Study of Efficacy and Safety of VAY736 in Patients With Pemphigus Vulgaris

A Randomized, Partial-blind, Placebo-controlled Trial Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of VAY736 in the Treatment of Patients With Pemphigus Vulgaris

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01930175

Enrollment

Registered

2013-08-28

Start date

2013-12-18

Completion date

2019-09-25

Last updated

2021-10-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pemphigus Vulgaris

Keywords

Pemphigus vulgaris, pemphigus, blistering disease

Brief summary

The study evaluated the efficacy, safety and pharmacokinetics of VAY736 in the treatment of patients with pemphigus vulagaris (PV).

Detailed description

This was a non-confirmatory, randomized, partial-blind, placebo-controlled trial evaluating the efficacy, safety and pharmacokinetics (PK) of VAY736 in the treatment of PV patients. A total of 13 patients were enrolled and randomized into the study. Of these 13 patients,seven were randomized to the 3 mg/kg VAY736 group, two were randomized to the 10 mg/kg VAY736 group and four were randomized to the placebo group.In the placebo group, three out of the four patients consented to open-label VAY736 treatment and received 10 mg/kg VAY736 after Week 24 onwards. Thus, a total of 12 patients received VAY736, 7 patients received 3 mg/kg and 5 patients 10 mg/kg. The Screening period consisted of a Screening Visit performed within 28 days prior to randomization to assess patient eligibility. Following Screening, patients underwent pre-dose procedures which included assessment of their PV by Pemphigus Disease Area Index (PDAI), Autoimmune Bullous Skin disease Intensity Score (ABSIS) and Investigator Global Assessment (IGA), and blood sampling for PK endpoints. Patients then received the study drug, which was administered over approximately a 2 hour period. The patients remained in the study center overnight post-infusion for observation and for measurement of safety parameters and PK samples approximately 24 h post-infusion (start of infusion: ±2 h). Patients were then discharged from the study site and returned as per the schedule. Patients were evaluated at Week 1, Week 2 and Week 3, then every 3 weeks through to Week 12, and every 4 weeks through to Week 24. At Week 24, the blind was broken to confirm treatment allocation. If a patient was on placebo, such patient completing the Week 24 visit and after unblinding had the option of receiving open label VAY736 10mg/kg. Recruitment was paused in Mar-2015 and at the time 13 patients were enrolled. The study recruitment was then terminated in Dec-2015 for strategic reasons related to the development of the compound.

Interventions

DRUGVAY736

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

20 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Adult patients 20 to 70 years of age * Confirmed diagnosis of pemphigus vulgaris * Presence of mild to moderate pemphigus vulgaris * Patients must weight between 40 kg and 150 kg inclusive * on a stable dose of oral corticosteriod therapy (with or without azathioprine or mycophenolate)

Exclusion criteria

* Pregnant or nursing (lactating) women * Women of child-bearing potential unless they are using a highly effective method of birth control during dosing and for 4 months following study treatment * Recent previous treatment with photo therapy, biological therapy, steroids, immunosuppresive agents (unless washout period applied) * Active or recent history of clinically significant infection * use of rituximab within 1 year Other protocol-defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Pemphigus Disease Area Index (PDAI) at Week 12	Week 12	PDAI is specific cutaneous and mucosal disease activity assessment performed by investigator based on evaluation of lesions in well-defined anatomical locations. The score weighted for the number and size of lesions with score of 0 (absent) to 10 given for skin (12 body locations), scalp and mucous membrane showing disease activity (erosions/blisters or new erythema). Damage, such as post inflammatory hyperpigmentation or erythema from resolving lesion, scored separately from the main score as absent (0) or present (1) for each body area or scalp resulting in a score of 0 to 12 or 0 to 1, respectively. Thus, PDAI ranged from 0 to 263, with 250 points representing disease activity (120 points for skin activity; 10 points for scalp activity; 120 points for mucosal activity) and 13 points representing disease damage.

Secondary

Measure	Time frame	Description
Change From Baseline in Investigator Global Assessment (IGA) at Week 12	Baseline, Week 12	The IGA score ranges from 0 to 4 and the decrease or reduction from baseline in IGA score indicates improvement in patients. IGA score scale: 0=Clear, 1=Near Clear, 2=Mild, 3=Moderate, 4=Severe active disease
VAY736 Serum Concentration - AUCinf	predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks	The area under the serum concentration-time curve from time zero to infinity \[mass × time / volume\]. The concentration of VAY736 was measured in the serum.
VAY736 Serum Concentration - AUClast	predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks	The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration \[mass × time / volume\]. The concentration of VAY736 was measured in the serum.
Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Baseline, Week 12	The ABSIS Score is a quality- and quantity-based score for cutaneous and oral mucosal lesions combining the extent of the affected body surface area (BSA), the quality of the skin lesions and oral involvement. The ABSIS score ranged from 0 to 206 with 150 points for skin involvement, 11 points for oral involvement and 45 points for subjective discomfort during eating and drinking. A reduction from baseline (or, a negative change from baseline) in ABSIS indicates improvement in patients.
VAY736 Serum Concentration - Tmax	predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks	Tmax is the time to reach the maximum concentration after drug administration \[time\]. The concentration of VAY736 was measured in the serum.
VAY736 Serum Concentration - T1/2	predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks	T1/2 is the terminal elimination half-life \[time\]. The concentration of VAY736 was measured in the serum.
VAY736 Serum Concentration - Cmax	predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks	The observed maximum serum concentration following drug administration \[mass / volume\]. The concentration of VAY736 was measured in the serum.

