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Systemic Rapamycin (Sirolimus) to Prevent In-Stent Restenosis Following Pulmonary Artery Stent Placement

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ClinicalTrials.gov Identifier: NCT02365415
Recruitment Status : Withdrawn (Unable to enroll appropriate patients)
First Posted : February 19, 2015
Last Update Posted : April 5, 2018
Sponsor:
Information provided by (Responsible Party):
Jesse J Esch, Boston Children's Hospital

Brief Summary:

This is a research study to assess whether an oral medication can benefit some patients being treated for peripheral pulmonary stenosis (PPS), which is narrowing of the blood vessels that send blood to the lungs (pulmonary arteries).

In the cardiac catheterization laboratory, the investigators treat PPS by dilating the narrowed segments of pulmonary arteries using balloon catheters. Sometimes the investigators also place stents which are mesh tubes that help keep the narrowed vessel open. Some stents suffer from in-growth of tissue into the stents which causes recurrent obstructions inside the stent (i.e. making the opening inside the mesh tube narrow again), so called in-stent stenosis (ISS).

The purpose of this study is to use a medication that is approved for use in children (for a different purpose) to decrease the amount of cell ingrowth inside the stents (i.e. decrease the problematic in-stent stenosis). The medication is called rapamycin, also known as sirolimus (trade name Rapamune). It has antiproliferative properties which means that it slows down cell division which the investigators believe cause the recurrent narrowing inside stents.

Rapamycin is a medicine that can be taken by mouth as a liquid or pill or via a feeding tube. There will still be a need for interventions in the catheterization laboratory but the investigators hope that by taking this medicine some children would need fewer catheterizations in the future. Our early experiences with a few patients who have been treated with rapamycin due to in-stent stenosis in the pulmonary arteries suggest that it may be helpful.

In this study, patients and families who are interested in possibly trying this new approach will be randomized to sirolimus or no sirolimus. The investigators will compare the developement of ISS over time between these groups, in a hope to learn whether oral sirolimus reduces ISS development.


Condition or disease Intervention/treatment Phase
Peripheral Pulmonary Stenosis In-stent Stenosis Drug: Sirolimus Phase 2

Detailed Description:

This is a research study to assess whether an oral medication can benefit some patients being treated for peripheral pulmonary stenosis (PPS). PPS, which can be associated with several different congenital heart diseases, is narrowing of the blood vessels that send blood to the lungs (pulmonary arteries) to pick up oxygen before returning the blood to the heart and the rest of the body. The right ventricle (RV) is the pumping chamber that pumps blood into the pulmonary arteries and the lungs.

PPS can result in high RV pressure, reduced blood flow to one lung, or uneven blood flow within either lung. If left untreated these abnormalities place affected children at risk for abnormal RV function and failure of this pumping chamber which may be seen as decreased ability to do exercise, heart rhythm problems, fainting, or even death.

In the cardiac catheterization laboratory, the investigators treat PPS by dilating the narrowed segments of pulmonary arteries using balloon catheters. Sometimes the investigators also place stents which are mesh tubes that help keep the narrowed vessel open. Some stents suffer from in-growth of tissue into the stents which causes recurrent obstructions inside the stent (i.e. making the opening inside the mesh tube narrow again), so called in-stent stenosis (ISS). This effectively causes recurrent PPS and recurrence of the associated risks listed above.

The purpose of this study is to use a medication that is approved for use in children (for a different purpose) to decrease the amount of cell ingrowth inside the stents (i.e. decrease the problematic in-stent stenosis). The medication is called rapamycin, also known as sirolimus (trade name Rapamune), and has been used safely for many years in children and adults after organ transplantation to prevent rejection of the new organ. It has antiproliferative properties which means that it slows down cell division which the investigators believe cause the recurrent narrowing inside stents. By slowing down the cell division the investigators believe that the stents will stay open instead of becoming narrowed inside again. This medicine is found in many types of stents placed in adults with narrowed arteries around the heart (so called drug-eluding stents) and appear to help keep these blood vessels open after heart attacks (or to prevent heart attacks). Such stents are currently not available for pulmonary arteries; therefore the investigators give the medicine by mouth instead (which has also been used in adults with stents in narrowed arteries around the heart).

Rapamycin is a medicine that can be taken by mouth as a liquid or pill or via a feeding tube. There will still be a need for interventions in the catheterization laboratory but the investigators hope that by taking this medicine some children would need fewer catheterizations in the future. The investigators believe it may help lessen the risk of recurrent in-stent stenosis and the associated problems listed above. Our early experiences with a few patients at BCH who have been treated with rapamycin due to in-stent stenosis in the pulmonary arteries suggest that it may be helpful.

In this study, patients and families who are interested in possibly trying this new approach will be randomized to sirolimus or no sirolimus. The investigators will compare the developement of ISS over time between these groups, in a hope to learn whether oral sirolimus reduces ISS development.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Systemic Rapamycin (Sirolimus) to Prevent In-Stent Restenosis Following Pulmonary Artery Stent Placement
Actual Study Start Date : February 2015
Actual Primary Completion Date : April 2018
Actual Study Completion Date : April 2018


Arm Intervention/treatment
Experimental: Sirolimus
Patients randomized to this arm will receive 8 weeks of enteral Rapamycin (sirolimus), with dosage titrated to achieve target blood levels.
Drug: Sirolimus
8 weeks oral sirolimus, following drug levels
Other Name: Rapamycin, Rapamune

No Intervention: Control
No treatment.



Primary Outcome Measures :
  1. Percent change in in-stent stenosis [ Time Frame: 6 months ]

Secondary Outcome Measures :
  1. RV pressure [ Time Frame: 6 months ]
  2. Adverse drug event [ Time Frame: 6 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • In-stent stenosis: At least one stent from at least one prior catheterization affected by in-stent stenosis (≥25% stenosis and a diameter narrower or equal to the distal vessel).
  • At least one of the following:

    • RV hypertension: At least one half systemic RVp or ≥ 70 mm Hg by echocardiogram or per baseline hemodynamics on most recent catheterization
    • Pulmonary blood flow maldistribution: ≤ 25% of flow to either lung or regional decrease in individual lobar segments.
    • Pulmonary hypertension: Mean PA pressure ≥ 20 mmHg in unobstructed segments by most recent catheterization.
  • Informed consent of patient and/or parent/guardian
  • Agreement to participate in protocol, including follow-up testing

Exclusion Criteria:

  • Age ≤ 6 months
  • Pulmonary artery surgery or transcatheter PA dilations in the past 6 weeks.
  • Malignancy (past or present)
  • Active infection
  • Pregnancy (current or planned within the next 1 year)
  • Organ dysfunction as evidenced by laboratory abnormalities

    • Renal: BUN > 40 mg/dL, or Cr > normal limit for age (by powerchart). Exceptions can be made at the discretion of the study physician if BUN or Cr elevation is known to be due to diuretic management with plan to reduce dosing, or other reversible mechanism.
    • Hepatic: AST or ALT > 120 unit/L, or total bilirubin > 3 mg/dL
    • Immune: WBC < 2,000, or ANC or ALC < 1,000
    • Hematologic: Hgb< 7 g/dL, or Hct< 21%, or platelet count < 80,000. Exceptions can be made at the discretion of the study physician if plans include transfusion of blood products in the catheterization laboratory and a known reversible etiology for the anemia.
  • Lipids: Total cholesterol > 250 mg/dL, HDL < 30 g/dL

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02365415


Locations
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United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Boston Children's Hospital
Investigators
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Study Director: Audrey Marshall, MD Boston Children's Hospital
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Responsible Party: Jesse J Esch, Staff Cardiologist, Instructor in Pediatrics, Boston Children's Hospital
ClinicalTrials.gov Identifier: NCT02365415    
Other Study ID Numbers: IRB-P00005257
First Posted: February 19, 2015    Key Record Dates
Last Update Posted: April 5, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Pulmonary Valve Stenosis
Constriction, Pathologic
Pathological Conditions, Anatomical
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs