Abstract
Background:
Deer antlers have been used as strong tonifying medicine in Asian countries, especially for the growth and development of children in pediatrics of Korean medicine. The safety of deer antler in adults cannot be applied directly to children because of their physiological characteristics. To accumulate reliable data on the safety of deer antler in pediatric populations, well-designed clinical studies are required.
Methods:
This research is a 12-week, randomized, double-blind, placebo-controlled clinical trial evaluating the safety of deer antler extract (DAE) in children. The DAE group received an intervention containing 1586 mg of DAE, whereas the control group received a placebo for 12 weeks. The safety was assessed by monitoring adverse drug reactions (ADRs) and laboratory test results.
Results:
One hundred participants were included in the safety analysis. Three and 2 participants in the DAE and control groups, respectively, reported ADRs. There was no significant difference in incidence between the 2 groups. ADRs are categorized into gastrointestinal and skin-related symptoms. No serious ADR was observed throughout the study. The laboratory test results were within or outside the normal range at clinically insignificant levels.
Conclusion:
The research discovered that the DAE is safe in terms of ADRs and laboratory parameters under the conditions studied. Further studies are required to accumulate safety data about DAE dosage adjustment and potential interactions with other medicines.
Keywords: children, clinical trial, deer antler, safety
1. Introduction
Deer antler, called Cervi parvum cornu, refers to the dried section of a young deer antler acquired from male Cervus nippon Temminck, Cervus elaphus Linne, or Cervus canadensis Erxleben. It is a representative tonifying medicine in Korean medicine that activates overall physiological functions by warming the internal organs of the human body.[1] Various effects of deer antlers including immune regulation,[2] antioxidant,[3] antiinflammatory,[4] anticancer,[5] antiobesity,[6] antifatigue,[7] and strengthening bones by expressing bone formation genes[8] have been proved through pharmacological studies.
Therefore, deer antlers have been used as health supplements in several Asian countries for thousands of years. It is widely used in pediatrics of Korean medicine, especially in the growth and development of children. Children undergo changes in drug absorption, distribution, metabolism, and elimination during their growth and development. Proven safety in adults cannot be applied equally to children.[9] Moreover, children cannot identify potential errors independently, making them more susceptible to adverse drug reactions (ADRs).[10] Therefore, careful monitoring of the responses of children to drug administration and continuous accumulation of safety data is essential.
However, most studies on the safety of deer antlers have been conducted on animals.[11,12] with very few clinical studies targeting humans, and none have specifically focused on children. It is difficult to conduct clinical trials in children because of the unique characteristics of this population and ethical considerations. Nevertheless, well-designed studies on the safety of oral administration in children are necessary considering that most pediatric patients take deer antlers orally.
This clinical study evaluated the safety of the deer antler extract (DAE) after 12 weeks of administration in children aged 3 to 12 years old.
2. Material and methods
2.1. Study design
This was a 12-week, randomized, double-blind, placebo-controlled, parallel-group, single-center clinical trial assessing the safety of DAE in children. The study protocol was registered with Clinical Research Information Service (KCT0007386).[13] This trial adhered to the guidelines outlined in the Declaration of Helsinki. Informed consent was obtained from the parents of each participant, and participants voluntarily assented to participate in the study. Each participant was identified by an assigned number and confidentiality was maintained.
The sample size was determined at a 5% significance level, 80% power, and an equal allocation ratio, resulting in 100 participants (50 in each group), considering a 30% dropout rate. Participants were screened based on specific criteria and then randomly assigned to either the DAE or control group using a random number generation program in the SAS system by the AllLive Square Co., Ltd., Gyeonggi-do, Republic of Korea.
Blinding was maintained for all participants, caregivers, and investigators throughout the study. The DAE group received an intervention containing DAE, while the control group received a placebo. Three visits were scheduled at 6-week intervals except for screening. Compliance with the intervention was evaluated at week 6 and 12. Adverse events (AEs) were continuously monitored during the study period, and laboratory tests were performed at screening and week 6 and 12.
Human-derived samples collected during laboratory tests such as blood and urine were managed at the Kyung Hee University Korean Medicine Hospital and discarded after analysis without secondary use. The trial, protocol, and related matters were approved by the Institutional Review Board of Kyung Hee University Korean Medicine Hospital on December 30, 2021, (KOMCIRB2021-08-003-006). The initial recruitment began on March 15, 2022, and concluded on February 16, 2023.
