Standard Therapy Using Tacrolimus, Mycophenolate Mofetil and Prednisone For Chronic Lung Transplant Rejection (BOS)

A Randomized, Open-label,Controlled Phase II b Study to Demonstrate Efficacy and Safety of Sirolimus Chronic Rejection After Lung Transplant

This is a prospective single-center, open-label, randomized, controlled pilot

study in the treatment of chronic rejection (CR), defined as grade 1 and 2

BOS, in adult recipients of a pulmonary allograft (single or double lungs).To assess the efficacy and safety of sirolimus plus tacrolimus and prednisone

(S) compared to standard therapy (tacrolimus, mycophenolate mofetil

(MMF) and prednisone) (ST) for chronic rejection, defined as grades 1 and 2

bronchiolitis obliterans syndrome (BOS); BOS defined as ≥ 20% decline

from maximal post-transplant FEV1.

This is a prospective single-center, open-label, randomized, controlled pilot

study in the treatment of chronic rejection (CR), defined as grade 1 and 2

BOS, in adult recipients of a pulmonary allograft (single or double lungs).

Patients meeting entry criteria shall demonstrate a sustained decline in FEV1

having met stage 1 or 2 BOS. Patients randomized to the study arm, will be

treated with Sirolimus (S) orally in place of MMF in addition to tacrolimus

and prednisone compared to those patients randomized to defined ST alone

(tacrolimus, MMF and prednisone). The trial duration will be approximately

Primary endpoints will include:

Efficacy failure between ST and S randomized group investigational treatment regimens will be determined at 96 weeks after the last patient is randomization and enrolled at approximately study year 2. The control arm will receive standard of care treatment (ST) and immunosuppression according to the University of Maryland lung transplant protocol. Efficacy failure will be defined as the combined end point of progression of BOS (defined as at least a 20 % decline from the initial randomization FEV1 value confirmed by two separate measurements three weeks apart or more) or re-transplantation or death. The co-primary end point of FEV1 and FVC changes to define functional stabilization in the S arm compared to ST is to be completed when the last patient randomized (patient #30) has been enrolled for 2 years as well.

Efficacy of S is to be assessed using following parameters to determine its effect on lung function:

1. Forced expiratory volume in one second (FEV1)
2. Forced vital capacity (FVC)
3. FEF 25-75

Secondary endpoints will include:

• General S tolerability
• Incidence and severity of adverse events (AE)
• Changes in clinical laboratory parameters from baseline after randomization
• Changes in vital signs
• Changes in physical examinations
• Incidence of infections
• Average maintenance doses of calcineurin inhibitors, antimetabolite agents, and corticosteroids
• Number of courses of augmented immunosuppressants
• Number and days of hospitalization
• Incidence of malignancies
• Overall mortality (including transplant-related mortality)
• Retransplantation

Inclusion Criteria:

1. Age: 18 or older.
2. Recipient of a single or double pulmonary allograft at least twelve months before study entry.
3. Clinically diagnosed BOS grade 1 or 2
4. Receiving oral TAC-based immunosuppression according to institutional standards.
5. Capable of understanding the purposes and risks of the study, has given written informed consent and agrees to comply with the study requirements and capable of protocol adherence.
6. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry.
7. Stable to enable routine pre and post-transplant bronchoscopy with BAL and biopsy.
8. Fasting cholesterol < 250 mg/dL, fasting triglycerides < 250 mg/dL -

Exclusion Criteria:

1. Active bacterial, viral or fungal infection not successfully resolved at least 4 weeks prior to study entry.

2. Mechanical ventilation.

3. At screening FEV1 < 1 liter and/or < FEV1 of 25 % predicted.

4. Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy.

5. Women who breastfeed.

6. Known hypersensitivity to sirolimus.

7. Serum creatinine value of > 2.5 mg/dL or chronic dialysis use or liver disease with a bilirubin > 2 mg/dL.

8. Subjects with severe underlying disease other than BOS that is thought to become fatal within four months of clinical assessment.

9. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to study entry. This is defined as any treatment that is implemented under an Investigational New Drug.

10. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.

11. Any co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the patient's participation in the clinical trial.

12. Clinically significant bronchial strictures unresponsive to dilatation procedures.

13. Subjects with malignancy diagnosed within one year prior to screen (with the exception of skin cancers).

14. Lipid panel fasting cholesterol > 250 mg/dL, fasting triglycerides >250 mg/dL

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