Phase-II Study of the Use of PulmoBind for Molecular Imaging of Pulmonary Hypertension
Phase-II Study of the Use of PulmoBind for Molecular Imaging of Pulmonary Hypertension
Pulmonary hypertension or elevation of the pressure in the pulmonary vessels, results from
 various clinical conditions. It may be idiopathic (of unknown cause) or associated with
 numerous diseases including cardiovascular and lung disorders. Affected individuals suffer
 from progressive shortness of breath and, in its most sever forms; pulmonary hypertension
 carries a worse prognosis than many types of cancer. There is no test currently that can
 easily and non-invasively detect abnormalities of the pulmonary circulation. Presently there
 is no cure for pulmonary hypertension and substantial research efforts are dedicated to the
 development of new drugs that will stop progression or better yet, reverse the disease
 process. The investigators do not know if any of the drugs currently commercialized for
 pulmonary hypertension directly improve the status of the pulmonary vessels since no test
 currently provides this information. Direct earlier detection of lung vessel abnormalities
 associated with pulmonary hypertension using a sensitive and non-invasive test would allow
 not only earlier testing of these and of new drugs, but would provide a much better surrogate
 of disease severity allowing more efficient pre-clinical drug testing. The aim of this phase
 II study is to evaluate the safety of PulmoBind in participants with pulmonary hypertension
 and its potential to detect abnormal pulmonary circulation associated within pulmonary
 hypertension.
Currently there is only one radiopharmaceutical agent approved in Canada (and the world) for
 clinical imaging of the pulmonary circulation, metastable isotope 99 of technetium. This
 agent is exclusively used for the diagnosis of physical defects of the circulation due to
 pulmonary embolus. There is imperative need for new lung tracers that will provide a greater
 safety profile while enabling functional as well as anatomical imaging of the pulmonary
 circulation. A novel adrenomedullin derivative has been developed, for molecular imaging of
 the pulmonary circulation. PulmoBind is labelled with metastable isotope 99 of technetium,
 the most commonly used imaging isotope in clinical nuclear medicine. PulmoBind is a
 adrenomedullin derivative specifically designed to bind to the adrenomedullin receptor while
 avoiding any hemodynamic effects. This novel tracer has the potential to help in the
 diagnosis and follow-up of various disorders of the pulmonary circulation for which there is
 currently no alternative. In PulmoBind I three escalating doses were administered and safety
 was assessed. The product was well tolerated and there were no safety concerns. Imaging
 revealed predominant lung uptake.
HEALTHY VOLUNTEERS:

 Inclusion Criteria:

 -  Male of female participants greater than 18 years of age,

 -  Female participants must be post-menopausal (defined as two year after last menstrual
 cycle) or surgically sterilized or use 1 form of contraception with a urine negative
 pregnancy test (commercial brand: first response kit) within 2 hours of study drug
 injection,

 -  Baseline measurements must be within limits of normal or judged non-clinically
 significant by the investigator:

 -  Blood pressure systolic 90 mmHg to 140 mmHg,and diastolic 50 mmHg to 90 mmHg;

 -  Heart rate: 50 to 100 beats per minute;

 -  Oral temperature: less than 37.6C;

 -  Respiratory rate: 12 to 20 breaths per minute;

 -  Lung function testing within 6 months;

 -  Electrocardiogram in the past three years;

 -  Chest X-Ray in the past three years;

 -  Electrocardiogram.

 Exclusion Criteria:

 -  Any known chronic or acute medical condition with or without the need for chronic
 pharmacologic therapy or any condition that may interfere with normal biodistribution
 of PulmoBind. This includes but is not restricted to: lung parenchymal or lung
 vascular diseases such as chronic obstructive pulmonary disease, bronchitis, lung
 cancer, pleural effusion, emphysema, asthma, pulmonary fibrosis, occupational lung
 disease,pulmonary hypertension (primary or secondary), systemic hypertension,
 diabetes, cancer, kidney disease, liver disease, heart failure or previous myocardial
 infarction, coronary artery disease, peripheral vascular disease or inflammatory
 disease,

 -  Participants requiring chronic administration of any substance for a medical
 condition,

 -  Active smoking or history of smoking within 6 months,

 -  Alcoholism or known substance abuse,

 -  Psychotic,addictive or other disorder limiting the ability to provide informed consent
 or to comply with study requirements,

 -  Unable to tolerate study procedures (e.g. venipuncture, movement restrictions during
 imaging),

 -  Previous nuclear medicine study within one week (to avoid cross-contamination).

 PULMONARY HYPERTENSION PARTICIPANTS:

 Inclusion Criteria:

 -  Male of female participants greater than 18 years of age and upper age 70,

 -  Female participants must be post-menopausal (defined as two year after last menstrual
 cycle) or surgically sterilized or use 1 form of contraception with a urine negative
 pregnancy test (commercial brand: first response kit) within 2 hours of study drug
 injection,

 -  Diagnosis of pulmonary hypertension (PH) according to the Dana Point PH classification
 of the following types:

 -  Type I: idiopathic, heritable or scleroderma spectrum of disease,

 -  Type IV: unoperated chronic thromboembolic PH.

 -  Participants with chronic thromboembolic pulmonary hypertension (CTEPH) must have a
 previous positive V/Q scan and multiple chronic/organised occlusive thrombi/emboli in
 the pulmonary arteries (main, lobar, segmental, subsegmental) on CT angiogram or
 conventional pulmonary angiography,

 -  Documented hemodynamic diagnosis of significant PH by right heart catheterization -
 performed at any time prior to Screening showing:

 -  Resting mean pulmonary arterial pressure (mPAP) > 25 mmHg and

 -  Resting pulmonary vascular resistance (PVR) > 240 dyn/s.cm5 and

 -  Resting capillary wedge pressure (PCWP) or left ventricular end diastolic
 pressure (LVDEP) ≤ 15 mmHg (if available),

 -  New York Heart Association (NYHA) functional class II-III,

 -  Six minutes walking distance test of ≥ 250 meters, and ≤ 450 meters within 6 months,

 -  Echocardiogram documented in the participants medical history (including an agitated
 saline study),

 -  Computed tomography of the chest documented in the participants medical history.

 Exclusion Criteria:

 -  Participants with impaired renal function defined as estimated creatinine clearance ≤
 30 ml/min (eGFR with modification of diet in renal disease (MDRD) calculator formula),

 -  Significant liver impairment:

 -  Aspartate alanine transferase ( ALT) and/or Aspartate transaminase (AST) ≥ 3 x
 upper limit of normal (ULN)

 -  Bilirubin ≥ 1.5x ULN ( > 35% direct bilirubin)

 -  Unstable pulmonary arterial hypertension defined as recent syncope or World Health
 Organization (WHO) functional class IV,

 -  Participants with CTEPH not on anticoagulant therapy,

 -  Echocardiographic restrictive lung disease (total lung capacity < 70% of predicted) or
 obstructive (FEC1/Forced Vital Capacity < 70%),

 -  Systemic blood pressure < 90 mmHG systolic or less than 50 mmHG diastolic,

 -  Patient foramen ovale with significant right to left shunting with hypoxia (room air
 saturation < 88%),

 -  Active smoking within six months,

 -  More than minimal pulmonary fibrosis on high resolution computed tomography of the
 chest,

 -  The subject's clinical condition is such that they are not expected to remain
 clinically stable for the duration of the study,

 -  Active coronary artery disease or stable coronary artery disease that has required an
 intervention or any change of therapy within 6 months,

 -  Alcoholism or known substance abuse,

 -  Psychotic,addictive or other disorder limiting the ability to provide informed consent
 or to comply with study requirements,

 -  Participants who have participated in a clinical study involving another
 investigational drug or devise within four weeks before screening,

 -  Female participants who are pregnant or breastfeeding,

 -  Previous nuclear medicine study within one week,

 -  Unable to tolerate study procedures (e.g. venipuncture, movement restrictions during
 imaging).