IVIG in Patients With VGKC Ab Associated Autoimmune Epilepsy

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02697292
• Collaborator: Grifols Shared Services North America (Other), Option Care (Other)
• Enrollment: 17
• Location: 1
• Arms: 2
• Duration (Months): 34
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether intravenous immunoglobulin (IVIG) treatment reduces significantly the number of epileptic seizures in cases of autoimmune epileptic seizures.

Condition or Disease	Intervention/Treatment	Phase
Autoimmune Epilepsy	Drug: Intravenous Immunoglobulin; Drug: Placebos; Drug: Normal Saline	Phase 3

Detailed Description

The purpose of this study is to determine if intravenous immunoglobulin (IVIG) treatment significantly reduces the number of epileptic seizures in cases of autoimmune epilepsy. Potential participants will be screened at an outpatient neurology clinic visit appointment. Interested qualified potential participants will be consented and offered participation in this trial. Once consent has been obtained, and it is determined that the participant meets all inclusion criteria, the participant will be randomized to either IVIG or placebo treatment for the next 5 weeks. Participants will return to Mayo Clinic for an evaluation. Those participants that received the placebo for 5 weeks will be given IVIG in an open label fashion for 5 weeks (week 7-11) then return to Mayo Clinic for evaluation. All participants will receive monthly phone calls after they complete the IVIG treatment for a period of 1 year from the end of IVIG 5 week course.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Double Blind Placebo Controlled Study of Intravenous Immunoglobulin (IVIG) Patients With Voltage Gated Potassium Channel Complex (VGKC) Antibody Associated Autoimmune Epilepsy
• Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Dec 3, 2018
• Actual Study Completion Date: Dec 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo/Normal Saline Group Subjects will receive placebo for 4 infusions. After completion of the blinded phase, subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.	Drug: Intravenous Immunoglobulin; GAMUNEX-C is a clear a ready-to-use sterile solution of human immune globulin protein for intravenous administration. Dose will be determined based on ideal wt. with not to exceed 80 grams. Subjects will receive 0.5g/kg daily for 1 day [week 1 day 1], then will receive 1g/kg not exceeding 80 grams daily for 1 day [week 1 day 2]. Then once every 2 weeks subjects will receive 0.6g/kg IVIG for 4 weeks [week 3 and 5] for 2 infusions.; Other Names: Gamunex-C ; Drug: Placebos; Normal Saline is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment. Dose will be determined based on ideal wt. with not to exceed 80 grams. Dose will be determined based on ideal wt. with not to exceed 80 grams. Subjects will receive 0.5g/kg daily for 1 day [week 1 day 1], then will receive 1g/kg not exceeding 80 grams daily for 1 day [week 1 day 2]. Then once every 2 weeks subjects will receive 0.6g/kg for 4 weeks [week 3 and 5] for 2 infusions.; Other Names: Normal Saline ; Drug: Normal Saline; Normal Saline is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment. Subjects will receive 500 ml normal saline before and after the higher dose infusion of 1g/kg
Active Comparator: Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group Subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.	Drug: Intravenous Immunoglobulin; GAMUNEX-C is a clear a ready-to-use sterile solution of human immune globulin protein for intravenous administration. Dose will be determined based on ideal wt. with not to exceed 80 grams. Subjects will receive 0.5g/kg daily for 1 day [week 1 day 1], then will receive 1g/kg not exceeding 80 grams daily for 1 day [week 1 day 2]. Then once every 2 weeks subjects will receive 0.6g/kg IVIG for 4 weeks [week 3 and 5] for 2 infusions.; Other Names: Gamunex-C ; Drug: Normal Saline; Normal Saline is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment. Subjects will receive 500 ml normal saline before and after the higher dose infusion of 1g/kg

Outcome Measures

Primary Outcome Measures

1. Change in Seizure Frequency From Baseline to 5 Weeks [baseline, 5 weeks]

   The number of subjects who experience a ≥ 50% reduction in seizure frequency

Secondary Outcome Measures

1. Change in Cognitive Assessment [baseline, 5 weeks]

   Number of subjects who experienced stable or improved cognitive assessment. Cognitive status was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The RBANS is a individually administered standardized battery of 12 tests that measure cognitive decline or improvement taking approximately 30 minutes. Five index scores are computed from the RBANS (immediate memory, language, visuospatial, attention, delayed memory) that are combined to provide the Total Score (range 40-160)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Seropositivity for Voltage Gated Potassium Channel Complex (VGKC) complex antibodies or positive for Leucine-Rich, Glioma Inactivated 1 (LGI1)/contactin-associated protein-like 2 (CASPR2) Antibody by cell based assay.

• And ≥ 2 seizures per week (mean of total over 1 week)

• And duration of epilepsy <3 years

• Male or female between the ages of 18 and 80 years of age

• Women and men of child bearing potential must agree to use a reliable form of contraception throughout the course of the study.

• Homecare treatment agency available at place of residence.

