A Safety and Dose-Finding Study of SYNT001 in Subjects With Pemphigus (Vulgaris or Foliaceus)

• Sponsor: Alexion Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03075904
• Collaborator: (none)
• Enrollment: 8
• Locations: 3
• Arms: 2
• Actual Duration (Months): 18
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a multicenter, open-label safety study to determine the dose regimen of SYNT001 (ALXN1830) administered intravenously in participants with pemphigus (vulgaris or foliaceus).

Condition or Disease	Intervention/Treatment	Phase
Pemphigus; Pemphigus Vulgaris; Pemphigus Foliaceus	Drug: ALXN1830	Phase 1/Phase 2

Detailed Description

This study planned to evaluate 2 cohorts: up to 8 participants to receive 5 weekly intravenous (IV) doses of ALXN1830 at 10 milligram/kilogram (mg/kg) (Cohort 1) and up to 12 participants to receive 3 x 30 mg/kg weekly doses of ALXN1830 IV (loading) followed by 5 x 10 mg/kg doses of ALXN1830 IV every other week or 10 weekly doses of ALXN1830 IV (maintenance) (Cohort 2).

This study was terminated after the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy were characterized in participants with pemphigus at a single dose level (10 mg/kg) in Cohort 1, before any participants were enrolled in Cohort 2.

The study consisted of 3 periods: Screening, Treatment, and Follow-Up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1B/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of SYNT001 in Subjects With Pemphigus (Vulgaris or Foliaceus)
• Actual Study Start Date: Jul 18, 2017
• Actual Primary Completion Date: Jan 16, 2019
• Actual Study Completion Date: Jan 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: ALXN1830 Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.	Drug: ALXN1830; Administered via IV infusion.; Other Names: SYNT001
Experimental: Cohort 2: ALXN1830 Participants were to receive 3 doses of ALXN1830 30 mg/kg administered weekly (loading) followed by 5 doses of ALXN1830 10 mg/kg administered every other week or 10 weekly doses of ALXN1830 IV (maintenance).	Drug: ALXN1830; Administered via IV infusion.; Other Names: SYNT001

Outcome Measures

Primary Outcome Measures

1. Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs) [Day 1 (after first dose) through Day 112]

   A TEAE was defined as any adverse event (AE) that starts on or after the first dose of study drug or occurs prior to the first dose and worsens in severity on or after the first dose of study drug, during the Treatment Period and Follow-up Period. A TEAE was considered "serious" (Grade 3) if, in the view of either the investigator or sponsor, it resulted in any of the following outcomes: death, life-threatening adverse drug event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or an event that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the previously listed outcomes. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Secondary Outcome Measures

1. Maximum Percent Reduction Of Mean Total Immunoglobulin G (IgG) Levels From Baseline [Baseline through Day 112]

   Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean serum total IgG levels from Baseline observed during the study is presented.

2. Maximum Percent Reduction In Mean Pemphigus Disease Area Index (PDAI) Total Activity Score From Baseline [Baseline through Day 112]

   Pemphigus severity and disease activity was measured using the PDAI in regions where a validated questionnaire was available. The PDAI was administered during Treatment Period and Follow-up Period. PDAI total activity was comprised of scores for the skin, mucous membrane, and scalp subscales. The investigator determined a PDAI score as 0 to 250 points for total activity score (0 to 120 for skin, 0 to 10 for scalp, and 0 to 120 for mucosa). A higher score indicated higher impact on skin disease. The maximum percent reduction in PDAI total activity score from Baseline observed during the study is presented.

3. Maximum Percent Reduction Of Mean Circulating Immune Complexes (CIC) Levels From Baseline [Baseline through Day 112]

   Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean CIC levels from Baseline observed during the study is presented.

4. Maximum Percent Reduction Of Mean Anti-Desmoglein (Dsg) 1 And 3 Antibodies From Baseline [Baseline through Day 112]

   Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean anti-Dsg 1 and 3 antibodies from Baseline observed during the study is presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Participants must have meet the following criteria to be included:

• Were willing and able to read, understand and sign an informed consent form

• Documented diagnosis of pemphigus vulgaris or foliaceus

• Were required to use medically acceptable contraception

Exclusion Criteria:

Participants meeting any of the following criteria were excluded:

• Were unable or unwilling to comply with the protocol

• Active non-hematologic malignancy or history of non-hematologic malignancy in the 3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in situ)

• Positive for human immunodeficiency virus (HIV) or hepatitis C antibody

• Positive for hepatitis B surface antigen

• IV immunoglobulin treatment within 30 days of screening

• Any exposure to an investigational drug or device within the 30 days prior to screening

• Plasmapheresis or immunoadsorption within 30 days of screening

• Participant had any current medical condition that, in the opinion of the Investigator, may have compromised their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alexion Study Site	Chapel Hill	North Carolina	United States	27516
2	Alexion Study Site	Durham	North Carolina	United States	27710
3	Alexion Study Site	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Alexion Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 25, 2019
• Study Protocol - Sep 18, 2018

More Information

Publications

None provided.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03075904
• Other Study ID Numbers: SYNT001-103
• First Posted: Mar 9, 2017
• Last Update Posted: Feb 5, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pemphigus

Study Results

Participant Flow

Pre-assignment Detail	This study was terminated after the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy were characterized at a single dose level (10 milligram/kilogram [mg/kg]) in Cohort 1, before any participants were enrolled in Cohort 2. This results disclosure is for Cohort 1 only.

