Postural Tachycardia Syndrome
Conditions
Brief summary
The purpose of this trial is to evaluate the symptomatic benefits of immunomodulatory treatment with IVIG for POTS (postural tachycardia syndrome) patients with evidence of autoimmunity.
Detailed description
Gammunex-C, a form of intravenous immunoglobulin (IVIG), is approved for the treatment of chronic inflammatory demyelinating neuropathy (CIDP) or idiopathic thrombocytopenic purpura (ITP). IVIG has been in use for many decades in the treatment of these disorders and many other inflammatory/autoimmune diseases. It is generally very safe and well tolerated. More recently, IVIG has been proposed as an effective treatment for presumed inflammatory neurological disorders which do not meet the criteria for CIDP. Specifically, case reports and cases series have indicated therapeutic responses to IVIG in autonomic neuropathies. Intravenous Albumin is approved for the treatment of hypovolemia (see attached package insert). The use of albumin to increase plasma volume in patients with POTS has been suggested. In this study, albumin will be used as an active control treatment to provide the same volume and protein load as IVIG but without the immunomodulatory effects. There have been few well designed clinical therapy trials aimed at POTS patients and even fewer that are aimed at a particular pathophysiological subtype of POTS. Evidence suggests that POTS is a heterogeneous disorder with differing underlying mechanisms. Several uncontrolled case series have suggested a benefit of IVIG for POTS, but the volume expansion associated with infusion of IVIG make it difficult to assess the immunomodulatory effects of this treatment. We propose to evaluate the efficacy of IVIG using a double-blind randomized cross over design that will determine efficacy while reducing effects of inter-subject variability and placebo effect which are common problems in POTS therapy research. Even with the statistical advantages of a crossover design, the treatment cohort will be small, and this study is designed to be a pilot (phase II) study to evaluate the feasibility, tolerability and potential benefits of treatment. The results of this pilot study will provide the impetus and rationale for a larger multicenter clinical trial to definitively evaluate immunomodulatory treatment in POTS.
Interventions
DRUGIVIG
If you participate in this study there will be 18 scheduled treatment infusions during the 30 week study period. All the study visits and treatment visits will be outpatient visits. Once you qualify to participate in the study and begin treatment, there will be two 12 week treatment periods separated by a 6 week washout period. The infusion visits will take approximately 3-4 hours each.
DRUGAlbumin
This will be the matching placebo used in the study.
Sponsors
Grifols Biologicals, LLC
Dysautonomia International
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double-blind
Intervention model description
double-blind randomized controlled crossover pilot study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age or older, and able to provide informed consent * Diagnosis of POTS (see Table 1) * COMPASS-31 symptom score showing moderate to severe autonomic symptoms * At least 3 of the following clinical or laboratory features of autoimmunity * One or more serum autoantibodies (ANA ≥ 1:160, gAChR antibody \> 0.2 nmol/L, positive ENA, aPL, TTG, gliadin) or inflammatory markers (ESR \> 30, CRP \> 2, low C3 complement or low immunoglobulin IgG level) * Confirmed personal history or family history of defined autoimmune disease including Hashimoto's thyroiditis, celiac disease, antiphospholipid syndrome, rheumatoid arthritis, SLE, or Sjogren's syndrome * Clear history of acute or subacute onset following infection, immunization, injury/concussion, surgery or pregnancy. * Evidence of esophageal, gastric or intestinal dysmotility (with weight loss) * Evidence of small fiber neuropathy (abnormal QSART or IENFD) * Stable oral medical therapy for past 3 months * Ambulatory at time of screening
Exclusion criteria
* Current or previous immunosuppression therapy or IVIG treatment * Contraindication to intravenous immunoglobulin or intravenous albumin * Known allergic reactions to blood products including intravenous immunoglobulin (IVIG) and/or subcutaneous immunoglobulin (SCIG), such as history of clinically relevant hemolysis after IVIG infusion, aseptic meningitis, recurrent severe headache, hypersensitivity, severe generalized or severe local skin reaction. * Inadequate peripheral venous access * Evidence of renal insufficiency (Cr \> 1.5 x elevated) or liver disease (transaminases \> 2.5x upper limit) at screening * History of thrombotic episode within 3 years of enrollment * Other major medical issue which, in investigators opinion, increases risk for adverse event over the next 12 months or may require separate management. * Female patients who are premenopausal and are (a) pregnant based on serum pregnancy test, or (b) breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Symptoms Measured by Change in COMPASS-31 Score (After Initial Treatment Phase) | Baseline,13 weeks | Primary outcome was change in autonomic symptom burden, assessed by total COMPASS-31 (sum of scaled subscores), comparing assessment at week 13 (2 weeks after final infusion) minus the assessment at baseline. This questionnaire generates a weighted score from 0 to 100, and questions fall into one of six domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor function. A COMPASS-31 (Composite Autonomic Symptom Score-31) score of ≥20 suggests moderate-to-severe autonomic dysfunction. Higher scores indicate more severe symptoms. A reduction in score (negative change over time) indicates better outcome or response to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Improvement | 13 weeks | The count of participants with clinical improvement at 13 weeks is being reported here. Clinical improvement was defined as a reduction of the COMPASS-31 total score by 20% or more. Lower scores are associated with improvement and a 20% reduction was used as a meaningful change in previous studies of POTS |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IVIG First, Then Albumin Once qualified for the study and starting treatment, there are two 12 week treatment periods separated by a 6 week washout period. The infusion visits will take approximately 3-4 hours each. All the study visits and treatment visits are outpatient visits.
