Peripheral Artery Disease (PAD)

This study is designed to determine whether LLG783 displays the clinical safety and efficacy profile, after multiple i.v. doses, to support further development in patients with PAD and intermittent claudication.

LLG783

LLG783

Solution for infusion/injection

150

Primary endpoint:
 To evaluate the safety and tolerability of LLG783 in patients with PAD and intermittent
claudication after 16 weeks of exposure to LLG783
 To evaluate the effect of LLG783 on functional capacity after 3 months of treatment in
patients with PAD and intermittent claudiation

Secondary endpoints:
 To investigate the PK of LLG783 in patients with PAD and intermittent claudication
 To evaluate the effect of LLG783 on symptomatic functional capacity after 3 months of
treatment in patients with PAD and intermittent claudication

Exploratory endpoints:
 To assess the immunogenicity (IG) of LLG783 after repeat dosing of i.v. infusion of LLG783
 To explore the PD and additional PK of LLG783 after i.v. infusion and potentially s.c.
administration
 To explore the effects of LLG783 on exploratory biomarkers of lipids, inflammation and
coagulation
 To explore the effects of LLG783 on lower extremity blood pressure before and after exercise
in patients with PAD and intermittent claudication
 To explore the effects of LLG783 on spontaneous physical activity in patients with PAD and
intermittent claudication
 To explore the effects of LLG783 on self-reported QoL in patients with PAD and intermittent
claudication
 To compare exercise treadmill testing (ETT) at 4 months to the 6MWT at 4 months
 To perform exploratory DNA assessments to examine whether individual genetic variation in
genes relating to drug metabolism, PAD, the drug target pathway, or other relevant genetic
pathways confer differential response to investigational drug, LLG783

Main inclusion criteria:
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any study assessment is performed.
2. Male and female patients 40 to 85 years of age (inclusive) at screening with clinical
evidence of PAD and intermittent claudication (Fontaine stage II) (Hardman et al 2014)
Intermittent claudication, as defined by pain with exertion in either leg (this may include
atypical symptoms, e.g. fatigue, paresthesias, pallor, etc.) AND any one of the following:
a. resting ABI of 0.40-0.90 (inclusive) in at least one leg;
b. OR for patients with a resting ABI > 0.90 but ≤ 1.0, a decrease in ABI of ≥ 20% with
exercise (to be measured immediately following completion of 6MWT at screening) in at
least one leg;
c. OR a decrease in ankle pressure ≥ 30 mmHg with exercise in at least one leg;
d. OR for patients with an ABI > 0.90, an abnormal toe-branchial index (TBI) < 0.70
Note: documented values within 3 months of signing the informed consent are acceptable
provided that there has been no peripheral revascularization in the interim.
3. On stable medical therapy, including statins, aspirin, and anti-hypertensive medications (as
medically indicated) unless individually contraindicated, for at least 4 weeks prior to the screening visit.
4. Vital signs must be within the following ranges:
a. body temperature between 35.0-37.5 °C
b. systolic blood pressure, 90-159 mmHg
c. diastolic blood pressure, 50-99 mmHg
d. pulse rate, 50-90 bpm
5. Moderately impaired ambulatory function judged by the investigator to be due primarily to
PAD and assessed by a maximum walk distance between 50 and 400 meters (inclusive of
these values) at the screening 6MWT.
6. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.