2.2. Participants
2.2.1. Inclusion criteria
Children (boys and girls) aged 3 to 12 years.
Children who voluntarily agreed to participate and signed the consent form or from whom written consent from their parents or legal guardians could be obtained.
Children determined to be suitable participants based on screening conducted according to the protocol.
2.2.2. Exclusion criteria
Children with endocrine diseases (e.g., juvenile diabetes, hyperlipidemia, and hypertension), diseases causing growth retardation (e.g., growth hormone deficiency due to pituitary disease), chromosomal abnormalities, or abnormal appearance.
Children with clinically significant acute or chronic cardiovascular, endocrine, immune, respiratory, hepatobiliary, kidney, urological, neuropsychiatric, musculoskeletal, inflammatory, haemato-oncological, or gastrointestinal diseases.
Children with birth weight outside the normal range (<2.6 kg or > 4.4 kg).
Children who received hormone replacement therapy, calcitonin, phosphonate, and growth hormone treatment within 6 months before screening.
Children who received growth-related medications or supplements within 3 months before the screening.
Children who received antipsychotics within 3 months before screening.
Participation in another study within 1 month of screening.
2.2.3. Concomitant medication
Detailed information on concomitant medications, including product name, purpose, dosage, and duration of administration, was carefully recorded.
Permitted concomitant medications include:
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Medications administered consistently within 4 weeks before screening and could be continued throughout the study without any changes.
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Medications administered before joining the study and determined to not influence the interpretation of the study results.
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Medications episodically used to treat other conditions or AEs.
Prohibited concomitant medications include:
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Foods, drugs, herbal medicines, and injections related to growth.
2.3. Intervention
The intervention products were manufactured by Korean Ginseng Co., Ltd., Daejeon, Republic of Korea, using deer antlers (Cervus elaphus) according to the guidelines provided in the Korean Food Code. The DAE group received products containing DAE, whereas the control group received a placebo similar in packaging, color, and taste, but without any actual DAE. Both groups consumed 20 mL of their respective products before meals once daily for 12 weeks. The dosage of DAE was set at an average recommended intake of 1586 mg for both boys and girls aged 12 to 13 years, following the 2020 Dietary Reference Intakes for Koreans (KDRIs). This calculation was based on the reference daily intake of 1800 mg of DAE, which is considered the guideline for adult consumption. The DRIs during the growth period were calculated by extrapolating from the estimated average requirement (EAR) or adequate intake (AI) of adults, taking into account metabolic weight and the growth factor. The growth factor was used by applying the values from the Food and Agriculture Organization (FAO)/ World Health Organization (WHO)/United Nations University (UNU) to fit the age category of the KDRIs.
2.4. Outcome measures
2.4.1. Adverse events
Information on AEs was collected through voluntary reports of participants from the time of intervention administration to the final visit. The date of onset and resolution, severity and results, causal relationship with the intervention, actions taken for the intervention, suspected drugs other than the intervention, and additional treatment details were recorded. The causality between the intervention and the AEs was classified into “definitely related,” “probably related,” “possibly related,” “probably not related,” “definitely not related,” and “unknown.”
AEs referred to all harmful and unintended signs, symptoms, or diseases that occur in participants who receive the intervention, regardless of whether there is a causal relationship with the intervention. AEs included abnormal test results, clinically significant signs or symptoms, changes in laboratory test results, hypersensitivity reactions, and the progression or exacerbation of preexisting conditions.
ADRs referred to all harmful and unintended reactions occurring at random doses of the intervention for which causality cannot be denied. All classifications of causality, except “definitely not related,” were included as part of ADRs.
Serious adverse events (SAEs) referred to other medically significant situations such as death risk, hospitalization or extension of the hospitalization period, permanent or serious impairment, dysfunction, deformity, or abnormality in the fetus.
Serious adverse drug reactions (SADRs) were defined as a significant SAE for which it was impossible to deny causality with the intervention.
2.4.2. Laboratory tests
Laboratory tests included a complete blood count (CBC), blood chemistry, hormone levels, and urinalysis. CBC consist of red blood cells (RBC), white blood cells (WBC), hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Blood chemistry included aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GTP), total protein, albumin, glucose, total bilirubin, sodium (Na), potassium (K), chloride (Cl), creatinine, blood urea nitrogen (BUN), uric acid, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and estradiol levels. Urinalysis included the measurement of pH, specific gravity, blood, protein, and glucose.
