| Background: End Stage Renal Disease (ESRD) is the
advance stage of Chronic Kidney Disease which develops from stage I within a
course of few years. Its incidence in worldwide as well as in India is
increasing day by day. Globally, more than 100 countries (with a combined
population of more than 1 billion) have no provisions for chronic maintenance
dialysis or kidney transplantation and thus, more than 1 million people die
annually from ESRD on a global scale. Data suggests that about
220,000–275,000 new patients need a renal replacement therapy (RRT) every year
in India and Pakistan. It is estimated that there are about 55,000 dialysis
patients in India, and this population is growing at the rate of 10–20 percent annually because of the increasing incidence (increase nearly doubled from 2003
to 2013). Hemodialysis cost in India is also high in comparison to income
level. Hence, efforts are needed to develop strategies which decelerate the
progression of CKD. A 10 or a 20 percent improvement in the eGFR decreases the need
of renal replacement therapy and estimated cumulative savings may be of 25 and
55 percent respectively. Studies suggest that the cumulative economic impact of
slowing the progression of CKD, even by 10 percent, would be staggering. The
acceleration of disease progression of CKD can be judged by observing changes
in eGFR within a 6 months period. Some preliminary scientific evidence exists,
suggesting beneficial effects of Ayurvedic treatments in signs and symptoms as
well as in renal function tests of CKD patients. Findings of one pilot study
conducted in P D Patel Ayurveda Hospital, Nadiad revealed that the Ayurvedic
treatment might be effective to reduce the disease progress of CKD and postpone
renal transplant as well as the need of dialysis. This may be a valuable
addition to conventional medicine. However, it was a pilot study, conducted in
non-dialysis patients of stage IV-V of CKD with data of sixty-four
participants.
Patient come to the Ayurveda intentionally
for the Ayurveda treatment. Hence, randomization or controlled trial creates
ethical issues which can’t be resolved and hence, randomization and taking
control group is difficult for research in this type of disease especially for
exploring the Ayurveda treatment effect. Hence, this study protocol is
projected to evaluate the effects of Ayurvedic treatment on the deceleration of
the disease progress of all stages of CKD patients with more number of
participants by comparing the mean changes of eGFR and renal function tests
(RFT) at three different time points (TP) i.e. six months before the beginning
of the Ayurvedic treatment (TP-6), at baseline (TP0) and six months after
baseline (TP+6). In this specific design, mean changes of TP0 and TP-6 would
become control for the mean changes between the TP0 and TP+6. Objectives: a. Primary: To
compare the mean changes of eGFR at different time points i.e. TP-6, TP0 and
TP+6 in the patients of CKD. b. Secondary: 1. To evaluate the grade score changes of
signs and symptoms before and after the administration of intervention 2.To evaluate the effect of ayurvedic
treatment on renal function tests as well as the mean changes of grade score of
signs and symptoms at different time points i.e. TP-6, TP0 and TP+6. 3. To evaluate the change in Quality of life of CKD patients managed with
Ayurvedic treatment by extended versions
adapted for specific use in kidney patients (KD-QoL) 4. To evaluate the safety of Ayurvedic treatment in the
management of CKD 5.
To assess the occurrence of AE/ADR if any. Study design: This study will be an open labelled,
quasi-experimental clinical study with Dependent Pretest and Post test Samples
using a Double Pretest Inclusion criteria:
i.
Participants of both genders aged 18–65 years
ii.
Participants who are non-dialysis dependent known
patients of CKD (up to stage 4) with or without · diagnosed as
DM and on medication, · diagnosed as
hypertensive and on medication. Exclusion criteria: 1.
Patients with cystic and tubulointerstitial
nephropathy, Left ventricular hypertrophy, and dilated cardiomyopathy
conditions associated with hyporeninemic hypoaldosteronism, and renal diseases
that preferentially affect the distal nephron, such as obstructive uropathy and
sickle cell nephropathy. 2.
Patients diagnosed as having later stages of CKD
with prolonged bleeding time, decreased activity of platelet factor III,
abnormal platelet aggregation and adhesiveness, and impaired prothrombin
consumption, clinically increased tendency to bleeding and bruising, prolonged
bleeding from surgical incisions, menorrhagia, and GI bleeding. 3.
Patients diagnosed as having recent acute kidney
injury (more than 50 percent increase in serum creatinine in the preceding 30 days) 4.
Patients on chronic dialysis therapy or had
episode(s) of dialysis in the last 3 months; had renal replacement therapy in
the prior 3 months; had renal transplants or planning renal transplantation
during the trial period 5.
Known case of amyloidosis, HIV nephropathy,
a genetic disorder that causes many
cysts to grow in the kidneys, polycystic kidney disease (PKD) that has
reached some degree of renal failure with enlarged kidneys and multiple cysts 6.
Patients diagnosed as having heritable form of
CKD Alport or Fabry disease, cystinosis 7.
Known case of Secondary or Malignant
Hypertension, clinically significant cardiac arrhythmias, severe aortic
stenosis, unstable angina pectoris, myocardial infarction, percutaneous
transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG)
surgery, symptomatic congestive heart failure (HF), atrial fibrillation (AF),
acute coronary syndrome (ACS), increased risk of major adverse cardiac events
(MACE), HF and arrhythmogenic cardiomyopathy (ACM), with atherosclerotic
cardiovascular disease and stroke. 8.
Known case of uncontrolled Type 1 and Type 2
Diabetes Mellitus whose diabetes has not been stable and controlled for the
previous three months and with HbA1c value more than 8% 9.
Known case of abnormal Liver Function Test with
values more than 3 times the upper limit of normal 10.
Known case of autoimmune diseases such as lupus
and underlying infectious etiologies such as hepatitis B and C and HIV; IgA glomerulonephritis, Anti-GBM (Goodpasture’s) disease, IgA vasculitis, renal artery stenosis 11.
Known case having any drugs such as nonsteroidal
anti-inflammatory agents, cyclooxygenase-2 (COX-2) inhibitors, antimicrobials,
chemotherapeutic agents, antiretroviral agents, proton pump inhibitors,
phosphate-containing bowel cathartics, and lithium. 12.
Known case of heavy metal poisoning, such as lead poisoning 13.
Female patients who are pregnant, lactating or
planning to concieve during the trial
period. 14.
Known case as Chronic smoker, alcoholic or drug
abuse suspected. 15.
Patients with medical history of oncological
conditions since last 2 years. 16.
Patients who have participated in other clinical
trials within 6 months prior to the screening examination. 17.
Known case of hypersensitivity to any of the
trial formulations/ingredients. 18.
Patients contraindicated for niruhabast i.e having
anorectal disorders, diarrhoea, severe debility, hypokalemia, ascites etc. 19.
Patients who are not
willing to participate in the study
20.
Any other condition
that PI thinks may jeopardize the study Study protocol and timeline: Methods: Masking: Open
label Control: Not
controlled Timing: Prospective End point: Efficacy
and Safety No. of Groups: One Sample size:
130 Milestone
with deliverables: Timelines: Total
Study Period 24 months Pre-trial
preparation 3 months Recruitment, Follow up and protocol publication 19
months Statistical Analysis 2 months Washout period: 6 months prior to
initiation of treatment Treatment duration for the
patient 06 months (01
month in IPD and 05 months OPD) Follow-up visit
schedule during treatment:
All the enrolled patients will be
hospitalized for a period of one month. They will be assessed with signs and
symptoms and laboratory investigations on the day of hospitalization. After the
period of one month of the above treatment, patients will be relieved from the
hospital and instructed to take all medicaments (without niruhabasti) and food
regimen at home as per the schedule. They will be instructed to come every
month for the check-up for next 5 months. Total duration of the treatment
period will be 6 months. Preparation of Trial Medicine: All the medicaments will be
prepared by Sundar Ayurveda Pharmacy, Nadiad under the expert supervision. This
pharmacy is a GMP certified and supervised by RS&BK department of J S
Ayurved Mahavidyalaya, Nadiad. This Pharmacy supplies the medicaments to the P
D Patel Ayurveda hospital (where this research study will be performed) only
and not selling any medicine to elsewhere. Hence, maintaining of quality is
possible.
