A Phase II/III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Relaxin in Subjects with Acute Heart Failure

Relaxin is believed to orchestrate many of the maternal physiological responses
to pregnancy, including increases in renal function, decreases in systemic
vascular resistance, and increases in cardiac output mediated largely by
increased stroke volume. These effects have been replicated in numerous
non-clinical studies using relaxin, which has also demonstrated the ability to
prevent or reverse the effects of two potent mediators in acute heart failure,
angiotensin (Ang) II and endothelin. The presence of relaxin receptors, LGR7
and LGR8, in blood vessels strongly suggests that relaxin engages these
receptors when given therapeutically. Relaxin's pharmacology is believed to be
mediated by activation of the endothelin type B receptor and by nitric oxide
locally within blood vessels.

Relaxin has been tested in a pilot, open label, dose ranging hemodynamic study
in patients with compensated CHF (Protocol RLX.CHF.001). Relaxin administration
was associated with decreases in pulmonary capillary wedge pressure (PCWP) and
systemic vascular resistance (SVR) and with increases in cardiac index (CI)
during infusion, with a return to baseline values by 24 hr post-dosing.
Administration of relaxin was also associated with decreases in serum
creatinine, BUN and uric acid,consistent with its ability to increase GFR.
Relaxin showed excellent safety in these patients and appeared to be most
efficacious in the lower dose groups tested.

Pre-RELAX-AHF, the dose ranging Phase 2 portion of the current protocol
(RLX.CHF.003), was conducted with the objective of evaluating the efficacy and
safety of IV relaxin in patients hospitalized with dyspnea due to AHF, normal
to high systolic blood pressure and impaired renal function. Patients were
randomized to placebo or 10, 30, 100 or 250 µg/kg/day relaxin infused IV
continuously for up to 48 hours, in addition to standard therapy for HF.
Serial assessments of symptom relief were made through Day 14 using 2 well
accepted dyspnea scales,the Likert scale and VAS. Additional measures of
efficacy included AHF signs, symptoms and outcomes, length of hospital stay,
days alive and out-of-hospital to Day 60, and morbidity and mortality to Day
180.

A total of 234 patients enrolled from 8 countries. The relaxin doses evaluated
were 10, 30, 100, and 250 µg/kg/day compared to placebo. Baseline
characteristics were balanced among all groups. Improvement in dyspnea was
greater in the active relaxin arms vs placebo, with the largest apparent
effects observed at a relaxin dose of 30 µg/kg/day. Relaxin at 30 µg/kg/day
also showed trends indicating benefit in in-hospital measures of HF, including
greater weight loss and resolution of symptoms and signs of congestion, less IV
loop diuretic use, lower incidence of in-hospital worsening heart failure and
shorter length of stay. Improvements in intermediate term outcomes, including
the number of days alive and out-of-hospital to Day 60 and reduced rate of HF
re-admission and cardiovascular death to day 60 were also observed in the 30 µg/
kg/day group. There were also positive trends in reduction of all-cause and CV
mortality at Day 180.

Decreases in blood pressure were observed across all dose groups. The decreases
were generally asymptomatic and manageable. There were 2 SAEs of hypotension,
assessed as unrelated to study drug, following dosing with the highest relaxin
dose. Relaxin administration was not associated with symptomatic renal
worsening, either during or post-dosing. However, in the 250 µg/kg/day dose
group, small and asymptomatic increases from baseline in serum creatinine were
observed at Day 14, suggesting nascent dose limiting renal toxicity at a dose
8-times the proposed dose for the RELAX-AHF-1 study, which is 30 µg/kg/day.
There were 2 SAEs of renal failure in the study, one in the placebo group and
one in the 30 µg/kg/day relaxin group. The latter was believed to be possibly
related to study drug by the investigator. Overall in Pre-RELAX-AHF, there were
no apparent patterns of adverse events indicating safety or tolerability issues
that preclude further study of 30 µg/kg/day relaxin in patients with heart
failure in RELAX-AHF-1 (the Phase III portion of the study).

The objectives of this phase of the study are to confirm the efficacy of IV
relaxin, in addition to standard therapy, in improving symptoms of heart
failure, dyspnea, and in preventing intermediate term re-admission for HF or
renal failure and cardiovascular death in subjects hospitalized for AHF with
normal to elevated blood pressure and mild to moderate renal impairment. The
study*s safety objective is to assess the overall safety of IV relaxin in this
patient population.

