Pulmonary Arterial HypertensionPhase 2TransformPAHNCT01647945
FK506 (Tacrolimus) in Pulmonary Arterial Hypertension
A Phase 2 study testing FK506 level < 2 ng/ml, FK506 level 2-3 ng/ml and FK506 level 3-5 ng/ml in people with Pulmonary Arterial Hypertension, run by Edda Spiekerkoetter at 1 site in United States.
Trial summary
Mutations in bone morphogenetic protein receptor 2 (BMPR2) are present in >80% of familial and ~20% of sporadic pulmonary arterial hypertension (PAH) patients. Furthermore dysfunctional BMP signaling is a general feature of pulmonary hypertension even in non-familial PAH. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Pulmonary Arterial Hypertension
- What is being tested?
- FK506 level < 2 ng/ml, FK506 level 2-3 ng/ml and FK506 level 3-5 ng/ml
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 23 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2012to 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 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 and < 70 years
- Diagnosis of WHO Group I Pulmonary Arterial Hypertension (PAH) (Idiopathic (I)PAH, Heritable PAH (including Hereditary Hemorrhagic Telangiectasia), Associated (A)PAH (including collagen vascular disorders, drugs+toxins exposure, congenital heart disease, and portopulmonary disease).
- Stable on active PAH treatment including any prostacycline or phosphodiesterase inhibitors and the endothelin antagonist Ambrisentan alone or in combination (stability defined as: <10% change in 6MWD, no change in NYHA class, no hospitalization or addition of PAH therapy for at least 3 months).
- Previous Right Heart Catheterization that documented:
- Mean PAP ≥ 25 mmHg.
- Pulmonary capillary wedge pressure < 15 mmHg.
- Pulmonary Vascular Resistance ≥ 3.0 Wood units or 240 dynes/sec/cm5
- WHO functional class I to IV as judged by the investigator.
Who cannot join
- WHO Group II - V Pulmonary Hypertension.
- Current or prior experimental PAH treatments within the last 6 months (including but not limited to tyrosine kinase inhibitors, rho-kinase inhibitors, or cGMP modulators).
- Current active treatment with the dual endothelin receptor antagonist bosentan.
- TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
- FEV1 / FVC < 70% predicted and FEV1 < 60% predicted
- Significant left-sided heart disease (based on screening Echocardiogram):
Show all 26Show fewer
- Significant aortic or mitral valve disease
- Diastolic dysfunction ≥ Grade II
- LV systolic function < 45%
- Pericardial constriction
- Restrictive cardiomyopathy
- Significant coronary disease with demonstrable ischemia.
- Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation).
- Current atrial arrhythmias not under optimal control.
- Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm
- Severe hypotension: SBP < 80 mmHg.
- Pregnant or breast-feeding.
- Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions.
- Active cyclosporine use.
- Known allergy or hypersensitivity to FK-506.
- Planned initiation of cardiac or pulmonary rehabilitation during period of study.
- Human Immunodeficiency Virus infection.
- Moderate to severe hepatic dysfunction with a Pugh score >10.
- Hyperkalemia defined as Potassium > 5.1 mEq/L at screening .
- Known active infection requiring antibiotic, antifungal, or antiviral therapies.
- Co-morbid conditions that would impair a patient's exercise performance and ability to assess WHO functional class, including but not limited to chronic low-back pain or peripheral musculoskeletal problems.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Single-Center Randomized Controlled Phase II Study of Safety and Efficacy of FK-506 (Tacrolimus) in Pulmonary Arterial Hypertension
Mutations in bone morphogenetic protein receptor 2 (BMPR2) are present in >80% of familial and ~20% of sporadic pulmonary arterial hypertension (PAH) patients. Furthermore dysfunctional BMP signaling is a general feature of pulmonary hypertension even in non-familial PAH.
We therefore hypothesized that increasing BMP signaling might prevent and reverse the disease. We screened > 3500 FDA approved drugs for their propensity to increase BMP signaling and found FK506 (Tacrolimus) to be a strong activator of BMP signaling. Tacrolimus restored normal function of pulmonary artery endothelial cells, prevented and reversed experimental PAH in mice and rats.
Read more
Given that Tacrolimus is already FDA approved with a known side-effect profile, it is an ideal candidate drug to use in patients with pulmonary arterial hypertension.
The aims of our trial are:
- Establish the Safety of FK506 in patients with PAH.
- Evaluate the Efficacy of FK506 in PAH
- Identify ideal candidates for future FK506 phase III clinical trial.
Read the detailed description
Study Design:
Randomized, placebo-controlled, four arm clinical trial.
Sample Size: 10 subjects in each arm, Total enrollment = 40 patients.
- 10 patients: FK-506 blood level: 3 - 5 ng/ml
- 10 patients: FK-506 blood level: 2 - 3 ng/ml
- 10 patients: FK-506 level: < 2.0 ng/ml
- 10 patients: Placebo
Study Duration:
16 weeks
Primary Endpoints:
- Safety of low-dose FK506 in PAH
Secondary Objectives/Endpoints:
- Combined Clinical Events/Time to Clinical Worsening @ 16 weeks:
- All cause mortality
- Transplantation
- Atrial septostomy
- Need for escalation of therapies as deemed by site investigator
- Worsening of NYHA/WHO classification by at least 1 point.