2.5. Statistical analysis
Statistical analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC). All statistical significance tests were 2-tailed with a significance level (α) of 5%. Continuous data were expressed as mean ± standard deviation, and categorical data were expressed as frequencies and percentages up to 2 decimal places.
For demographic details and baseline data, continuous data were analyzed using a 2-sample t-test or Wilcoxon rank-sum test, whereas categorical data were analyzed using the chi-square test or Fisher exact test to determine whether there were any statistical differences between the DAE and control groups.
For safety assessments, participants who were randomly assigned and consumed the intervention at least once were included in the safety analysis set to check all AEs that may occur. The type, frequency, and proportion of reported AEs were analyzed and the chi-square test or Fisher exact test was used to compare the differences between the 2 groups.
For laboratory tests, either the 2-sample t-test or Wilcoxon rank-sum test was used for continuous data, whereas the chi-square test or Fisher exact test was used for categorical data to compare intergroup differences at baseline and at the end of the study period.
3. Results
3.1. Demographic details and baseline data
A total of 105 participants who consented to participate were screened according to the inclusion and exclusion criteria, and 100 participants who met these criteria were included in this study. All 100 participants were included in the safety analysis set. Among them, 6 participants dropped out, and 94 completed the study (Fig. 1).
Figure 1.
CONSORT flow diagram: Participant distribution and study design.
A total of 100 participants were randomly assigned to the DAE and control groups (48 and 52 participants, respectively). The sex distribution was 62 boys and 38 girls. Thirty boys (62.5%) and 18 girls (37.5%) were assigned to the DAE group, and 32 boys (61.54%) and 20 girls (38.56%) were assigned to the control group. There was no statistically significant difference in the sex distribution between the DAE and control groups (P > .99).
The mean ages were 8.4 ± 2.5 years and 8.3 ± 2.3 years in the DAE and control groups, respectively, with no significant difference between the 2 groups (P = .76).
The participants with past medical history were 4 (8.33%) in the DAE group and 6 (11.54%) in the control group, and there was no statistically significant difference between the groups (P = .74).
In the DAE group, 3 participants (6.25%) had a medication history compared to 2 (3.85%) in the control group. There was no statistically significant difference between the groups (P = .67).
Six participants in the DAE and control groups received concomitant medications (12.5% and 11.54%, respectively). There was no statistically significant difference between the groups (P > .99; Table 1).
Table 1.
Demographic details and baseline data of the study participants.
| Parameters | DAE group (n = 48) | Control group (n = 52) | P value |
|---|---|---|---|
| Sex | >.99* | ||
| Boy | 30 (62.5%) | 32 (61.54%) | |
| Girl | 18 (37.5%) | 20 (38.46%) | |
| Age | 8.4 ± 2.5 | 8.3 ± 2.3 | 0.76† |
| Past history | 4 (8.33%) | 6 (11.54%) | 0.74‡ |
| Medication history | 3 (6.25%) | 2 (3.85%) | 0.67‡ |
| Concomitant medication | 6 (12.5%) | 6 (11.54%) | >.99‡ |
Data are presented as number (%) or mean ± standard deviation. DAE = deer antler extract.
Chi-square test.
Two-sample t test.
Fisher exact test.
3.2. Safety assessments
3.2.1. Adverse events
The total number of reported AEs was 23, 13 cases in 11 participants (22.92%) and 10 cases in 8 (15.38%) in the DAE and control groups, respectively. There was no statistically significant difference in the incidence rates between the 2 groups (P = .34).
As for ADR, 5 cases were reported in 3 participants (6.25%) in the DAE group and 4 cases in 2 participants (3.85%) in the control group. There was no statistically significant difference in incidence between the 2 groups (P = .67; Table 2).
Table 2.
Frequency of adverse events and adverse drug reactions.
| DAE group (n = 48) | Control group (n = 52) | Total (n = 100) | P value* | ||||
|---|---|---|---|---|---|---|---|
| N (%) | Case | N (%) | Case | N (%) | Case | ||
| Adverse events | 11 (22.92%) | 13 | 8 (15.38%) | 10 | 19 (19%) | 23 | .34 |
| Adverse drug reactions | 3 (6.25%) | 5 | 2 (3.85%) | 4 | 5 (5%) | 9 | .67 |
DAE = deer antler extract, N = number.