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Period Title: Overall Study
STARTED	8
Received at Least 1 Dose of Study Drug	8
COMPLETED	4
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Overall Participants	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.4 (16.43)
Sex: Female, Male (Count of Participants)
Female	5 62.5%
Male	3 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	8 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 37.5%
White	5 62.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Type of Pemphigus (Count of Participants)
Vulgaris	7 87.5%
Foliaceus	1 12.5%
Age at Diagnosis of Pemphigus (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.3 (18.90)

Outcome Measures

1. Primary Outcome

Title	Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs)
Description	A TEAE was defined as any adverse event (AE) that starts on or after the first dose of study drug or occurs prior to the first dose and worsens in severity on or after the first dose of study drug, during the Treatment Period and Follow-up Period. A TEAE was considered "serious" (Grade 3) if, in the view of either the investigator or sponsor, it resulted in any of the following outcomes: death, life-threatening adverse drug event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or an event that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the previously listed outcomes. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	Day 1 (after first dose) through Day 112

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug.

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Measure Participants	8
TEAEs	7 87.5%
Serious TEAEs	1 12.5%
Discontinuations due to TEAEs	0 0%
Deaths	0 0%

2. Secondary Outcome

Title	Maximum Percent Reduction Of Mean Total Immunoglobulin G (IgG) Levels From Baseline
Description	Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean serum total IgG levels from Baseline observed during the study is presented.
Time Frame	Baseline through Day 112

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Measure Participants	8
Number [percentage of reduction]	57.3

3. Secondary Outcome

Title	Maximum Percent Reduction In Mean Pemphigus Disease Area Index (PDAI) Total Activity Score From Baseline
Description	Pemphigus severity and disease activity was measured using the PDAI in regions where a validated questionnaire was available. The PDAI was administered during Treatment Period and Follow-up Period. PDAI total activity was comprised of scores for the skin, mucous membrane, and scalp subscales. The investigator determined a PDAI score as 0 to 250 points for total activity score (0 to 120 for skin, 0 to 10 for scalp, and 0 to 120 for mucosa). A higher score indicated higher impact on skin disease. The maximum percent reduction in PDAI total activity score from Baseline observed during the study is presented.
Time Frame	Baseline through Day 112

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Measure Participants	8
Number [percentage of reduction]	45.7

4. Secondary Outcome

Title	Maximum Percent Reduction Of Mean Circulating Immune Complexes (CIC) Levels From Baseline
Description	Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean CIC levels from Baseline observed during the study is presented.
Time Frame	Baseline through Day 112

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Measure Participants	8
Number [percentage of reduction]	51.4

5. Secondary Outcome

Title	Maximum Percent Reduction Of Mean Anti-Desmoglein (Dsg) 1 And 3 Antibodies From Baseline
Description	Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean anti-Dsg 1 and 3 antibodies from Baseline observed during the study is presented.
Time Frame	Baseline through Day 112

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.

Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
Measure Participants	8
anti-Dsg 1	8.9
anti-Dsg 3	20.4

Adverse Events

Time Frame	Baseline through Day 112
Arm/Group Title	Cohort 1: ALXN1830
Arm/Group Description	Participants received 5 doses of ALXN1830 10 mg/kg administered weekly.
All Cause Mortality
	Cohort 1: ALXN1830
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	Cohort 1: ALXN1830
	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)
General disorders
Disease progression	1/8 (12.5%)
Renal and urinary disorders
Acute kidney injury	1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Cohort 1: ALXN1830
	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)
Eye disorders
Dry eye	1/8 (12.5%)
Gastrointestinal disorders
Diarrhoea	1/8 (12.5%)
Nausea	2/8 (25%)
Vomiting	1/8 (12.5%)
General disorders
Fatigue	2/8 (25%)
Malaise	1/8 (12.5%)
Pyrexia	1/8 (12.5%)
Hepatobiliary disorders
Hepatic cyst	1/8 (12.5%)
Infections and infestations
Herpes simplex	1/8 (12.5%)
Staphylococcal infection	1/8 (12.5%)
Tinea barbae	1/8 (12.5%)
Injury, poisoning and procedural complications
Infusion related reaction	1/8 (12.5%)
Investigations
Urine analysis abnormal	1/8 (12.5%)
Nervous system disorders
Headache	6/8 (75%)
Sinus headache	1/8 (12.5%)
Renal and urinary disorders
Acute kidney injury	1/8 (12.5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/8 (12.5%)
Rash	1/8 (12.5%)
Vascular disorders
Pallor	1/8 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding study results for a period that is less than or equal to 60 days from the date that the communication is submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot unilaterally extend the embargo.