- Hospitalization for right heart failure.
- Change in 6MWD at 16 weeks
- Change in NT-Pro-BNP at 16 weeks
- Change in Uric Acid at 16 weeks
- Change in DLCO at 16 weeks
- Change in novel RV parameters by transthoracic echocardiography: Change in RV size, RA size, RV function, TAPSE, RVSP
- Conditions
- Pulmonary Arterial Hypertension
- Being tested
- Placebo, FK506 level < 2 ng/ml, FK506 level 2-3 ng/ml, FK506 level 3-5 ng/ml
- Keywords
- PAH WHO group 1
- Medical subject headings
- Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
placebo pill
FK506 level < 2 ng/mlDrug
FK506 goal trough blood level < 2 ng/ml
FK506 level 2-3 ng/mlDrug
FK506 goal trough blood level 2-3 ng/ml
FK506 level 3-5 ng/mlDrug
FK506 goal trough blood level 3-5 ng/ml
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
| FK506 level < 2 | Experimental | Not described Receives: Drug: FK506 level < 2 ng/ml |
| FK506 level 2-3 | Experimental | Not described Receives: Drug: FK506 level 2-3 ng/ml |
| FK506 level 3-5 | Experimental | Not described Receives: Drug: FK506 level 3-5 ng/ml |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of Low-dose FK-506 in PAH
Total number of adverse events measured between baseline and end of study at 18 weeks as reported by study subjects such as nausea/diarrhea, URI, sinus congestion, infection, fluid retention/edema, cough, headache, bronchitis, fatigue, drug reaction/hives, flushing, anxiety, tremor, fever, shingles, SOB, insomnia, pain
Measured: 18 weeks
Secondary outcomes (2)
Number of Combined Clinical Events
Combined Clinical Events @ 16 weeks:
Number of patients who died Number of patients who got transplanted Number of patients who needed escalation of therapies Number of patients who had worsening of NYHA/WHO classification by at least 1 point Number of patients who require hospitalization for right heart failure
Low numbers would suggest either efficacy of the study drug or slowly progression of disease that is studied during the 16 week study period or short observation period or small study population
Measured: Baseline to 16 weeks
Efficacy of Low-dose FK-506 in Pulmonary Arterial Hypertension (PAH) Measured by Change in 6-min Walk Distance (6MWD)
Change in 6MWD in meter between baseline and 16 weeks
A large number would indicate an increase in exercise capacity
Measured: baseline to 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jul 2012 (estimated)
- Study startJul 2012
- Primary completionMay 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 (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Arterial HypertensionStudies of the same condition, open and under way.
- 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
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Edda Spiekerkoetter
- Sponsor type
- University, hospital or other
- Collaborators
- Stanford University
- Responsible party
- Sponsor-investigator, Edda Spiekerkoetter, Stanford University
- Investigators
- Edda Spiekerkoetter, MD, Principal investigator, Stanford UniversityRoham Zamanian, MD, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01647945
- Sponsor's protocol ID
- PAH-70522
- Acronym
- TransformPAH
- Status last verified
- Aug 2016
- First submitted
- 18 Jul 2012
- Last updated
- 5 Oct 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Spiekerkoetter E, Sung YK, Sudheendra D, Scott V, Del Rosario P, Bill M, Haddad F, Long-Boyle J, Hedlin H, Zamanian RT. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017 Sep 11;50(3):1602449. doi: 10.1183/13993003.02449-2016. Print 2017 Sep.
PubMed 28893866
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Single-Center Randomized Controlled Phase II Study of Safety and Efficacy of FK-506 (Tacrolimus) in Pulmonary Arterial Hypertension
- ClinicalTrials.gov ID
- NCT01647945
- Acronym / sponsor ID
- TransformPAH / PAH-70522
- Conditions
- Pulmonary Arterial Hypertension
- Keywords
- PAH WHO group 1
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Edda SpiekerkoetterUniversity, hospital or other
- Collaborators
- Stanford University
- Study start
- Jul 2012
- Primary completion
- May 2014 (actual)
- Study completion
- Aug 2014 (actual)
- First posted
- 24 Jul 2012 (estimated)
- Results
- Posted 5 Oct 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Mutations in bone morphogenetic protein receptor 2 (BMPR2) are present in >80% of familial and ~20% of sporadic pulmonary arterial hypertension (PAH) patients. Furthermore dysfunctional BMP signaling is a general feature of pulmonary hypertension even in non-familial PAH.
We therefore hypothesized that increasing BMP signaling might prevent and reverse the disease. We screened > 3500 FDA approved drugs for their propensity to increase BMP signaling and found FK506 (Tacrolimus) to be a strong activator of BMP signaling. Tacrolimus restored normal function of pulmonary artery endothelial cells, prevented and reversed experimental PAH in mice and rats.