The raw material will be
authenticated by the expert of Dravyaguna and RS-BK department of J S Ayurveda
College, Nadiad. Necessary test related to quality control of trial medicaments
will be performed in QC lab. Outcomes and measurements: Renal functions tests (eGFR, serum creatinine, blood
urea, serum electrolytes, serum calcium) and the hemoglobin level will be
recorded 6 months before baseline (+/- 5 days) (TP-6). The same investigations
will be performed in the laboratory of the study institute at the date of
starting Ayurvedic treatment (TP0, baseline). The final assessment with
laboratory investigations will be performed 6 months after completion of
Ayurveda treatment in the same laboratory (TP+6). CRF specific signs and symptoms will be assessed by
using a grade score (Table 1), which was adopted from a previously published
research article. Changes in signs and symptoms, eGFR, albuminuria, serum creatinine, blood urea,
serum electrolytes, serum calcium and hemoglobin level will be observed. For
the calculation of eGFR the DaVita
Glomerular Filtration Rate calculator will be used, which applies the 2009
CKD-EPI creatinine equation, recommended by the KDIGO Clinical Practice
Guidelines for Management of Chronic Kidney Disease. Table – 1:
Grade score of signs and symptoms
|
Signs and
symptoms
|
Grade 0
|
Grade 1
|
Grade 2
|
Grade 3
|
|
Oedema
|
No oedema
|
Slight oedema in
lower legs
|
Severe oedema in
lower legs
|
Anasarca
|
|
General weakness
|
No weakness
|
Mild weakness
|
Moderate
weakness
|
Severe weakness
|
|
Loss of appetite
|
Good appetite
|
Mild loss of
appetite
|
Moderate loss of
appetite
|
Complete loss of
appetite
|
|
Nausea /
Vomiting
|
Absent
|
Occasional
|
Once or twice a
week
|
Daily
|
|
Muscle cramps
|
Absent
|
Occasional
|
Once or twice a
week
|
Daily
|
|
Breathlessness
|
Absent
|
On fast walking
or climbing stairs
|
Sometimes at
rest
|
Generally,
occurs at rest.
|
|
Hiccup
|
Absent
|
Occasional
|
Once or twice a
week
|
Daily
|
|
Pruritus
|
Absent
|
Mild
|
Moderate
|
Severe
|
Primary Outcome Measure Change in eGFR Secondary Outcome Measure 1. Change in UACR 2. Change in BUN and electrolytes with
serum calcium. 3.Change in Serum Creatinine 4. Change in Cystatin C 5. Changes in CBC, C Reactive Protein 6. Improvement in USG whole abdomen 7.Change in Kidney Disease Quality of Life
(KDQOL-SFTM) Version 1.3 8.Change in Grade score of signs and
symptoms before and after the administration of intervention 9. Change in safety laboratory parameter
LFT 10. Incidence rate of AE/ SAE Assessment Criteria: 1.KFT (eGFR,
serum creatinine, blood urea, serum electrolytes, serum calcium) 2.Urine albumin-to-creatinine ratio (UACR) 3.Serum Cystatin C 4.C-reactive protein 5.CBC 6. FBS and HbA1C 7.LFT 8.Kidney Disease Quality of Life
(KDQOL-SFTM) Version 1.3 9.specific signs and symptoms by using a
grade score (Table 1), which is adopted from a previously published research
article Serum Cystatin C, UACR and HbA1C
will be performed on initial visit, after 3 months and on last visit (after 6
months) of the patients. USG – whole abdomen will be performed at initial and
last visit of the patients. All other laboratory tests will be done on every
visit of the patients. Laboratory investigations will
be performed in the clinical pathology laboratory of NABH accredited
Mahagujarat Medical General Hospital which is parent organization of J S
Ayurveda College (research site), Nadiad. |