Fisher exact test.
According to the System Organ Class in the Medical Dictionary for Regulatory Activities (MedDRA), “gastrointestinal disorders” were observed in 2 participants in the DAE and control groups (4.17% and 3.85%, respectively). “Skin and subcutaneous tissue disorders” were observed in 2 participants (4.17%) in the DAE group and one (1.92%) in the control group.
When looking at the Preferred Terms (PT), a term for a single medical concept in the MedDRA, 2 participants (4.17%) in the DAE group experienced urticaria, whereas 1 participant (2.08%) experienced diarrhea, nausea, and pruritus. In the control group, diarrhea, constipation, urticaria, and pruritus were observed in 1 participant each (1.92%; Table 3).
Table 3.
Adverse drug reactions categorized by system organ class.
| System organ class | DAE group (n = 48) | Control group (n = 52) | ||
|---|---|---|---|---|
| N (%) | Case | N (%) | Case | |
| Gastrointestinal disorders | 2 (4.17%) | 2 | 2 (3.85%) | 2 |
| Diarrhea | 1 (2.08%) | 1 | 1 (1.92%) | 1 |
| Nausea | 1 (2.08%) | 1 | 0 (0%) | 0 |
| Constipation | 0 (0%) | 0 | 1 (1.92%) | 1 |
| Skin and subcutaneous tissue disorders | 2 (4.17%) | 3 | 1 (1.92%) | 2 |
| Urticaria | 2 (4.17%) | 2 | 1 (1.92%) | 1 |
| Pruritus | 1 (2.08%) | 1 | 1 (1.92%) | 1 |
System organ class is based on medical dictionary for regulatory activities version 26.0. DAE = deer antler extract, N = number.
No SAEs, including SADRs, were observed throughout the study.
3.2.2. Laboratory tests
3.2.2.1. Complete blood cell count
All results were within or outside the normal range at clinically insignificant levels. Significant intergroup differences were observed in WBC (P = .02), neutrophil (P = .003), lymphocyte (P = .03), and basophil (P = .04) counts at baseline and in hematocrit (P = .05) and basophil (P = .02) levels at week 12. No other markers showed statistically significant differences between the DAE and control groups (P > .05; Table 4).
Table 4.
The complete blood cell count results at the baseline and wk 12.
| Parameters | DAE group (n = 48) | Control group (n = 52) | P value† | |||
|---|---|---|---|---|---|---|
| N | Mean ± SD | N | Mean ± SD | |||
| RBC (106/μL) | Baseline | 48 | 4.65 ± 0.29 | 52 | 4.67 ± 0.27 | .73 |
| Wk 12 | 47 | 4.65 ± 0.26 | 47 | 4.74 ± 0.27 | .08 | |
| WBC (103/μL) | Baseline | 48 | 6.92 ± 1.6 | 52 | 7.77 ± 1.83 | .02* |
| Wk 12 | 47 | 6.93 ± 1.61 | 47 | 7.38 ± 1.84 | .22 | |
| Hemoglobin (g/dL) | Baseline | 48 | 13.3 ± 0.7 | 52 | 13.4 ± 0.66 | .47 |
| Wk 12 | 47 | 13.3 ± 0.68 | 47 | 13.5 ± 0.6 | .19 | |
| Hematocrit (%) | Baseline | 48 | 39 ± 2.26 | 52 | 39.3 ± 1.83 | .51 |
| Wk 12 | 47 | 39.4 ± 2.26 | 47 | 40.2 ± 1.99 | .048* | |
| Platelet (103/μL) | Baseline | 48 | 316 ± 62 | 52 | 341 ± 77.2 | .07 |
| Wk 12 | 47 | 304 ± 58.5 | 47 | 311 ± 58.2 | .51 | |
| Neutrophil (%) | Baseline | 48 | 43.7 ± 8.47 | 52 | 49.3 ± 10.1 | .003* |
| Wk 12 | 47 | 45.3 ± 8.61 | 47 | 49.1 ± 10.1 | .06 | |
| Lymphocyte (%) | Baseline | 48 | 45.1 ± 8.72 | 52 | 40.9 ± 9.75 | .03* |
| Wk 12 | 47 | 43.6 ± 8.09 | 47 | 41 ± 9.81 | .17 | |
| Monocyte (%) | Baseline | 48 | 4.51 ± 0.97 | 52 | 4.26 ± 1.04 | .21 |
| Wk 12 | 47 | 4.53 ± 1.47 | 47 | 4.25 ± 1.2 | .32 | |
| Eosinophil (%) | Baseline | 48 | 3.66 ± 2.87 | 52 | 2.97 ± 2.12 | .17 |
| Wk 12 | 47 | 3.55 ± 2.7 | 47 | 2.77 ± 2.16 | .13 | |
| Basophil (%) | Baseline | 48 | 0.66 ± 0.29 | 52 | 0.54 ± 0.29 | .04* |
| Wk 12 | 47 | 0.69 ± 0.3 | 47 | 0.56 ± 0.23 | .02* | |
DAE = deer antler extract, N = number, RBC = red blood cells, SD = standard deviation, WBC = white blood cells.
