Efficacy of Gum Arabic as Anti-inflammatory Agent in Sickle Cell Anemia Pediatric Patients : A randomized, double-blind, placebo-controlled Phase III trial

doi:10.21203/rs.3.rs-2109339/v1

Background: Sickle cell disease is one of the common genetic diseases with an autosomal recessive inheritance. SCD have been acknowledge as an inflammatory condition with several indicators of an inflammatory response involving high level of white blood cell, CRP, cytokines as well as elevated monocytes, neutrophils, platelets and endothelial cells. Oral intake of gum Arabic elevates serum level of short chain fatty acids concentration especially levels of butyrate and propionate. Butyrate is a potent anti-inflammatory, that lowers pro-inflammatory cytokines expression through inhibition of NF-kB. GA works as anti-inflammatory through short chain fatty acids.

Methods: Twenty- one sickle cell anemia patients recruited and giving 30g of gum arabic daily for 12 weeks and levels of CRP, ESR and uric acid were measured before and after full dose of oral GA. Another Twenty- one patient were recruited and this time giving placebo treatment. Same GA investigations were done for placebo group.

Results: Gum Arabic has significant anti-inflammatory effects in SCD patients as CRP level decrease significantly after taking GA.

Conclusion: GA is a potent anti Inflammatory. It reduces Inflammatory markers like CRP in patients with sickle cell disease.

Trial registration: clinicalTrial.gov identifier: NTC04191213. First posted December 9, 219. Retrospective regestriation.

Gum Arabic

placebo

anti-inflammatory

Sickle Cell Disease (SCD)

ESR

CRP

Uric acid

Sickle cell disease is one of the common genetic diseases with an autosomal recessive inheritance (1). It is an outcome of single point mutation in position 6 on Beta globin chain resulting in production of hemoglobin S (HbS) (2),(3). Polymerization of deoxygenated sicke hemoglobin is the fundamental incident in the molecular pathogenesis of sickle cell disease(2),(4).

SCD have been acknowledge as an inflammatory condition (2) with several indicators of an inflammatory response involving high level of white blood cell, CRP, cytokines as well as elevated monocytes, neutrophils, platelets and endothelial cells (2),(4). CRP is generated, in response to host pro inflammatory cytokines, from the liver as a part of Acute phase reaction (2),(5),(6). CRP has been broadly approved as reliable indicators of systemic inflammation and tissue damage (2),(6),(7). In sickle cell disease patients, high levels of CRP have been reported. (2),(6),(7).

Gum Arabic (GA) was defined by the FAO/WHO Joint Expert Committee for Food and Additives (JECFA) as acacia Senegal exudate (1),(8). GA remains undigested in both animals and humans (1),(9). The enteric ingestion of GA is related to a considerable decrease in C- Reactive Protein level among Chronic Kidney Disease patient (1),(10). The wholesome influence of GA also is intermediated by its immune-modulatory and anti-inflammatory actions. (1),(11),(12),(13). GA adjusts immunity in mice (1),(11) by debilitating TNF-ɑ, CRP and elevating anti-inflammatory cytokine IL-10 (1),(11),(14),(15). It also has local anti-inflammatory effect by modifying nuclear factor kappa B (NF-KB) on the small intestine (1),(16). GA elevates hemoglobin level and RBC count with no effect on other blood parameter (1).

Oral intake of gum Arabic elevates serum level of short chain fatty acids concentration especially levels of butyrate and propionate (2)(9)(17). Butyrate concentration in the serum increases following ingestion of GA (2)(9)(18). Butyrate is a potent anti-inflammatory, that lowers pro-inflammatory cytokines expression through inhibition of NF-kB (2)(19)(20). GA works as anti-inflammatory through short chain fatty acids (2).

Inflammation among sickle cell disease patients is ceaseless process occurs even during steady state (2). GA considerably decreases CRP level in the serum. Anti-inflammatory effect of GA is by lowering TNF-ɑ and ESR.

The present study tested whether gum Arabic influence inflammatory markers or not. As far as we know few studies conducted to investigate the effect of oral administration of GA on inflammatory markers in sickle cell anemia patients.

Study Design:

Hospital-based Randomized Double blind two-armed, parallel-group Placebo Controlled trial.

