Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05869565 |
| Other study ID # |
2022-7608-22106 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2023 |
| Est. completion date |
March 31, 2024 |
Study information
| Verified date |
May 2023 |
| Source |
Aga Khan University |
| Contact |
MUHAMMAD WASAY, MD FRCP FAAN |
| Phone |
+923332234688 |
| Email |
mohammad.wasay[@]aku.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hypothesis:
Hyper chloremia is associated with poor outcome in Intracerebral Hemorrhage (ICT).
Hyperchloremia is defined as serum chloride level of 110mmol/L or greater. This clinical
study is assuming that, by increasing the ratio of Sodium-acetate to Sodium-chloride
solutions in IV treatment, the incidence of Hyperchloremia can be lowered significantly. This
result can be demonstrated by measuring serum chloride levels at Baseline, 24Hr, 48Hr and 72
Hours' time intervals and compare them between the three treatment and one Control arm.
Intervention (drug/biologic/device/behavioral):
Phase 2-dose finding Patients will be enrolled in the study and randomized into one of the
four study treatment arms(target fluid administration rate 1 ml/kg/hour) initiated within 12
hours. IVF will be prepared in the main hospital pharmacy.
1. Sodium chloride (0.9%) referred as 0.9% NaCl for 72 hours post symptom onset (60-72
hourspost randomization);
2. Sodium chloride (0.9%) and sodium acetate (0.9%) mixture 3:1 ratio for 72 hours post
symptom onset (60-72 hours post randomization);
3. Sodium chloride (0.9%) and sodium acetate (0.9%) mixture 2:1 ratio for 72 hours post
symptom onset (60-72 hours post randomization);
4. Sodium chloride (0.9%) and sodium acetate (0.9%) mixture 1:1 ratio for 72 hours post
symptom onset (60-72 hours post randomization).
Description:
Background and Rational:
Acute stroke and intracerebral hemorrhages are most common admissions in neurological
intensive care units. Proper management of these diseases helps to achieve better outcomes
and reduce the burden on family and society. Proper volumes and concentration of intravenous
fluids maintains sufficient blood flow to the brain. Several studies have demonstrated a
relationship between hyperchloremia and death or disability observed in neurological diseases
particularly ischemic stroke and ICH. The association between hyperchloremia and death or
disability in patients with ischemic stroke and ICH is independent from the effect of
patients' age or stroke severity. Hyperchloremia is also associated with occurrence of Acute
Kidney injury in patients with subarachnoid hemorrhage and AKI was associated with higher
mortality.
Hyperchloremia may induce metabolic acidosis which can results in intra- and extra- cellular
acidosis in the brain leading to cytotoxicity via activation of enzymes and alteration in
ionic movements and dysfunction of aquaporin-4 receptor leading to edema formation (9) and
neural excitotoxicity.
Hyperchloremia may also augment pro-inflammatory response and modification of neutrophil and
myeloperoxidase activity. Therefore, avoidance of hyperchloremia may be a therapeutic target
in reducing death or disability among patients with ischemic stroke or ICH. The most
effective strategy for reducing hyperchloremia is to reduce the chloride load through IV
fluids.
A pilot study is proposed to identify the best" dose (ratio) of sodium chloride (0.9%) and
sodium acetate (0.9%) mixture for reduction of hyperchloremia by using chloride efficient
fluids in patients with acute stroke initiated within 12 hours of symptom onset and continued
for 72hours.
Ethical and Regulatory Compliance:
This study will be conducted in accordance with all regulatory requirements. The trial will
be conducted in compliance with the latest version of the Declaration of Helsinki, GCP, ICH
and Ethics Review Committee guidelines and standards. Informed Consent Form will be
administered in English and Urdu languages. A signed copy of the ICF will be provided to the
subject for reference and record. Ethics Committee of Aga Khan Contact Person: Secretary ERC
Research office Clinical Data Relevant Clinical Trial data will be transcribed from patient
hospital file into study Case Report Forms (CRFs). Successively, all CRFs will be entered
into Electronic Data Capture (EDC) software. All data collection, transmission and storage
processes will be GCP compliant. Clinical data will be archived for 25 years after completion
of study. Data access will be controlled by Principal Investigator and will only be granted
to trained and delegated study staff.
