trial evaluated the efficacy and safety of Everolimus in combination with tacrolimus versus a standard immunosuppressive regimen concerning kidney function in liver transplant recipients. Read more about this study

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Liver Transplantation
What is being tested?: Everolimus, Tacrolimus and Corticosteroids
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 339 participants
Where: 15 sitesGermany
Study dates: 24 May 2012to 8 Aug 2017
Phase: Phase 4
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 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Male or female recipients of a full-size liver allograft, aged 18 to 65 years.

Who cannot join

Patients with thrombocytopenia (platelets <50,000/mm³), with an absolute neutrophil count of <1,000/mm³ or leucopenia (leucocytes <2000/mm³), with anemia with Hb < 6g/dl at time of randomization
Patients with uncontrolled hypercholesterolemia (>350mg/dL; >9mmol/L) or hypertriglyceridemia (>750 mg/dL; >8.5 mmol/L) at time of randomization
History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC

Trial locations and contacts

15 sites in 1 country.

City, postcode or hospital

15 sites in 1 country

Germany15 sites

Novartis Investigative Site
Aachen, 52074
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Bonn, 53105
Novartis Investigative Site
Erlangen, 91052
Novartis Investigative Site
Essen, 45147
Novartis Investigative Site
Frankfurt, 60590
Novartis Investigative Site
Hamburg, 20246
Novartis Investigative Site
Hanover, 30625
Novartis Investigative Site
Heidelberg, 69120
Novartis Investigative Site
Kiel, 24105
Novartis Investigative Site
Leipzig, 04103
Novartis Investigative Site
Mainz, 55131
Novartis Investigative Site
München, 81377
Novartis Investigative Site
Regensburg, 93053
Novartis Investigative Site
Tübingen, 72076

Other trials in Germany

About this study

Official title: A 12-month, Multi-center, Open-label, Randomized, Controlled Study to Evaluate Efficacy/Safety and Evolution of Renal Function of Everolimus in Co-exposure With Tacrolimus in de Novo Liver Transplant Recipients

This trial evaluated the efficacy and safety of Everolimus in combination with tacrolimus versus a standard immunosuppressive regimen concerning kidney function in liver transplant recipients.

Conditions: Liver Transplantation
Being tested: Everolimus, Tacrolimus, Corticosteroids
Keywords: Liver transplantation, Everolimus, Tacrolimus, Renal function

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

EverolimusDrug
Also called RAD001 / Certican
tablet containing 0.25mg, 0.5mg, 0.75mg or 1.0mg
TacrolimusDrug
Also called Tacrolimus Hexal
capsule containing 0.5, 1.0, or 5.0mg
CorticosteroidsDrug
For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids may have been used for the duration of the study according to the investigator's discretion, but may not have been eliminated sooner than 6 months post-transplantation.

Study groups in NCT01551212
Study group	Role	What they receive
EVR/TAC	Experimental	Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: < 5 ng/mL) Receives: Drug: Everolimus; Drug: Tacrolimus; Drug: Corticosteroids
TAC	Active comparator	Tacrolimus (C0-h: 6-10 ng/ml) Receives: Drug: Tacrolimus; Drug: Corticosteroids

What is being measured

The primary outcome is the main question the study is designed to answer.

Estimated Glomerular Filtration Rate (GFR)
The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group).
Measured: month 12

Secondary outcomes (6)

Estimated GFR - PP Set
This was a sensitivity analysis for the primary outcome measure based on the per-protocol set of patients.
Measured: month 12
Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
Percentage of Participants with Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death at Month 12
Measured: 12 months
Number of Participants With HCV
Number of Participants with HCV (hepatitis C virus) assessed as treatment emergent adverse events of special interest
Measured: 12 months
Incidence of HCV Related Fibrosis
Incidence of hepatitis C virus (HCV) related fibrosis assessed as treatment emergent adverse events of special interest
Measured: 12 months
Incidence of de Novo HCC Malignancies
Incidence of de novo Hepatocellular Carcinoma (HCC) malignancies assessed as treatment emergent adverse events of special interest
Measured: 12 months
Incidence and Severity of CMV Viral Infections.
Incidence and severity of cytomegalovirus (CMV) viral infections assessed as treatment emergent adverse events of special interest.
Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

24 May 20128 Aug 2017

First posted12 Mar 2012 (estimated)
Study start24 May 2012
Primary completion8 Aug 2017
Study completion8 Aug 2017

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 Liver TransplantationStudies 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 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 339 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01551212
Sponsor's protocol ID: CRAD001HDE13
Other IDs: 2011-003118-17
Acronym: HEPHAISTOS
Status last verified: May 2019
First submitted: 8 Mar 2012
Last updated: 10 May 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Nashan B, Schemmer P, Braun F, Schlitt HJ, Pascher A, Klein CG, Neumann UP, Kroeger I, Wimmer P; Hephaistos Study Group. Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial. Liver Transpl. 2022 Jun;28(6):998-1010. doi: 10.1002/lt.26298. Epub 2021 Oct 12.
PubMed 34525259
Nashan B, Schemmer P, Braun F, Dworak M, Wimmer P, Schlitt H. Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial. Trials. 2015 Mar 26;16:118. doi: 10.1186/s13063-015-0626-0.
PubMed 25873064

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Expanding Liver Transplant Immunosuppression Minimization Via Everolimus
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All Liver Transplantation trials

Study at a glance

From the registry record, last updated by the sponsor on 10 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A 12-month, Multi-center, Open-label, Randomized, Controlled Study to Evaluate Efficacy/Safety and Evolution of Renal Function of Everolimus in Co-exposure With Tacrolimus in de Novo Liver Transplant Recipients
ClinicalTrials.gov ID: NCT01551212
Acronym / sponsor ID: HEPHAISTOS / CRAD001HDE13
Conditions: Liver Transplantation
Keywords: Liver transplantation, Everolimus, Tacrolimus, Renal function
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 339 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 24 May 2012 (actual)
Primary completion: 8 Aug 2017 (actual)
Study completion: 8 Aug 2017 (actual)
First posted: 12 Mar 2012 (estimated)
Results: Posted 10 May 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

This trial evaluated the efficacy and safety of Everolimus in combination with tacrolimus versus a standard immunosuppressive regimen concerning kidney function in liver transplant recipients.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
EVR/TAC	Experimental	Drug: Everolimus, Drug: Tacrolimus, Drug: CorticosteroidsTacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: < 5 ng/mL)
TAC	Active comparator	Drug: Tacrolimus, Drug: CorticosteroidsTacrolimus (C0-h: 6-10 ng/ml)

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

Male or female recipients of a full-size liver allograft, aged 18 to 65 years.

Key exclusion criteria (3 listed)

Patients with thrombocytopenia (platelets <50,000/mm³), with an absolute neutrophil count of <1,000/mm³ or leucopenia (leucocytes <2000/mm³), with anemia with Hb < 6g/dl at time of randomization
Patients with uncontrolled hypercholesterolemia (>350mg/dL; >9mmol/L) or hypertriglyceridemia (>750 mg/dL; >8.5 mmol/L) at time of randomization
History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC

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
EverolimusAlso: RAD001 / Certicantablet containing 0.25mg, 0.5mg, 0.75mg or 1.0mg	Drug	EVR/TAC
TacrolimusAlso: Tacrolimus Hexalcapsule containing 0.5, 1.0, or 5.0mg	Drug	EVR/TAC, TAC
CorticosteroidsFor patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids may have been used for the duration of the study according to the investigator's discretion, but may not have been eliminated sooner than 6 months post-transplantation.	Drug	EVR/TAC, TAC

Primary outcome

Estimated Glomerular Filtration Rate (GFR)
Time frame: month 12
The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group).

6 secondary outcomes

Estimated GFR - PP Set
Time frame: month 12
Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
Time frame: 12 months
Number of Participants With HCV
Time frame: 12 months
Incidence of HCV Related Fibrosis
Time frame: 12 months
Incidence of de Novo HCC Malignancies
Time frame: 12 months
Incidence and Severity of CMV Viral Infections.
Time frame: 12 months

Results and safety

Results posted to the registry on 10 May 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Everolimus/Tacrolimus	171	166
Tacrolimus	168	148

Primary outcome: Estimated Glomerular Filtration Rate (GFR)

Time frame: month 12. Mean (Standard Deviation). Unit: mL/min

Measure	Everolimus/Tacrolimus n = 169	Tacrolimus n = 164
Value	73.46 (25.57)	71.95 (27.17)

Everolimus/Tacrolimus vs Tacrolimus: Mean Difference (Final Values): 4.09 (95% CI -0.74 to 8.91), p = 0.097, ANCOVA

Population analysed: FAS (Full Analysis Set - All Randomized AND Treated Patients) with LOCF (last observation carried forward)

6 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 12 months. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Everolimus/Tacrolimus	111 of 169 (65.7%)	164 of 169 (97%)	3 of 169
Tacrolimus	101 of 164 (61.6%)	153 of 164 (93.3%)	4 of 164

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 May 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 34525259Nashan B, Schemmer P, Braun F, Schlitt HJ, Pascher A, Klein CG, Neumann UP, Kroeger I, Wimmer P; Hephaistos Study Group. Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial. Liver Transpl. 2022 Jun;28(6):998-1010. doi: 10.1002/lt.26298. Epub 2021 Oct 12.
Derived from this study: PubMed 25873064Nashan B, Schemmer P, Braun F, Dworak M, Wimmer P, Schlitt H. Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial. Trials. 2015 Mar 26;16:118. doi: 10.1186/s13063-015-0626-0.

Related trials for Liver Transplantation

Not yet recruitingObservational study
Prevalence and Development of Liver Dysfunction in Hematopoietic Stem Cell Transplant
Hematopoietic Stem Cell Transplant
Not yet recruiting
Efficacy of Carnitine Complex in Improving Hepatic Steatosis in Potential Liver Donors
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Not yet recruiting
New Biomarkers for Organ Viability Assessment During Hypothermic Machine Perfusion in Liver Transplantation: the Role of Extemporaneous Histological Examination.
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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

15 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Everolimus, Tacrolimus and Corticosteroids in people with Liver Transplantation, run by Novartis Pharmaceuticals at 15 sites in Germany.

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 3 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 10 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Germany. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

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 10 May 2019). 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?

Estimated Glomerular Filtration Rate (GFR) (time frame: month 12). 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 NCT01551212, 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 10 May 2019.