Study Area:

Military Hospital in the city of Omdurman, Khartoum state and Jafar Ibnauf paediatrics hospital's outpatient clinic (Abdalrahman Albashir) – Sudan in the period between May to July 2021.

Study Population:

Sudanese Sickle cell anaemia patients on regular follow up encountered in paediatrics outpatient clinics in Military hospital in Khartoum state and Jafar Ibnauf paediatrics hospital's outpatient clinic (Abdalrahman Albashir) – Sudan.

Inclusion criteria:

Sudanese nationals.
Homozygous for Sickle Cell Disease (SS) as documented by Haemoglobin electrophoresis.
Aged 5 years or greater and less than 18 years
Subjects whom medications and dosages had been stable for 2 weeks before study entry.

Exclusion criteria:

Non-Sudanese patients.
Patients with history of Gum Arabic allergy.
Patients who received blood transfusion within the last 2 weeks.
Patients who had sickle-cell-disease-related event or crisis that required or did not require hospital admission within the last 2 weeks.
Patients who have ischemic heart disease, liver dysfunction or hepatitis.
Pregnant female patients or who plan to conceive in the next 4 months and fertile female patients who are not using an effective contraception method.
Patients who are currently using Gum Arabic.
Patients who are on steroids or chemotherapy.
Cigarette smokers.

Method of recruitment:

The study group was selected by inviting patients with sickle cell anaemia encountered in paediatrics haematology outpatient clinics in Military Teaching Hospital in Khartoum state who undergo regular follow up.

Patients were be offered any cash payment.

Patients were offered a patient information sheet to explain the eligibility criteria, aims and objectives of the experiment ( Annex A).

A standardized interviewer-administered assessment form (Annex B) was used along with clinical examination to assess trial eligibility/suitability for interested patients who offer verbal consent by themselves and/ or by their parent(s). This form was used for participants as well.

Eligible subjects who are interested in participation in the study were provided with information about the purpose of the study and detailed explanation of the instructions to be followed by them if enrolled in the study by well-trained study assistants. After which an informed consent (Annex C) was obtained from the subjects by the investigators. The informed consent must be signed by the parents (or caregiver) of participants. Illiterate subjects can use thumbprint instead of signature. Participants who speak languages other than Arabic and English (e.g. local or tribal languages) were offered a translator who is not involved in the study.

Eligible subjects who are interested in participation in the study but have not provided a signed consent were offered two weeks duration to decide.

Trial Intervention:

Gum Arabic powder is 100% natural extract powder produced mechanically from the wildly grown Acacia Senegal tree with a particle size less than 210 μm (22) 23). No significant adverse or toxic actions have been associated with the use of Gum Arabic (24). Properties and composition of Gum Arabic are listed elsewhere (21).

Pectin is a complex mixture of polysaccharides that makes up about one third of the cell wall dry substance of higher plants (25) with Lemon and orange rinds being among the richest sources (26). Commercial pectins are derived from citrus peel or apple pomace, both by-products from juice (or cider) manufacturing (25). It is a gel forming carbohydrate used as dietary fiber (because it resist digestion in the alimentary tract) (27) and is used in the food industry to add body and texture to jellies, jams, puddings,…etc. (26). The use of pectin as a food additive contribute several times to the exposure from all sources, when compared to the exposure from the regular diet for both adults and children (26). Pectin is used as an active ingredient in antidiarrheal medicinal products and for the treatment of regurgitation in infants due to its water-binding properties (28). In medical research pectin has been shown to reduce post-prandial blood glucose levels in healthy volunteers, insulin requirements in diabetics, the rapid gastric emptying associated with dumping syndrome (27), reduce cholesterol levels in adults and ensure linear growth in children in doses higher (28) than the dose used in this study. According to the reviewed literature (27)(28)(29) it has been concluded that the dose of pectin used in this study (1 gram) is safe for both children and adults.

Sealed boxes were prepared containing packages of either the intervention supplement (Gum Arabic) or placebo (pectin). Eligible participants who are enrolled were randomly allocated into either intervention (to receive Gum Arabic supplement) or placebo (to receive pectin supplement) group by a blinded investigator. The randomization was achieved by stratified sampling technique that uses age and gender as strata.