Countries

Austria, Bulgaria, Taiwan, United States

Participant flow

Recruitment details

A total of 13 participants were enrolled and randomized into the study from Austria (1 center); Bulgaria (1 center); Taiwan (1 center); USA (2 centers).

Pre-assignment details

The study was planned to be conducted in approximately 32 patients. However, after enrolling 13 patients, the recruitment was terminated due to strategic reasons related to the development of the compound.

Participants by arm

Arm	Count
VAY736 3 mg/kg single dose iv of VAY736 at a dose of 3mg/kg	7
VAY736 10 mg/kg single dose iv of VAY736 at a dose of 10mg/kg initiated following a safety review of patients receiving VAY736 3 mg/kg or placebo	2
Placebo single dose iv of Placebo	4
Total	13

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Core Study	Adverse Event	0	0	1
Core Study	Lost to Follow-up	0	1	0

Baseline characteristics

Characteristic	VAY736 3 mg/kg	VAY736 10 mg/kg	Placebo	Total
Age, Continuous	51.6 Years STANDARD_DEVIATION 10.45	35.0 Years STANDARD_DEVIATION 8.49	56.0 Years STANDARD_DEVIATION 8.83	50.4 Years STANDARD_DEVIATION 11.44
Race/Ethnicity, Customized Asian	2 Participants	1 Participants	1 Participants	4 Participants
Race/Ethnicity, Customized Caucasian	4 Participants	1 Participants	3 Participants	8 Participants
Race/Ethnicity, Customized Other	1 Participants	0 Participants	0 Participants	1 Participants
Sex: Female, Male Female	3 Participants	0 Participants	2 Participants	5 Participants
Sex: Female, Male Male	4 Participants	2 Participants	2 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 7	0 / 2	0 / 4	0 / 3
other Total, other adverse events	6 / 7	2 / 2	3 / 4	3 / 3
serious Total, serious adverse events	1 / 7	0 / 2	1 / 4	1 / 3

Outcome results

Primary

Pemphigus Disease Area Index (PDAI) at Week 12

PDAI is specific cutaneous and mucosal disease activity assessment performed by investigator based on evaluation of lesions in well-defined anatomical locations. The score weighted for the number and size of lesions with score of 0 (absent) to 10 given for skin (12 body locations), scalp and mucous membrane showing disease activity (erosions/blisters or new erythema). Damage, such as post inflammatory hyperpigmentation or erythema from resolving lesion, scored separately from the main score as absent (0) or present (1) for each body area or scalp resulting in a score of 0 to 12 or 0 to 1, respectively. Thus, PDAI ranged from 0 to 263, with 250 points representing disease activity (120 points for skin activity; 10 points for scalp activity; 120 points for mucosal activity) and 13 points representing disease damage.

Time frame: Week 12

Population: All evaluable patients.

Arm	Measure	Value (MEAN)	Dispersion
VAY736 3 mg/kg	Pemphigus Disease Area Index (PDAI) at Week 12	5.90 Score on the scale	Standard Deviation 1.836
VAY736 10 mg/kg	Pemphigus Disease Area Index (PDAI) at Week 12	10.15 Score on the scale	Standard Deviation 8.273
Placebo	Pemphigus Disease Area Index (PDAI) at Week 12	22.07 Score on the scale	Standard Deviation 25.628

Secondary

Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.

The ABSIS Score is a quality- and quantity-based score for cutaneous and oral mucosal lesions combining the extent of the affected body surface area (BSA), the quality of the skin lesions and oral involvement. The ABSIS score ranged from 0 to 206 with 150 points for skin involvement, 11 points for oral involvement and 45 points for subjective discomfort during eating and drinking. A reduction from baseline (or, a negative change from baseline) in ABSIS indicates improvement in patients.

Time frame: Baseline, Week 12

Population: All evaluable patients.

Arm	Measure	Group	Value (MEAN)	Dispersion
VAY736 3 mg/kg	Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Baseline	13.26 Score on the scale	Standard Deviation 7.621
VAY736 3 mg/kg	Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Week 12	2.19 Score on the scale	Standard Deviation 3.465
VAY736 10 mg/kg	Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Baseline	16.38 Score on the scale	Standard Deviation 12.905
VAY736 10 mg/kg	Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Week 12	5.55 Score on the scale	Standard Deviation 7.707
Placebo	Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Baseline	33.75 Score on the scale	Standard Deviation 21.62
Placebo	Autoimmune Skin Disease Intensity Score (ABSIS) at Baseline and Week 12.	Week 12	16.17 Score on the scale	Standard Deviation 25.838

Secondary

Change From Baseline in Investigator Global Assessment (IGA) at Week 12

The IGA score ranges from 0 to 4 and the decrease or reduction from baseline in IGA score indicates improvement in patients. IGA score scale: 0=Clear, 1=Near Clear, 2=Mild, 3=Moderate, 4=Severe active disease

Time frame: Baseline, Week 12

Population: All evaluable patients.

Arm	Measure	Value (MEAN)	Dispersion
VAY736 3 mg/kg	Change From Baseline in Investigator Global Assessment (IGA) at Week 12	-1.4 Score on the scale	Standard Deviation 0.79
VAY736 10 mg/kg	Change From Baseline in Investigator Global Assessment (IGA) at Week 12	-1.0 Score on the scale	Standard Deviation 0
Placebo	Change From Baseline in Investigator Global Assessment (IGA) at Week 12	-0.7 Score on the scale	Standard Deviation 0.58

Secondary

VAY736 Serum Concentration - AUCinf

The area under the serum concentration-time curve from time zero to infinity \[mass × time / volume\]. The concentration of VAY736 was measured in the serum.

Time frame: predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks