Peripheral Artery Disease (PAD); Intermittent Claudication
Conditions
Keywords
PAD, peripheral artery/arterial disease, peripheral vascular disease, leg pain, claudication, leg pain with exercise, exercise test, walk test
Brief summary
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.
Interventions
DRUGLLG783
LLG783 concentrate solution for infusion/injection suitable for i.v. administration as well as s.c. administration.
DRUGPlacebo
Placebo to LLG783 concentrate solution for infusion/injection suitable for i.v. administration as well as s.c. administration.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Randomized, patient and investigator-blinded, placebo controlled, parallel group study
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* claudication, as defined by pain with exertion in either leg; * On stable medical therapy, including statins, aspirin, and antihypertensive medications (as medically indicated) unless individually contraindicated, for at least 4 weeks prior to the screening visit; * Vital signs must be within the following ranges: * body temperature between 35.0-37.5°C * systolic blood pressure, 90-159 mm Hg * diastolic blood pressure, 50-99 mm Hg * pulse rate, 50 - 90 bpm * 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 6-minute walk test (6MWT).
Exclusion criteria
* Pregnant or nursing (lactating) women; * Patients who meet any of the following PAD related criteria: * 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). * Patients with any condition other than PAD that limits walking ability. * Known inflammatory disease of the arteries (other than atherosclerosis; e.g. Thromboangiitis obliterans). * 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 extremities particularly at night (felt secondary to critical limb ischemia) and/or gangrene of the lower extremities (Fontaine stage III-IV) . * 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. * Any of the following concomitant cardiovascular or metabolic conditions or diseases: * Myocardial infarction within 6 months of screening. * Stroke within 6 months of screening. * History of clinically significant ventricular arrhythmias, according to the discretion of the investigator, within 6 months of screening. * Significant ECG abnormalities, according to the discretion of the investigator, at screening. * History of sustained and clinically significant supraventricular arrhythmias (e. g. associated with hemodynamic compromise) within 6 months of screening. * Chronic heart failure New York Heart Association Class III or IV. * Known presence of aortic aneurysm \> 5 cm. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | Up to 32 Weeks | An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign, including abnormal laboratory findings, symptom or disease) in a participant after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. An SAE is defined as any AE which is is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect in offspring, requires inpatient hospitalization or prolongation of existing hospitalization and is is medically significant. |
| Change From Baseline in Maximum Walking Distance (MWD) as Assessed by 6-minute Walk Test (6MWT) at Week 16 | Baseline, Week 16 (Day 113) | MWD was assessed by the 6MWT prior to dosing was used to evaluate functional capacity of peripheral artery disease (PAD) participants. 6MWT test included measurement of total distance walked in 6 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration-time Curve From Time Zero to Defined Time Point 't' (AUC[0-t]) | 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85 | AUC(0-t)is defined as the area under the serum concentration-time curve from time zero to time 't' where is a defined time point after administration. |
| Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) | 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85 | AUCtau is defined as the area under the serum concentration-time curve from time zero to the end of the dosing interval tau. |
| Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) | 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose and 1, 2 and 4 hours postdose on Day 85 | AUCinf is defined as the area under the serum concentration-time curve from time zero to infinity. |
| Time to Reach the Maximum Concentration After Drug Administration (Tmax) | 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85 | Tmax is defined as the time to reach the maximum concentration after drug administration. |
| Change From Baseline in Pain-free Walking Distance (PFWD) as Assessed by 6-minute Walk Test at Week 16 | Baseline, Week 16 (Day 113) | PFWD was defined as the distance walked up to the point of onset of claudication symptoms (pain) recorded during the 6MWT and was used to evaluate symptomatic functional capacity of PAD participants. The PFWD was measured as the distance walked up to the time/place where the participant first experiences symptoms typical of their claudication which included pain, cramps, or other discomfort in the buttocks, thighs, calves or feet that occurs during the 6MWT exercise period. |
| Observed Maximum Serum Concentration (Cmax) Following Drug Administration | 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85 | Cmax is defined as the observed maximum serum concentration following drug administration. |
| Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85 | AUClast is defined as the area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration. |
Countries
Germany, Taiwan, United States
Participant flow
Pre-assignment details
A total of 46 subjects with clinical evidence of PAD and intermittent claudication were enrolled and randomized in this study.
Participants by arm
| Arm | Count |
|---|---|
| LLG783 6mg/kg Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks. | 23 |
| Placebo Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks. | 23 |
| Total | 46 |
Baseline characteristics
| Characteristic | Placebo | Total | LLG783 6mg/kg |
|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 6.9 | 66.7 years STANDARD_DEVIATION 6.9 | 67.0 years STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 46 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Maximum walking distance (MWD) | 311.3 meters STANDARD_DEVIATION 84 | 314.3 meters STANDARD_DEVIATION 73 | 317.3 meters STANDARD_DEVIATION 62 |
| Pain Free Walking Distance (PWFD) | 156.0 meters STANDARD_DEVIATION 86.7 | 158.3 meters STANDARD_DEVIATION 82.3 | 160.7 meters STANDARD_DEVIATION 79.4 |
| Sex: Female, Male Female | 5 Participants | 13 Participants | 8 Participants |
| Sex: Female, Male Male | 18 Participants | 33 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 18 / 23 | 16 / 23 |
| serious Total, serious adverse events | 1 / 23 | 2 / 23 |
Outcome results
Primary
Change From Baseline in Maximum Walking Distance (MWD) as Assessed by 6-minute Walk Test (6MWT) at Week 16
MWD was assessed by the 6MWT prior to dosing was used to evaluate functional capacity of peripheral artery disease (PAD) participants. 6MWT test included measurement of total distance walked in 6 minutes.