Exclusion Criteria:

• History of thrombotic episodes within the 2 years prior to enrollment

• Known allergic or other severe reactions to blood products including intolerability to previous IVIG

• Immunoglobulin A (IgA) deficiency

• Prior failed trial of high dose steroid (prednisone >60mg daily or methylprednisolone

1g weekly for >2 weeks)

• Reproductive status:

• Women who are pregnant,

• Women who are breastfeeding,

• Women and men of childbearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period, as evaluated by the investigator. (Women of non-childbearing potential are those that have a history of hysterectomy, bilateral oophorectomy, or are postmenopausal with no history of menstrual flow for > 12 months prior to screen visit.)

• Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline.

• Evidence of serious uncontrolled concomitant diseases that may preclude patient participation (physician determined), as described; Other nervous system disease, cardiovascular disease, hematologic/hematopoiesis disease, respiratory disease, muscular disease, endocrine disease, renal/urologic disease, digestive system disease, congenital or acquired severe immunodeficiency

• Known active infection (excluding fungal infections of nail beds or caries dentium) within 4 weeks prior to baseline.

• Evidence of chronic active hepatitis B or C.

• Active ischemic heart disease in the past year prior to baseline.

• Patients should not have severe renal or hepatic disease (determined by treating physician).

• Severe hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Grifols Shared Services North America
• Option Care

Investigators

• Principal Investigator: Sean Pittock, M.D., Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 9, 2016

More Information

Additional Information:

• Mayo Clinic Clinical Trials
• PubMed

Publications

None provided.

• Responsible Party: Sean Pittock, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02697292
• Other Study ID Numbers: 15-005649
• First Posted: Mar 3, 2016
• Last Update Posted: Dec 30, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sean Pittock, Principal Investigator, Mayo Clinic: Intravenous Immunoglobulin; VGKC; Autoimmune epilepsy; Gamumex-C
• Additional relevant MeSH terms: Epilepsy; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin

Study Results

Participant Flow

Arm/Group Title	Placebo/Normal Saline Group	Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
Arm/Group Description	Subjects will receive placebo for 4 infusions. After completion of the blinded phase, subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.	Subjects who received IVIG for 4 infusions. Subjects maintained their stable dose of antiepileptic meds.
Period Title: Overall Study
STARTED	9	8
COMPLETED	9	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo/Normal Saline Group	Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group	Total
Arm/Group Description	Subjects will receive placebo for 4 infusions. After completion of the blinded phase, subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.	Subjects who received IVIG for 4 infusions. Subjects maintained their stable dose of antiepileptic meds.	Total of all reporting groups
Overall Participants	9	8	17
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	70	70	70
Sex: Female, Male (Count of Participants)
Female	3 33.3%	2 25%	5 29.4%
Male	6 66.7%	6 75%	12 70.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	9 100%	8 100%	17 100%

Outcome Measures

1. Primary Outcome

Title	Change in Seizure Frequency From Baseline to 5 Weeks
Description	The number of subjects who experience a ≥ 50% reduction in seizure frequency
Time Frame	baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo/Normal Saline Group	Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
Arm/Group Description	Subjects will receive placebo for 4 infusions. After completion of the blinded phase, subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.	Subjects who received IVIG for 4 infusions. Subjects maintained their stable dose of antiepileptic meds.
Measure Participants	9	8
Count of Participants [Participants]	2 22.2%	6 75%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Normal Saline Group, Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	t-test, 1 sided
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	10.5
	Confidence Interval	(2-Sided) 95%; 1.1 to 98.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Cognitive Assessment
Description	Number of subjects who experienced stable or improved cognitive assessment. Cognitive status was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The RBANS is a individually administered standardized battery of 12 tests that measure cognitive decline or improvement taking approximately 30 minutes. Five index scores are computed from the RBANS (immediate memory, language, visuospatial, attention, delayed memory) that are combined to provide the Total Score (range 40-160)
Time Frame	baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

One subject did not complete the assessment at week 5 for the placebo arm

Arm/Group Title	Placebo/Normal Saline Group	Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
Arm/Group Description	Subjects will receive placebo for 4 infusions. After completion of the blinded phase, subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.	Subjects who received IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.
Measure Participants	8	8
Count of Participants [Participants]	5 55.6%	8 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Normal Saline Group, Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	The study period during which adverse events were collected is defined as the period from the initiation of any study procedures to the end of the study treatment follow-up, approximately 6 weeks.
Arm/Group Title	Placebo/Normal Saline Group		Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
Arm/Group Description	Subjects will receive placebo for 4 infusions. After completion of the blinded phase, subjects will receive IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.		Subjects who received IVIG for 4 infusions. Subjects will maintain their stable dose of antiepileptic meds.
All Cause Mortality
	Placebo/Normal Saline Group		Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/8 (0%)
Serious Adverse Events
	Placebo/Normal Saline Group		Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Placebo/Normal Saline Group		Intravenous Immunoglobulin (IVIG) (Gamunex-C) Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/9 (44.4%)		1/8 (12.5%)
General disorders
Fall	1/9 (11.1%)	1	1/8 (12.5%)	1
Headache	1/9 (11.1%)	1	0/8 (0%)	0
Nervous system disorders
Encephalitis	1/9 (11.1%)	1	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/9 (11.1%)	1	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.