Two-sample t-test.
P < .05.
3.2.2.2. Blood chemistry
All the results were within or outside the normal range at clinically insignificant levels. Total bilirubin levels were significantly different within the normal range between the DAE and control groups at baseline (P = .03), however, there was no difference between the groups at the end of the study (P = .08). No other markers showed statistically significant differences between the DAE and control groups (P > .05).
Estradiol was not available results for the 18 participants before the study plan was changed. Therefore, at baseline, 37 and 45 participants in the DAE and control groups, respectively, underwent testing. Estradiol levels in all participants who underwent hormone testing were within the normal range. There were no statistically significant differences between the 2 groups at baseline (P = .46) or week 12 (P = .59; Table 5).
Table 5.
The blood chemistry results at the baseline and wk 12.
| Parameters | DAE group (n = 48) | Control group (n = 52) | P value† | |||
|---|---|---|---|---|---|---|
| N | Mean ± SD | N | Mean ± SD | |||
| AST (U/L) | Baseline | 48 | 26.88 ± 5.67 | 52 | 27.75 ± 5.17 | .42 |
| Wk 12 | 47 | 27.68 ± 6.72 | 47 | 26.64 ± 5.02 | .40 | |
| ALT (U/L) | Baseline | 48 | 14.31 ± 4.02 | 52 | 16.48 ± 6.97 | .06 |
| Wk 12 | 47 | 15.17 ± 10 | 47 | 15.02 ± 3.93 | .93 | |
| γ–GTP (U/L) | Baseline | 48 | 11.6 ± 2.86 | 52 | 12.71 ± 3.4 | .08 |
| Wk 12 | 47 | 11.53 ± 4.07 | 47 | 12.55 ± 2.78 | .16 | |
| Total protein(g/dL) | Baseline | 48 | 7.18 ± 0.4 | 52 | 7.28 ± 0.37 | .21 |
| Wk 12 | 47 | 7.21 ± 0.37 | 47 | 7.33 ± 0.34 | .11 | |
| Albumin (g/dL) | Baseline | 48 | 4.54 ± 0.2 | 52 | 4.59 ± 0.22 | .20 |
| Wk 12 | 47 | 4.53 ± 0.18 | 47 | 4.61 ± 0.2 | .06 | |
| Glucose (mg/dL) | Baseline | 48 | 98.08 ± 10.9 | 52 | 96.12 ± 10.3 | .36 |
| Wk 12 | 47 | 95.81 ± 9.71 | 47 | 98.13 ± 14.7 | .37 | |
| Total bilirubin (mg/dL) | Baseline | 48 | 0.51 ± 0.27 | 52 | 0.41 ± 0.12 | .03* |
| Wk 12 | 47 | 0.49 ± 0.23 | 47 | 0.42 ± 0.13 | .08 | |
| Na (mmol/L) | Baseline | 48 | 138.7 ± 1.26 | 52 | 138.9 ± 1.07 | .31 |
| Wk 12 | 47 | 138.7 ± 1.28 | 47 | 138.6 ± 1.28 | .81 | |
| K (mmol/L) | Baseline | 48 | 4.2 ± 0.26 | 52 | 4.21 ± 0.35 | .85 |
| Wk 12 | 47 | 4.16 ± 0.25 | 47 | 4.17 ± 0.33 | .80 | |
| Cl (mmol/L) | Baseline | 48 | 105 ± 1.71 | 52 | 104.9 ± 1.56 | .77 |
| Wk 12 | 47 | 104.4 ± 1.58 | 47 | 104.3 ± 1.5 | .64 | |
| Creatinine (mg/dL) | Baseline | 48 | 0.47 ± 0.11 | 52 | 0.46 ± 0.09 | .55 |
| Wk 12 | 47 | 0.47 ± 0.1 | 47 | 0.46 ± 0.09 | .91 | |
