Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02780570 |
| Other study ID # |
PR-15086 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
April 10, 2016 |
| Last updated |
July 26, 2017 |
| Start date |
January 1, 2016 |
| Est. completion date |
December 31, 2016 |
Study information
| Verified date |
July 2017 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Guillain-Barré syndrome (GBS) is the commonest form of acute flaccid paralysis and the
incidence is high in low-income countries. In Bangladesh, most GBS patients are poor.
Therefore patients cannot afford expensive specific treatments like intravenous
immunoglobulin (IVIg) or plasmapheresis (PE) in part explaining the high mortality and
disability compared to treated patients in high-income countries. Added difficulty in
traditional PE is its unavailability and specialized device and manpower dependency. Most
research in GBS has been conducted in high-income countries, largely in patients with a
demyelinating form of GBS. Axonal form of GBS is common in low-income and Asian countries
which has a different pathogenesis, clinical course and outcome than the demyelinating form.
Very few therapeutic studies have been conducted in low-income countries due to expensive
existing modalities of treatment. Here, the investigators propose SVPE as a treatment for GBS
in patients from low-income countries. SVPE is relatively cheap, can be done at the bedside
without any special device or electricity and eventually is expected to help poor severely
affected GBS patients in underdeveloped and developing countries. The main outcomes will be
the safety and feasibility of SVPE since this is yet to be established in the resource
limited settings. To be able to evaluate the safety of SVPE, additional information will be
acquired about the frequency of complications in non-GBS patients with a central line,
treated during the same time period at the same study facility as the GBS patients. Severe
sepsis due to central line associated blood stream infection and deep venous thrombosis in
the limb where the central venous catheter will be inserted during or following the SVPE
procedure, will be defined as severe adverse effect (SAE) and will be considered as primary
outcome measure for safety. Blood, cerebrospinal fluid and other relevant biological
specimens will be analysed for diagnosis and screening for infections. In addition clinical
and neurological outcome assessment will be monitored until discharge of the patient from the
hospital and up to four weeks since study entry. Confirmation of feasibility and safety, will
eventually lead to a randomized control trial in future with a primary focus on the clinical
efficacy of SVPE for the treatment of GBS in developing countries as an alternative for the
conventional treatment with IVIg or PE.
Description:
Study design:
In this safety and feasibility study, 20 GBS patients will be enrolled for SVPE as per
protocol criteria. Clinometric measurements (heart rate, blood pressure, temperature, oxygen
saturation (SpO2), neurological examination) along with documentation of central line
associated blood stream infection (CLABSI) and other complications related to central venous
(CV) catheter will be conducted daily and throughout the course of SVPE until the 2nd day of
the withdrawal of the CV catheter according to a predefined protocol. Diagnosed or strongly
suspected CLABSI and central venous catheter related deep venous thrombosis (DVT) will be
followed up for definite outcome to determine the frequency of severe adverse events
attributed to CLABSI until the patient discharges from the hospital. Neurological outcome
will be documented according to several disability assessment scales throughout the SVPE
until discharge and up to four weeks from the enrollment of the GBS patients. In addition,
the safety of the SVPE in GBS patients will be compared with the background complication risk
by determining the frequency of complications in non-GBS patients treated with a CV catheter
at the same intensive care unit (ICU) during the same period using the same protocol for
surveillance as in SVPE-treated GBS patients.
SVPE kit:
SVPE kit will be prepared with one blood transfusion set and two saline infusion sets
connected with a tri channel device. On the other end the blood transfusion set will be
connected with the blood bag, one saline infusion set is connected with 1 liter normal saline
mixed with 2500 unit of un fractionated heparin and one saline infusion set is connected with
500 ml hexa-ethyl starch solution. All the tubes should be made air free by fluid column from
respective bag. The tri channel is then attached to the central venous catheter.
Procedure of SVPE for GBS patients:
After the SVPE set is prepared, patient's whole blood will be drawn from central venous
catheter according to body weight (7 ml/kg) in each session in the blood transfusion bag with
gravitation force placing the blood bag below central venous catheter tip level.