Hypothesis:
Hyper chloremia is associated with poor outcome in Intracerebral Hemorrhage (ICT).
Hyperchloremia is defined as serum chloride level of 110mmol/L or greater. This clinical
study is assuming that, by increasing the ratio of Sodium-acetate to Sodium-chloride
solutions in IV treatment, the incidence of Hyperchloremia can be lowered significantly. This
result can be demonstrated by measuring serum chloride levels at Baseline, 24Hr, 48Hr and 72
Hours' time intervals and compare them between the three treatment and one Control arm.
Intervention (drug/biologic/device/behavioral):
Phase 2-dose finding Patients will be enrolled in the study and randomized into one of the
four study treatment arms(target fluid administration rate 1 ml/kg/hour) initiated within 12
hours. IVF will be prepared in the main hospital pharmacy.
1. Sodium chloride (0.9%) referred as 0.9% NaCl for 72 hours post symptom onset (60-72
hourspost randomization);
2. Sodium chloride (0.9%) and sodium acetate (0.9%) mixture 3:1 ratio for 72 hours post
symptom onset (60-72 hours post randomization);
3. Sodium chloride (0.9%) and sodium acetate (0.9%) mixture 2:1 ratio for 72 hours post
symptom onset (60-72 hours post randomization);
4. Sodium chloride (0.9%) and sodium acetate (0.9%) mixture 1:1 ratio for 72 hours post
symptom onset (60-72 hours post randomization).
Primary Objective:
To Determine the best dose of sodium chloride and sodium acetate mixture using efficient
statistical strategy and its effects on outcome
Primary Outcome:
Persistent hyperchloremia:
A complete chemistry panel will be performed at baseline, 24 hours, 48 hours, and 72
hours. "Persistent hyperchloremia within 72 hours will be the primary outcome. Patients
with an increased serum chloride at either baseline, or 24, 48, or 72 hours after
randomization were identified. Hyperchloremia will be defined by serum chloride of 110
mmol/L or greater consistent with previous studies.1-5 We will further grade
hyperchloremia into one occurrence or two or more occurrences within first 72 hours as
"persistent hyperchloremia". investigators anticipate that rate of persistent
hyperchloremia will be 10-15% based on ATACH 2 and ALIAS 1 and 2 studies in patients
with intracerebral hemorrhage and ischemic stroke, respectively.
Acute Kidney Injury:
investigators will ascertain and grade AKI severity after randomization based on the
guidelines provided by the acute kidney injury network (AKIN) classification.8,9
Severity of AKI will be based on increase in serum creatinine levels from baseline and
Urine Output. stage 1; ≥ 0.3 mg/dL (≥26.4 µmol/l) or A percentage increase in serum
creatinine of 50% or greater (1.5 - 2-fold increase from baseline) stage 2; > 2 to
3-fold increase, stage 3; > 3-fold increase in serum creatinine. Or Oliguria: Urine
output < 0.5 mL/kg per hour) for > 6hrs
Secondary Outcome/Objectives:
The secondary end point will be the mean score for disability on the utility-weighted
modified rankin score (UW-mRS) at 90 days. UW-mRS weights the mRS against a health
utility scale that reflects the spectrum between perfect health (a score of 1) and
outcomes worse than death (where death isa score of 0 and negative values indicate an
outcome worse than death).10,11 Thus, the UW-mRS ranges from 0 (death) to 10 (no
symptoms or disability) and indicates the value to patients, families, and health
providers of the long-term disability outcome, across a broad range from fully normal,
through varying degrees of disability, to death.