Given that Tacrolimus is already FDA approved with a known side-effect profile, it is an ideal candidate drug to use in patients with pulmonary arterial hypertension.
The aims of our trial are:
- Establish the Safety of FK506 in patients with PAH.
- Evaluate the Efficacy of FK506 in PAH
- Identify ideal candidates for future FK506 phase III clinical trial.
Detailed description
Study Design:
Randomized, placebo-controlled, four arm clinical trial.
Sample Size: 10 subjects in each arm, Total enrollment = 40 patients.
- 10 patients: FK-506 blood level: 3 - 5 ng/ml
- 10 patients: FK-506 blood level: 2 - 3 ng/ml
- 10 patients: FK-506 level: < 2.0 ng/ml
- 10 patients: Placebo
Study Duration:
16 weeks
Primary Endpoints:
- Safety of low-dose FK506 in PAH
Secondary Objectives/Endpoints:
- Combined Clinical Events/Time to Clinical Worsening @ 16 weeks:
- All cause mortality
- Transplantation
- Atrial septostomy
- Need for escalation of therapies as deemed by site investigator
- Worsening of NYHA/WHO classification by at least 1 point.
- Hospitalization for right heart failure.
- Change in 6MWD at 16 weeks
- Change in NT-Pro-BNP at 16 weeks
- Change in Uric Acid at 16 weeks
- Change in DLCO at 16 weeks
- Change in novel RV parameters by transthoracic echocardiography: Change in RV size, RA size, RV function, TAPSE, RVSP
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebo |
| FK506 level < 2 | Experimental | Drug: FK506 level < 2 ng/ml |
| FK506 level 2-3 | Experimental | Drug: FK506 level 2-3 ng/ml |
| FK506 level 3-5 | Experimental | Drug: FK506 level 3-5 ng/ml |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age ≥ 18 and < 70 years
- Diagnosis of WHO Group I Pulmonary Arterial Hypertension (PAH) (Idiopathic (I)PAH, Heritable PAH (including Hereditary Hemorrhagic Telangiectasia), Associated (A)PAH (including collagen vascular disorders, drugs+toxins exposure, congenital heart disease, and portopulmonary disease).
- Stable on active PAH treatment including any prostacycline or phosphodiesterase inhibitors and the endothelin antagonist Ambrisentan alone or in combination (stability defined as: <10% change in 6MWD, no change in NYHA class, no hospitalization or addition of PAH therapy for at least 3 months).
- Previous Right Heart Catheterization that documented:
- WHO functional class I to IV as judged by the investigator.
Key exclusion criteria (26 listed)
- WHO Group II - V Pulmonary Hypertension.
- Current or prior experimental PAH treatments within the last 6 months (including but not limited to tyrosine kinase inhibitors, rho-kinase inhibitors, or cGMP modulators).
- Current active treatment with the dual endothelin receptor antagonist bosentan.
- TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
- FEV1 / FVC < 70% predicted and FEV1 < 60% predicted
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 |
|---|---|---|
| Placeboplacebo pill | Drug | Placebo |
| FK506 level < 2 ng/mlFK506 goal trough blood level < 2 ng/ml | Drug | FK506 level < 2 |
| FK506 level 2-3 ng/mlFK506 goal trough blood level 2-3 ng/ml | Drug | FK506 level 2-3 |
| FK506 level 3-5 ng/mlFK506 goal trough blood level 3-5 ng/ml | Drug | FK506 level 3-5 |
Primary outcome
Safety of Low-dose FK-506 in PAH
Time frame: 18 weeks
Total number of adverse events measured between baseline and end of study at 18 weeks as reported by study subjects such as nausea/diarrhea, URI, sinus congestion, infection, fluid retention/edema, cough, headache, bronchitis, fatigue, drug reaction/hives, flushing, anxiety, tremor, fever, shingles, SOB, insomnia, pain
2 secondary outcomes
Number of Combined Clinical Events
Time frame: Baseline to 16 weeks
Efficacy of Low-dose FK-506 in Pulmonary Arterial Hypertension (PAH) Measured by Change in 6-min Walk Distance (6MWD)
Time frame: baseline to 16 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 28893866Spiekerkoetter E, Sung YK, Sudheendra D, Scott V, Del Rosario P, Bill M, Haddad F, Long-Boyle J, Hedlin H, Zamanian RT. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017 Sep 11;50(3):1602449. doi: 10.1183/13993003.02449-2016. Print 2017 Sep.
- Related InfoLink provided by the sponsor.
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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.
Edda Spiekerkoetter, MD principal investigator
Stanford University
Roham Zamanian, MD principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing FK506 level < 2 ng/ml, FK506 level 2-3 ng/ml and FK506 level 3-5 ng/ml in people with Pulmonary Arterial Hypertension, run by Edda Spiekerkoetter at 1 site in United States.
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 8 inclusion and 26 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 5 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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. Some participants in this study may receive a placebo. 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 5 Oct 2016). 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?
Safety of Low-dose FK-506 in PAH (time frame: 18 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 NCT01647945, which also lists 1 linked publication.
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 5 Oct 2016.