The blood column in the transfusion set and in the central venous catheter will be cleared
with normal saline mixed heparin solution attached previously through the side channel. The
blood bag will be hung beside the patient in a saline stand uninterrupted to separate the
plasma and blood cells which will eventually take 2.5 hours with gravitation. Blood cells
will be infused back to the patient and plasma will be discarded and replaced by Fresh Frozen
Plasma (FFP) and colloid solution alternately in equal volume through the side channel. One
blood bag will be used each day for 6 sessions. At the beginning of each session 70 ml of
heparin solution will be taken in the blood bag from the heparin mixed normal saline as
anticoagulant. Six sessions will be done daily for consecutive 8 days. A total of 48 sessions
will be done in eight days. These six sessions of small volume plasma exchange per day in an
adult patient will remove approximately 1200 ml of plasma daily and eventually 9600 ml of
plasma will be removed in total 48 sessions. All connection ports and tri channels of the
central venous catheter, the blood bag and the saline bag are disinfected by using alcohol
70% then dried on air before sampling blood or (dis)connection. These procedures are
performed aseptically. Internationally, endorsed guidelines on central venous catheter blood
stream infection prevention is followed throughout the entire period of the SVPE procedure.
Total active interference with the patient in each session will be 30 minutes and total daily
active interference with the patient will be three hours with a Daily schedule at 8AM, 11AM,
2PM, 5PM, 8PM and 11PM. Plasma replacement will be done alternately using fresh frozen plasma
and colloid solution (Hexa ethyl starch).
Anticoagulation therapy:
A loading subcutaneous low molecular weight heparin (1.5 mg/kg) will be given at least two
hours before the onset of SVPE. Thereafter daily maintenance dose of subcutaneous low
molecular weight heparin (1.5 mg/kg) will be continued for eight days or until SVPE
completed.
Indication of anti-platelet therapy:
Patients with excessive clotting tendency despite receiving low molecular weight heparin will
be subjected for evaluation of platelet activation. If the bleeding time is reduced by >50%
of the baseline of the particular GBS patient, investigators will introduce anti-platelet
medication. A loading oral dose of aspirin (500 mg) and clopidogrel (600 mg) will be given at
least two hours before the next session of SVPE. Thereafter daily maintenance dose of oral
aspirin (150 mg) and clopidogrel (75 mg) along with subcutaneous low molecular weight heparin
(1.5 mg/kg) will be continued for eight days or until SVPE completed.
Documentation of SVPE procedure:
To define the safety of SVPE, the six daily sessions of SVPE will be documented in terms of
duration and amount of the plasma removed in each session, type and volume of replacement
fluid and fresh frozen plasma used, and any inconvenience compromising the SVPE sessions
temporarily or permanently. Any difficulties hampering SVPE, which currently cannot be
anticipated, will be documented as verbatim.
Documentation of hemodynamic parameters and autonomic disturbance:
Throughout the procedure, haemodynamic status including blood pressure, heart rate, any
cardiac arrhythmia, oxygen (%) saturation in peripheral blood, fluid intake and output will
be monitored daily as per standard practice in all ICU patients. Blood coagulability will be
monitored with prothrombin time (PT) and bleeding time (BT) every alternate day. Autonomic
parameters will be documented daily as per the presence of high or low blood pressure,
increased or decreased pulse rate, orthostatic hypotension, cardiac arrhythmia, bladder and
gastrointestinal dysfunction, pupillary abnormality, unusual sweating or hyper salivation.
Documentation of infection:
Features of infections including pyrexia, leukocytosis in peripheral blood, C-reactive
protein and evidence of focal infections like positive blood, throat/tracheal aspirate or
urine culture for pathogenic organisms etc. will be documented per protocol as per respective
standard case record forms for specific hospital acquired infections (HAI). Clinical and
laboratory evidence of HAI especially CLABSI will be monitored and explored at anytime during
the SVPE procedure until the second day of withdrawal of the central venous catheter. A
definite or strongly suspected CLABSI will be followed up until discharge to document the
ultimate fate.
Documentation of HAI and complications:
An infection is considered HAI if all elements of a Centers for Disease Control and
Prevention/National Healthcare Safety Network (CDC/NHSN) site - specific infection criterion
are all present on or after the third calendar day of admission to the facility. Any
infection before the third calendar day of admission will be considered as infection present
on admission, except in case of CLABSI; which can occur even on day two of central venous
catheter insertion. CLABSI, primary and secondary bloodstream infections sepsis and severe
sepsis will be the main focus for infection documentation. All the patients eligible as per
the enrolment criteria for CLABSI surveillance will be monitored from admission to the ICU.
Ventilator associated pneumonia and catheter associated urinary tract infection will also be
monitored using established guidelines in order to have a more specific rate of CLABSI and
related complications. Appropriate clinical data, imaging, specimens for biochemical and
microscopic examination and culture will be documented at specific time points defined as per
specific HAI check list . Device associated complications include central venous catheter
occlusion, haemorrhage and deep venous thrombosis. All these safety margin indicators will be
defined as per specific guideline definitions.
Use antimicrobial agents:
Any infection will be treated by antimicrobial agents accordingly. Choice of the antibiotics
(oral or intravenous) will be based on the site of infection, specific organisms isolated
and/or severity of the infection reflected in clinical and laboratory features of systemic
inflammatory response (raised total white blood cell (WBC) count (>11,000/c mm of blood),
C-reactive protein (>40 mg/L) or positive culture of pathogenic organisms) and choices are
made after consultation of a microbiologist. Appropriate lower generations of antibiotics for
predicted site specific infection will be administered first if necessary before considering
subsequent higher generations until the culture sensitivity report is available.
Indications for withholding plasma exchange:
1. Development of severe or terminal concurrent medical illness
2. Hypotension (30 mm Hg decrease of systolic blood pressure or systolic blood pressure<90
or mean arterial pressure (MAP)<65mm Hg) after start of treatment
Indications for resuming plasma exchange:
1. Return of blood pressure to baseline or systolic blood pressure>90 or MAP<65.
2. After management of anaphylactic reaction following FFP or saline infusion.
Indications for replacement of central venous catheter (CVC) to another site:
1. CLABSI or catheter insertion site infection associated with CVC is diagnosed or strongly
suspected as per protocol.
Indications for guide wire replacement of central venous catheter (CVC) to the same site:
1. Complete CVC occlusion despite anticoagulant or thrombolytic administration in absence of
features of CLABSI
Indication for blood transfusion:
1. Anemia with hemoglobin concentration below 7 gm/dl during and after the SVPE procedure.
When to stop the trial (Stopping rule):
For feasibility purpose: A predictive success rate of 75% will be set regarding the SVPE
procedure. If in more than 5 out of 20 SVPE procedure violates the protocol, the procedure
will be considered not feasible and modification of the SVPE procedure will be considered
before any further re-evaluation of modified procedure for feasibility along with safety.
For safety purpose: A prior distribution of the success rate with regard to severe adverse
effect (SAE) will be set as 75%. The investigators will consider severe sepsis due to CLABSI
and venous thrombosis related to CVC use as SAE. If >5 patients had SAE at or before
completion of SVPE in 20 GBS patients; the study will be stopped. Otherwise an RCT will be
planned subsequently to evaluate the neurological efficacy of the SVPE procedure.
Baseline documentation and Initial screening:
Complete blood count including haemoglobin in g/L, total and differential WBC and platelet
count and erythrocyte sedimentation rate (ESR), C-reactive protein, prothrombin time, serum
creatinine, serum bilirubin and serum glutamic-pyruvic transaminase (SGPT) will be documented
as baseline status for GBS patients with SVPE along with screening for hepatitis B, C and
HIV.
Documentation of anti-ganglioside antibodies:
Serum concentration of anti-ganglioside antibodies (GM1 and GD1A) will be measured at the
beginning and at the end of SVPE to observe the trend in titre change in the serum of GBS
patients.
Documentation at the end of SVPE:
On the second day after removal of the central venous line, baseline documentations will be
re evaluated. These include complete blood count including haemoglobin in g/L, total and
differential WBC and platelet count and ESR, C-reactive protein, prothrombin time, serum
creatinine, serum bilirubin and SGPT.
Assessment of neurological function:
Neurological examination will be performed to see the clinical trend of motor, sensory &
autonomic parameters before, during the procedure and subsequently in the follow up of the
patients up to four weeks.
Assessment of Motor function:
Different clinical assessment scales will be used to monitor changes in motor function. These
are the GBS disability Score, Medical Research Council (MRC) sum score, Rasch-built MRC
score, Overall Neuropathy Limitation Scale (ONLS), Rasch-built Overall Disability Score
(R-ODS).
Sensory function:
Somatic and Gnostic sensation over the limbs will be examined bilaterally. Somatic sensation
will be evaluated by examining fine and crud touch and pain sensation over the specific
dermatomal regions and gnostic sensation will be evaluated by position & vibration sense.
Autonomic function:
Autonomic parameters will be documented as per the presence of high or low blood pressure,
increased or decreased pulse rate, cardiac arrhythmia, bladder and gastrointestinal
dysfunction, pupillary abnormality, unusual sweating, hyper salivation and abnormality in
hair growth.