Additional secondary endpoints include:
Metabolic alkalosis: Metabolic alkalosis will be defined by arterial pH >7.45 and HCO3-
is >28 mmol/l.12,13
All Serious Adverse Events:
An Adverse Event is serious IF it leads to death or serious deterioration in the health
of a subject that resulted in a life-threatening illness or injury, permanent impairment
of a body structure or a body function, hospitalization or prolongation of existing
hospitalization, medical or surgical intervention to prevent permanent impairment to a
body structure or a body function and/or caused congenital anomaly or birth defect. All
SAEs will be reported to the Sponsor, ERC, Hospital Incident Reporting system (AEMS)
within 24 Hours of Investigator awareness and Regulatory body NIH/NBC/DRAP as soon as
possible.
- Ethics Committee can suspend/discontinue study if greater than acceptable risk is
posed to the safety of participants.
- Regulatory Authorities can also suspend/terminate study progress.
- Sponsor may discontinue the study at any time with prior written notification.
Risks and Side Effects:
There are risks to taking part in any research study. There may also be other problems
(also called side effects) we do not know about yet. If we learn about new important
risks and side effects, we will inform the subject including any new information that
may affect subject's decision to continue taking part in the study.
Subjects may undergo a catheter-based procedure to remove the clot from the blood vessel
(regardless of study participation).
- There is a risk that any of the IV fluids will increase the fluid in subject's
lungs which may require medication called diuretics to remove the fluids from
lungs.
- There is a risk that any of the IV fluids will make the kidney function worse which
may require changing the IV fluids and additional treatment as considered
appropriate by the doctor.
- There is a risk that any of the IV fluids will cause increased acidity or
alkalinity of the blood which may require discontinuation of the IV fluids and
additional treatment as considered appropriate by the doctor.
- There can be infection at the injection site, a dislodged IV catheter, or a
collapsed vein when receiving any IV fluids. All of these are easily corrected or
treated.
- Finally, the experimental interventions in this study may have side effects that no
one knows about yet.
Settings:
ALL clinical trial related interactions and investigations will be conducted in Aga Khan
Hospital only.
Relevant departments include Emergency Department, Neurology Department, Wards,Stroke
Units, Main Lab and Out-Patient Clinics.
Randomization and Elimination of Bias:
A stratified randomization will be performed based on initial diagnosis of ischemic
stroke or intracerebral hemorrhage. Patients will be randomized in permuted blocks of
size 4 matched byclinical site (quadruplets) to 0.9% NaCl or one of the three doses of
0.9% NaCl: Na-acetate. Although patients were also randomized concurrently to 0.9% NaCl
to preserve the blinding and to eliminate other possible temporal biases, only the 0.9%
NaCl: Na-acetate arms will be involved in the section procedure. Furthermore, outcome
assessments such as AE/SAE, degree of disability and MRS score will be performed by
blinded and Independent medical staff to eliminate bias.
- Total Sample size is 80 subjects (20 subjects per treatment arm)
- Enrolment duration is 1year
- Follow-Up duration is 3 months for each subject
- Total study duration will be 18 months.
Statistical assumptions:
The dose finding trial will have Response Adaptive Randomization (RAR) updated beginning
at 50 subjects enrolled and updated every 25 subsequent enrollments to a maximum sample
size of 72 patients. The randomization will be after stratification based on ischemic
stroke and intracerebral hemorrhage. The currently proposed design was selected because
it collects information across a range of treatments, randomizes an increasing number of
patients to the "best" arm in proportion to the amount of information available about
the different treatments and quantifies the likelihood of success should a Phase III
study be initiated. The chosen approach is expected to control for type 1 error at 10%
and allows for greater than 80% power in all conditions tested.
Statistical analysis:
investigators will compare various measures of hyperchloremia between the four groups.
Hyperchloremia will be defined by serum chloride ≥110 mmol/L at either baseline, or 24,
48, or 72 hours after randomization consistent with existing literature and into 1
occurrence or ≥2 occurrences within first 72 hours. Metabolic acidosis (serum
bicarbonate of < 22 mmol/L consistent with previous studies) will also identified at
same timepoints after randomization. investigators will also calculate area under the
curve (AUC) to provide a summary of serum chloride levels over the 72-hour period.