The main phase of the study (*RELAX-AHF*) is designed to confirm the efficacy
and evaluate the safety of relaxin at 30 µg/kg/day, which is the optimal dose
selected based on the safety and efficacy results of the Pre-RELAX-AHF phase,
versus placebo infused for up to 48 hours in
subjects hospitalized with AHF. Eligible subjects will be randomized 1:1 to
receive either IV placebo or relaxin. A total of up to 1160 patients will be
enrolled in multiple countries in order to attain 1100 efficacy evaluable
patients.

After signing an Ethics Committee or Institutional Review Board-approved
Informed Consent Form, subjects will be asked to undergo screening procedures
for study eligibility. Study drug will be administered as an IV infusion for 48
hours. If at any time during dosing, the subject*s systolic blood pressure is
decreased by > 40 mm Hg from baseline but is > 100 mm Hg in 2 consecutive
measurements 15 min apart, the study drug infusion rate will be decreased by
50% for the remainder of the study drug administration. If at any time during
dosing, the subject*s systolic blood pressure is < 100 mm Hg in 2 consecutive
measurements 15 min apart, the study drug infusion will be permanently
terminated. All patients will be evaluated at screening and baseline and
thereafter at 6, 12 and 24 hours, daily while hospitalized through Day 4, and
at Days 5, 14 and 60 for symptoms and signs of heart failure. Patient-reported
AHF symptoms will be collected using both a 7-point Likert scale describing the
change in symptom severity from baseline, and a 100-mm Visual Analog Scale
(VAS) describing symptom severity at each point in time. These evaluations will
be done at baseline (VAS only), 6, 12 and 24 hours from start of study drug
infusion and then daily while hospitalized through Day 4, and at Days 5 and 14.
Subjects will have clinical evaluations, including AHF symptom assessments,
vitals signs,
physical examination emphasizing signs of HF, as well as an assessment of need
for further IV HF treatment and worsening HF events at least daily to the
earlier of Day 4 or discharge, and then at Days 5 and Days 14 and 60. Blood and
urine samples will be collected at baseline and at 24 hours (Day 1) and 48
hours (Day 2) for routine safety assessments and to evaluate renal function.
Blood samples will also be collected on Days 3, 4, 5, 14 and 60. Clinical and
laboratory evaluations, as detailed above, will be mandatory at Days 5, 14 and
60. If the patient is discharged from the hospital prior to these visits, these
evaluations will be performed as outpatient visits. Just prior to the time that
the last patient enrolled in the study reaches the Day 60 follow-up, patients
who have not completed the study will be contacted to ascertain an interim
vital status. All patients will be contacted by phone at Day 180 to ascertain
vital status. AEs will be collected through Day 5 and SAEs collected through
Day 14.

Patients will be randomized in a 1:1 fashion to receive either IV placebo or IV
relaxin at 30 µg/kg/day.

Patients will be asked to provide a self-report of dyspnea and general
well-being in the form of two visual analog scales at Baseline, 6 hours, 12, 24
, and 48 hours, Days 3, 4, 5, and 14. Patients will also be asked to provide
a self report of dyspnea and well-being in the form of two Likert scales at 6,
12, 24, 48 hours and Days 3, 4, 5 and Day 14. For this assessment, patients
will be positioned with the head of the bed elevated at approximately 30
degrees, and oxygen will be removed for 3-5 minutes, provided the patient is
able to tolerate the removal. Patients who are unable to tolerate removal of
oxygen will have it readministered immediately.

Patients will have 9 blood draws for a total volume of approximately 201 mls.
During screening, patients will be required to undergo a chest x-ray to
determine the presence of pulmonary congestion, and an electrocardiogram.

Patients will be examined by a physician to assess dyspnea on exertion,
orthopnea, edema, rales and jugular venous pulse at Baseline, 6, 12, 24, and 48
hours, and Days 3, 4, 5, 14 and 60. The physician will also evaluate the
patient for worsening failure at 24 and 48 hours, and Days 3,4,5 and 14. At
Day 14 and Day 60, the patient will be asked to complete the EQ-5D, a quality
of life scale. At Day 180, the patient will receive a phone call to determine
vital status.

Patients will undergo frequent vital sign assessments: between Baseline and 48
hours the patient will have 22 BP and heart rate assessments and temperature
and respiration will be collected at Baseline, 6, 12, 24 and 48 hours.
Following completion of the infusion (whether the patient receives the full 48
hours of infusion or only a partial infusion), the patient will undergo BP and
heart rate measurements at 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours.

Relaxin has been tested in three previous studies in patients who had heart
failure:
In the largest study, relaxin was given to 169 patients and placebo was given
to 61 patients with AHF. There was no difference between the relaxin and
placebo groups in the rate of the complications that are typically seen in
patients with AHF: heart failure, hypotension, hypertension, pneumonia and
cerebral vascular accident. Some patients died but there was no difference in
the rate between the relaxin groups and the placebo group. More patients in
the relaxin groups showed asymptomtic hypotension compared to those in the
placebo group. This is not unexpected in a drug that is being used to treat
patients with AHF and normal to high blood pressure. There were no cases of
serious decreases in blood pressure in subjects who received 30 µg/kg/day, but
there were 2 cases of serious hypotension in the highest relaxin dose group,
which was 8 times higher than the one being tested in the current study. The
group that received the highest dose of relaxin had some changes in their blood
tests that may have indicated some worsening kidney function but these patients
did not have any symptoms that needed treatment. There was one case of kidney
failure in the group of patients receiving relaxin and the investigator thought
that the event could have been due to relaxin. There was also one case of
kidney failure in the placebo group. Small changes in laboratory values for
the asymptomatic anemia were also seen in the relaxin groups.

In another study, relaxin was given to 16 patients with compensated heart
failure, a less serious form of HF. In this study, relaxin was found to be
safe for these patients, even at doses much higher than being studied in this
trial. In this trial, patients showed some improvement of kidney and heart
function during relaxin dosing, but some patients showed signs of worsening in
kidney function after relaxin dosing was stopped. This worsening was only
noticed in some laboratory measurements and the patients did not report any
symptoms or difficulties.

In a different study, 11 patients with severe AHF were recruited. Eight
patients received relaxin and three received placebo. Some of the patients
developed serious complications of AHF, such as pneumonia and cardiac arrest,
and 2 patients died, but these events were not unexpected in these patients and
occurred equally among the patients receiving relaxin and those receiving
placebo. Therefore, the doctor concluded that these serious adverse events and
deaths were related to the severity of the patients* disease and not to
relaxin.

Relaxin has also been tested before in 17 previous clinical trials involving
563 patients with medical conditions other than heart failure. Relaxin has
never been associated with any serious side effects in studies in normal
healthy male and female volunteers, patients with fibromyalgia , young women
undergoing egg donation, healthy male and female subjects undergoing dental
procedures or pregnant women at term. There were side effects that were common
in patients who received relaxin for long periods of time (weeks or months).
Since these patients will only be receiving relaxin for up to 48 hours, it is
unlikely they will experience any of these side effects:
• Heavy/irregular menstrual bleeding, mild to moderate reversible anemia,
diarrhea, abdominal pain, and nausea.
• Local pain, redness, swelling, irritation and infection at the site of
injection
• Antibody formation. These antibodies have caused no side effects and do not
appear to reduce the effects of relaxin.
• The largest clinical studies of relaxin involving 257 subjects have been in
patients diagnosed with scleroderma. Six deaths, serious worsening of kidney
function and hypertension were reported among patients with scleroderma that
received relaxin. The doctors believed that all of the deaths were caused by
scleroderma and were not related to relaxin

There is a possibility of a mild allergic reaction such as itching or skin
rash, as well as anaphylaxis.

Side effects that may associated with the different procedures that patients
will undergo during the study include:
• Chest x-ray: small dose of radiation
• Electrocardiogram (ECG or EKG): The electrode patches may feel cold when
first applied. In rare cases, some people may develop a rash or irritation
where the patches were placed.
• IV administration: There is the possibility of discomfort and/or pain, and a
very slight chance of infection at the site of the needle placement.
• Venipuncture: There is a possibility of some discomfort, pain, a small amount
of bleeding or bruising and a very small possibility of infection at the site
where the needle is inserted. A catheter (plastic tube) may remain in place
during your hospitalization so that a needle does not have to be inserted for
every blood draw. During the screening process and the whole study, up to 201
milliliters (approximately 13 * tablespoons) of blood will be drawn.
• There may be side effects not presently known associated with the use of
relaxin, as well as possible side effects related to the dose used, the
duration of treatment and the method of administration. Interactions between
relaxin and other medications have not been studied.

Being a part of this study while pregnant may expose the unborn child to
unnecessary risks. Therefore, pregnant women will be excluded from the study.
Males should not father a baby while on this study because it is not known if
the drugs in this study can affect an unborn baby.