Treatment period 1: IVIG (Gammunex-C) infusion (0.4 gm/kg) every week for 4 weeks, then every 2 weeks for 8 weeks (12 weeks total, 8 infusions).
Washout period: 6 weeks
Treatment period 2: Albumin infusion: (0.4 gm/kg) every week for 4 weeks then every 2 weeks for 8 weeks (12 weeks total, 8 infusions). This will be the matching control treatment used in the study. | 16 |
| Albumin First, Then IVIG Once qualified for the study and starting treatment, there are two 12 week treatment periods separated by a 6 week washout period. The infusion visits will take approximately 3-4 hours each. All the study visits and treatment visits are outpatient visits.
Treatment period 1: Albumin infusion: (0.4 gm/kg) every week for 4 weeks then every 2 weeks for 8 weeks (12 weeks total, 8 infusions). This will be the matching control treatment used in the study.
Washout period: 6 weeks
Treatment period 2: IVIG (Gammunex-C) infusion (0.4 gm/kg) every week for 4 weeks, then every 2 weeks for 8 weeks (12 weeks total, 8 infusions). | 14 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention- (12 Weeks) | Adverse Event | 1 | 1 |
| First Intervention- (12 Weeks) | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | IVIG First, Then Albumin | Albumin First, Then IVIG | Total |
|---|---|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 8.75 | 31.9 years STANDARD_DEVIATION 9.99 | 31.8 years STANDARD_DEVIATION 9.19 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 14 Participants | 30 Participants |
| Region of Enrollment United States | 16 participants | 14 participants | 30 participants |
| Sex: Female, Male Female | 16 Participants | 13 Participants | 29 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
| Time since symptom onset (years), median (IQR) | 4.0 years | 4.0 years | 4.0 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 26 |
| other Total, other adverse events | 25 / 28 | 22 / 26 |
| serious Total, serious adverse events | 2 / 28 | 2 / 26 |
Outcome results
Primary
Change in Symptoms Measured by Change in COMPASS-31 Score (After Initial Treatment Phase)
Primary outcome was change in autonomic symptom burden, assessed by total COMPASS-31 (sum of scaled subscores), comparing assessment at week 13 (2 weeks after final infusion) minus the assessment at baseline. This questionnaire generates a weighted score from 0 to 100, and questions fall into one of six domains: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor function. A COMPASS-31 (Composite Autonomic Symptom Score-31) score of ≥20 suggests moderate-to-severe autonomic dysfunction. Higher scores indicate more severe symptoms. A reduction in score (negative change over time) indicates better outcome or response to treatment.
Time frame: Baseline,13 weeks
Population: The primary outcome measure was assessed only during the first treatment phase and hence, only 15 participants who received IVIG treatment and 13 participants who received Albumin treatment were analyzed for this primary outcome measure. The 1 patient (Albumin- First intervention group) who was a protocol violation was included in the analysis. The 2 patients (1 each from IVIG and Albumin- first intervention groups) with SAEs were not included in the analysis since lost to follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment IVIG Arm | Change in Symptoms Measured by Change in COMPASS-31 Score (After Initial Treatment Phase) | -5.5 score on a scale |
| Treatment Albumin Arm | Change in Symptoms Measured by Change in COMPASS-31 Score (After Initial Treatment Phase) | -10.6 score on a scale |
Comparison: Intention-to-treat analysisp-value: 0.629Kruskal-Wallis
Secondary
Number of Participants With Clinical Improvement
The count of participants with clinical improvement at 13 weeks is being reported here. Clinical improvement was defined as a reduction of the COMPASS-31 total score by 20% or more. Lower scores are associated with improvement and a 20% reduction was used as a meaningful change in previous studies of POTS
Time frame: 13 weeks
Population: The secondary outcome measure was assessed only for the first treatment phase and hence, only 15 participants who received IVIG treatment and 13 participants who received Albumin treatment were analyzed for this outcome measure. The 1 patient (Albumin- First intervention group) who was a protocol violation was included in this analysis . The 2 patients (1 each from IVIG and Albumin- first intervention groups) with SAEs were not included in the analysis since lost to follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment IVIG Arm | Number of Participants With Clinical Improvement | 7 participants |
| Treatment Albumin Arm | Number of Participants With Clinical Improvement | 5 participants |
Comparison: comparison of proportion with positive treatment response (as defined) in IVIG group compared to albuminp-value: 0.718Fisher Exact