The boxes containing the supplements were given to the blinded study assistants responsible for enrolment. Each participant was supplemented with a daily dose of either Gum Arabic (Intervention group) or a placebo (Control group) as follows:

The daily dose provided to the intervention group consist of 30 grams of 100% natural gum provided in a powder form. The dose is determined based on previous studies (28)(23) (22). The dose was provided in one sachet to be consumed in the early morning dissolved in 250 ml of water; shaken well to ensure adequate mixing before intake. The Gum Arabic sachets were provided to the participants every 2 weeks for 12 weeks (14 sachet at each visit).

The daily dose provided to the control group consist of 1 g of pectin given in one sachet in the same way as the intervention group. Subjects were instructed to consume their dose in the early morning dissolved in 250 ml of water; shaken well to ensure adequate mixing before intake. The pectin sachets were provided to the participants every 2 weeks for 12 weeks (14 sachet at each visit).

Duration of intervention has been selected based on previous studies (23)(22)(29) that showed it to be sufficient for outcome measurement.

Participants are allowed to use the standard medications prescribed for sickle cell disease patients which include folic acid and other vitamins. In addition, participants are to use rescue-medication if need arise. Participants were not allowed to use other herbal or traditional medicines during trial period.

Follow up assessments were undertaken by the chief investigator who also be blinded to the randomization.

The Data Collection Methods and Study Instruments:

Demographic and health-related data including clinical examination findings were collected using a pre-coded pre-tested standardized interviewer-administered questionnaire (the questionnaire was pre-tested on a sample of 5 subjects not included in the study to assess its reliability and check for clarity and proper formulation of items). This questionnaire is to be filled at the initial visit before applying the study intervention (Gum Arabic or Placebo).
Outcome assessment:
Routine assessment: Participants at the initial visit and every four weeks thereafter, undergone

- clinical safety assessments (History and Examination)

- Complete blood count (CBC) : 3 ml of venous blood was collected for this test.

- C- reactive protein (CRP) level.

- Assessments done prior to applying intervention and after 12 weeks of intervention:

Regular clinical follow up was carried out by the consultant and medical officer in the unit.
Empty sachets were retained from participants at each visit as an indicator of compliance.
All blood samples were collected by certified nurses or doctors in the Hospital.

Sample Size and Sampling Technique:

Sample Size:

The sample size software (www.openepi.com) (34) was used to calculate the total sample size; assuming that:

Two-sided significance level = 95%, power = 80%, ratio of sample size (exposed : nonexposed) = 1, percent of unexposed with outcome = 5%, percent, percent of exposed with outcome = 25%, odds ratio = 6.3. The total sample size was determined to be 102 subjects which were divided into two equal groups (intervention group and control group); each group consists of 51 subjects.

Sampling Technique:

Proportional Stratified Sampling.

Ethical Considerations:

All procedures were insured to conform to the ethical principles of medical research as developed by the World Medical Association Declaration of Helsinki.

Ethical approval letter was obtained from the central institutional review board of Al Neelain University.

Ethical clearance was obtained from the national medicines and poisons board. Permission to conduct the study in hospitals was obtained from head of department. A written consent was obtained from each study participant individually after they are adequately informed about the purpose, method, anticipated benefit and risk of the study by the study assistants.

Data analysis plan:

Data was entered by the principal investigator in Excel sheet Microsoft 10. To ensure accuracy and precision of this process; data was entered separately and simultaneously by a well-trained study assistant.. Quantitative data was expressed using Range, mean and standard deviation. Independent sample t-tests were used to analyze the data. P value was assumed to be significant at 0.05. The master sheet was organized and analysed using R program version 3.4.3. (GNU) statistical software.

Twenty one sickle cell anemia patients were enrolled in the study. Results were recorded before and after taking placebo. Thirteen of them were males with mean age of 10.76 ± 3.49 (SD). Independent sample t-tests were performed and there was significant effect of placebo on CRP level which was increased after 12 weeks of taking placebo treatment (Fig. 1). Study reported no significant effect of placebo in ESR and uric acid (Table 1).

Table 1

Comparison between the mean of pre- and post-intervention (placebo) values of anti-inflammatory indices:
	Baseline Mean ± SD	12 weeks after Placebo intake Mean ± SD	p- value
ESR	28 ± 15	29 ± 15	0.927
CRP	8.6 ± 3.1	10.8 ± 3.6	0.045
Uric	5.6 ± 1.6	5.8 ± 1.5	0.611

Another twenty one patients of sickle cell anemia also recruited. All were Sudanese as well. Nine were males. Mean age was 8.62 ± 3.57 (SD) years old. We performed independent sample t-tests to see the difference before and after taking gum Arabic regarding inflammatory markers (ESR, CRP and uric acid) (Table 2). We found significant effects of gum Arabic on CRP (Fig. 2) and uric acid (Fig. 3) which both of them were reduced after 12 weeks of taking gum Arabic.

Table 2

Comparison between the mean of pre- and post-intervention (gum Arabic) values of anti-inflammatory indices:
	Baseline Mean ± SD	12 weeks after Placebo intake Mean ± SD	p- value
ESR	26 ± 12	21 ± 11	0.143
CRP	8.7 ± 3.2	5.5 ± 2.0	0.001
Uric	5.72 ± 1.78	4.40 ± 1.51	0.013

Sickle Cell Disease (SCD) is considered one of the most common Hemoglobinopathy in Sub-Saharan region in Africa (21).

Studies reported a very strong correlation between having SCD and chronic inflammation (22)(23). CRP levels are used to assessed the states of both acute and chronic inflammation along with another inflammatory markers like ESR (22). There was study which reported no significant correlation between CRP and Hb F (2).

Our study confirmed that there was no significant effect of placebo treatment on both the levels of ESR and uric acid (Table 1). But regarding CRP, our study confirm a significant increase in the level of CRP after taking placebo treatment (P value = 0.045) (Table 1).

This study reported that GA had significantly decrease the level of CRP (P value = 0.001) and uric acid (P value = 0.013) (Table 2).This is comparable to study carried out in Sudan which confirmed results we found (2).We considered GA's anti Inflammatory property of a very importance as the main pathophysiologic component in SCD (24).

In this study, GA reported no effect on the level of ESR (Table 2).

We conclude that oral administration of GA noticeably lowers CRP and uric acid levels, which is a great effect of GA ingestion. GA can be useful in any condition involving inflammation. ESR is not significantly affected by oral administration of GA.

GA: Gum Arabic, CRP: C-Reactive Protein; SCD: Sickle cell Disease; ESR: Erythrocyte Sedimentation Rate.

Acknowledgement

We would like to thank Dar Savanna Ltd. Khartoum, Sudan (www.darsavanna.net) for providing gum Arabic as gift for the study.

Funding

This research was funded by Ministry of Health. Supporting fund was also obtained from Alneelain University, Khartoum, Sudan to principal Investigator DA.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors’ contributions

LK is the direct supervisor. DA is the DA. DA, LK, HA and IF participated in study design. DA, LK and HA were involved in all aspects of the study conduct. DA, LK, HA, AM and IM participated in the writing and review of the manuscript. AM and DA analyzed data. LK, DA, AS and IM performed laboratory studies. HA and AS were significant clinical contributors to the study.

All authors approved final version of manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Principal investigator obtained informed consent from each participant or from parents when the patient was less than 18 years to publish the data without breaching confidentiality.

Ethics approval and consent to participate

All procedures were insured to conform to the ethical principles of medical research as developed by the World Medical Association Declaration of Helsinki.

Ethical approval letter was obtained from the central institutional review board of Al Neelain University.

Ethical clearance was obtained from the national medicines and poisons board. Permission to conduct the study in hospitals was obtained from head of department. A written consent was obtained from each study participant individually after they are adequately informed about the purpose, method, anticipated benefit and risk of the study by the study assistants.

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No competing interests reported.

Annex.doc

Efficacy of Gum Arabic as Anti-inflammatory Agent in Sickle Cell Anemia Pediatric Patients : A randomized, double-blind, placebo-controlled Phase III trial

Status:

Version 1

Abstract

Figures

Background:

Methods:

Results:

Discussion:

Conclusion:

Abbreviations:

Declarations:

References:

Additional Declarations

Supplementary Files

Status:

Version 1