Main exclusion criteria:
Patients fulfilling any of the following criteria are not eligible for inclusion in this study.
1. Participation in any clinical investigation within four (4) weeks prior to enrollment or use of
other investigational drugs at the time of enrollment, or within 5 half-lives at the time of
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or
longer if required by local regulations. Patients previously enrolled in clinical trials of stem
cell therapy for PAD may be included if this therapy ended at least 6 months prior to
enrollment.
2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
3. Patients who meet any of the following PAD related criteria:
a. Patients actively attending and participating in a supervised exercise rehabilitation
program (patients who have already completed such a program and remain symptomatic
may be included).
b. Patients with any condition other than PAD that limits walking ability.
c. Known inflammatory disease of the arteries (other than atherosclerosis; e.g.
Thromboangiitis obliterans).
d. Clinical evidence of critical limb ischemia including new or non-healing ulcers (felt
secondary to critical limb ischemia), new or recent onset of resting pain in the lower
extremitis particularly at night (felt secondary to critical limb ischemia) and/or gangrene
of the lower extremities (Fontaine stage III-IV).
4. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 150 days after stopping of investigational drug.
Highly effective contraception methods include:
a. Total abstinence from heterosexual intercourse (when this is in line with the preferred and
usual lifestyleof the patient, and only in countries that accept “total abstinence” as
effective contraception). Periodic abstinence (e.g. calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are NOT acceptable methods of contraception.
b. Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment (e.g. FSH)
c. Male sterilization (at least 6 months prior to screening). For female patients on the study
the vasectomized male partner should be the sole partner for that patient.
d. Use of oral (estrogen and progesterone), injected or implemented hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
or other forms of hormonal contraception that have comparable efficacy (failure rate <
1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception, women should be stable on the same pill for ≥ 3 months
before taking investigational drug.
If local regulations deviate from the contraception methods listed above and require more
extensive measures to prevent pregnancy, local regulations apply and will be described in
the Informed Consent Form (ICF).
Women are considered post-menopausal and not of child bearing potential if they have had
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
(with or without hysterectomy), total hysterectomy or tubal ligation ≥ 6 weeks prior to
screening visit. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment is she considered not of
child bearing potential.
5. Any of the following concomitant cardiovascular or metabolic conditions or diseases:
a. Myocardial infarction within 6 months of screening.
b. Stroke within 6 months of screening.
c. History of clinically significant ventricular arrhythmias, according to the discretion of the
investigator, within 6 months of screening.
d. Significant ECG abnormalities, according to the discretion of the investigator, at
screening.
e. History of sustained and clinically significant supraventricular arrhythmias (e.g. associated with hemodynamic compromise) within 6 months of screening.
f. Chronic heart failure New York Heart Associate Class III or IV.
g. Known presence of aortic aneurysm > 5 cm.
h. Uncontrolled diabetes as defined by a random fasting glucose level of 13 mmol/L or 240
mg/dL or a HbA1c greater than 9% as measured at screening. Diabetes should be treated
as appropriate during the study.
6. Any of the following concomitant hepatic or renal conditions or diseases:
a. Patients with severe renal impairement defined as eGFR < 15 ml/min/1.73m2
[as
calculated by the MDRD (Modification of Diet it Renal Disease) method] or those
receiving current or planned dialysis or ultrafiltration.
b. Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B and hepatitis
C – including positive hepatitis B surface antigen or hepatic C test), or alanine
aminotransferase/asparate aminotransferase (ALT/AST) levels > 2.5 times upper limits
of normal (ULN) or total bilirubin > 2 times ULN at screening.
7. History of any of the following chronic conditions:
a. Malignancy of any organ system (other than localized basal or squamous cell carcinoma
of the skin), treated or untreated, within the past 3 years, regardless of whether there is
evidence of local recurrence or metastases.
b. Hemoglobin levels < 10.6 g/dL at screening.
c. History of immunodeficiency disease, including a positive HIV (ELISA and Western
blot) test result.
d. History of any hypercoagulable or bleeding disorders.
8. Major surgical procedure (such as coronary artery bypass grafting, carotid endarterectomy,
abdominal surgery) ≤ 6 months before screening or planned coronary revascularization or
any other major surgical procedure planned to occur during the planned time frame of the
study. Patients who have undergone peripheral vascular intervention > 6 months prior to
screening may still be considered eligible, provided they meet all other inclusion/exclusion
criteria. Patients with actively planned/scheduled lower extremity peripheral vascular
interventions within the first 4 months after enrollment should not be enrolled. However, if
clinically indicated during the study, a patient may undergo peripheral vascular intervention.
9. Any surgical or medical condition that in the opinion of the Investigator may place the
patient at higher risk from his/her participation in the study.
10. History of significant and active drug or alcohol abuse that could interfere with conduct of
the trial within the 12 months prior to dosing. Note: Investigator may establish veracity of
patient history with drug or alcohol testing as deemed necessary.
11. History of multiple and clinically significant recurring drug allergies.
12. History of allergy to the investigational compound / compound class (e.g. allergic reactions
to other protein therapeutics) being used in this study.
13. History of any transplant with the exception of skin or cornea.
14. Patients unable to hold all nacrotic pain relievers for 24 hours prior to performance of the
6MWT. (Instructions to this effect will be provided to enrolled patients).
15. Patients who are taking any other monoclonal antibody at screening are not necessarily
excluded from the study, but the site MUST contact Novartis study safety monitor so that
the monoclonal antibody information can be reviewed before confirming whether or not the
patient can be enrolled.
No additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.