Time frame: Baseline, Week 16 (Day 113)
Population: Pharmacodynamic (PD) analysis set included all participants with available PD data, who received any study treatment and experienced no protocol deviations with relevant impact on PD data. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LLG783 6mg/kg | Change From Baseline in Maximum Walking Distance (MWD) as Assessed by 6-minute Walk Test (6MWT) at Week 16 | 19.10 meter (m) |
| Placebo | Change From Baseline in Maximum Walking Distance (MWD) as Assessed by 6-minute Walk Test (6MWT) at Week 16 | 36.84 meter (m) |
Comparison: Statistical analysis was done by mixed effect model repeat measurement (MMRM) model analysis.p-value: =0.261280% CI: [-38.03, 2.55]two-sided test
Primary
Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign, including abnormal laboratory findings, symptom or disease) in a participant after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. An SAE is defined as any AE which is is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect in offspring, requires inpatient hospitalization or prolongation of existing hospitalization and is is medically significant.
Time frame: Up to 32 Weeks
Population: Safety analysis set included all participants that received any study treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LLG783 6mg/kg | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | AEs | 18 Participants |
| LLG783 6mg/kg | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | Drug-related AEs | 4 Participants |
| LLG783 6mg/kg | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | Death | 0 Participants |
| LLG783 6mg/kg | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | SAEs | 1 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | Death | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | AEs | 17 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | Drug-related AEs | 4 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths | SAEs | 2 Participants |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to Defined Time Point 't' (AUC[0-t])
AUC(0-t)is defined as the area under the serum concentration-time curve from time zero to time 't' where is a defined time point after administration.
Time frame: 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85
Population: PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to Defined Time Point 't' (AUC[0-t]) | Day 1 | 1640 day*mcg/mL | Geometric Coefficient of Variation 34.1 |
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to Defined Time Point 't' (AUC[0-t]) | Day 85 | 3130 day*mcg/mL | Geometric Coefficient of Variation 34.7 |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf)
AUCinf is defined as the area under the serum concentration-time curve from time zero to infinity.
Time frame: 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose and 1, 2 and 4 hours postdose on Day 85
Population: PK analysis set: Participants with at least 1 available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. N (overall number of participants analyzed) = participants evaluable for this outcome measure and 'n' (number analyzed) = participants evaluable at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) | Day 1 | 2110 day*microgram per millileter (day*mg/mL) | Geometric Coefficient of Variation 21.1 |
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) | Day 85 | 4860 day*microgram per millileter (day*mg/mL) | Geometric Coefficient of Variation 39.1 |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau)
AUCtau is defined as the area under the serum concentration-time curve from time zero to the end of the dosing interval tau.
Time frame: 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) | Day 1 | 1640 day*mcg/mL | Geometric Coefficient of Variation 34.1 |
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) | Day 85 | 3130 day*mcg/mL | Geometric Coefficient of Variation 34.7 |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)
AUClast is defined as the area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration.
Time frame: 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85
Population: Pharmacokinetic (PK) analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | Day 1 | 1660 day*mcg/mL | Geometric Coefficient of Variation 33.6 |
| LLG783 6mg/kg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | Day 85 | 4930 day*mcg/mL | Geometric Coefficient of Variation 38.9 |
Secondary
Change From Baseline in Pain-free Walking Distance (PFWD) as Assessed by 6-minute Walk Test at Week 16
PFWD was defined as the distance walked up to the point of onset of claudication symptoms (pain) recorded during the 6MWT and was used to evaluate symptomatic functional capacity of PAD participants. The PFWD was measured as the distance walked up to the time/place where the participant first experiences symptoms typical of their claudication which included pain, cramps, or other discomfort in the buttocks, thighs, calves or feet that occurs during the 6MWT exercise period.
Time frame: Baseline, Week 16 (Day 113)
Population: PD analysis set included all participants with available PD data, who received any study treatment and experienced no protocol deviations with relevant impact on PD data. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LLG783 6mg/kg | Change From Baseline in Pain-free Walking Distance (PFWD) as Assessed by 6-minute Walk Test at Week 16 | 44.77 meters |
| Placebo | Change From Baseline in Pain-free Walking Distance (PFWD) as Assessed by 6-minute Walk Test at Week 16 | 57.09 meters |
Secondary
Observed Maximum Serum Concentration (Cmax) Following Drug Administration
Cmax is defined as the observed maximum serum concentration following drug administration.
Time frame: 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85
Population: PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LLG783 6mg/kg | Observed Maximum Serum Concentration (Cmax) Following Drug Administration | Day 1 | 203 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 40 |
| LLG783 6mg/kg | Observed Maximum Serum Concentration (Cmax) Following Drug Administration | Day 85 | 268 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 39.8 |
Secondary
Time to Reach the Maximum Concentration After Drug Administration (Tmax)
Tmax is defined as the time to reach the maximum concentration after drug administration.
Time frame: 1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85
Population: PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LLG783 6mg/kg | Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Day 1 | 0.0833 Days |
| LLG783 6mg/kg | Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Day 85 | 0.0833 Days |