| BUN (mg/dL) | Baseline | 48 | 13.25 ± 3.04 | 52 | 13.35 ± 2.94 | .87 |
| Wk 12 | 47 | 13.09 ± 2.73 | 47 | 13.26 ± 2.71 | .76 | |
| Uric acid (mg/dL) | Baseline | 48 | 4.36 ± 0.96 | 52 | 4.48 ± 0.89 | .53 |
| Wk 12 | 47 | 4.35 ± 0.89 | 47 | 4.21 ± 0.92 | .45 | |
| Total cholesterol (mg/dL) | Baseline | 48 | 176.1 ± 27.9 | 52 | 175.2 ± 27.8 | .87 |
| Wk 12 | 47 | 172.9 ± 26.5 | 47 | 176.4 ± 25.8 | .51 | |
| Triglyceride (mg/dL) | Baseline | 48 | 107.3 ± 71.6 | 52 | 122.8 ± 85.3 | .33 |
| Wk 12 | 47 | 109.8 ± 72.6 | 47 | 103.1 ± 35.7 | .58 | |
| HDL cholesterol (mg/dL) | Baseline | 48 | 59.31 ± 14.7 | 52 | 54.46 ± 11.6 | .07 |
| Wk 12 | 47 | 56.98 ± 12.7 | 47 | 55.7 ± 10.6 | .60 | |
| LDL cholesterol (mg/dL) | Baseline | 48 | 97.06 ± 27.4 | 52 | 101.6 ± 23.6 | .38 |
| Wk 12 | 47 | 96 ± 26.2 | 47 | 100.9 ± 19.2 | .30 | |
| Estradiol (pg/mL) | Baseline | 37 | 7.16 ± 5.24 | 45 | 9.34 ± 17.26 | .46 |
| Wk 12 | 47 | 10 ± 11.35 | 47 | 8.59 ± 13.65 | .59 | |
ALT = alanine transaminase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, DAE = deer antler extract, HDL = high density lipoprotein, LDL = low density lipoprotein, N = number, SD = standard deviation, γ–GTP = gamma–glutamyl transferase.
Two-sample t-test
P < .05
3.2.2.3. Urinalysis
Regarding the pH (P = .15 and P = .33) and specific gravity values (P = .27 and P = .82), there were no significant differences between the DAE and control groups at baseline and week 12, respectively. Blood (P = .72 and P = .64) and protein (P = .84 and P = .09) levels were not significantly different in the proportion of undetected participants between the groups at baseline and week 12, respectively (Table 6). As for Glucose, all participants had normal results.
Table 6.
The urinalysis results at the baseline and wk 12.
| Parameters | DAE group (n = 48) | Control group (n = 52) | P value | |||
|---|---|---|---|---|---|---|
| N | Results | N | Results | |||
| pH (mean ± SD) | Baseline | 48 | 6.24 ± 0.79 | 52 | 6.03 ± 0.64 | .15† |
| Wk 12 | 47 | 6.31 ± 0.72 | 47 | 6.16 ± 0.77 | .33† | |
| Specific gravity (mean ± SD) | Baseline | 48 | 1.02 ± 0.009 | 52 | 1.02 ± 0.008 | .27† |
| Wk 12 | 47 | 1.02 ± 0.009 | 47 | 1.02 ± 0.008 | .82† | |
| Blood (n [%]) | Baseline | 48 | 40 (83.33%) | 52 | 40 (76.92%) | .72* |
| Wk 12 | 47 | 39 (82.98%) | 47 | 35 (74.49%) | .64* | |
| Protein (n [%]) | Baseline | 48 | 31 (64.58%) | 52 | 32 (61.54%) | .84* |
| Wk 12 | 47 | 26 (55.32%) | 47 | 36 (76.6%) | .09* | |
DAE = deer antler extract, N = number, SD = standard deviation.
Two-sample t-test.
Fisher exact test.
4. Discussion
Deer antlers, which can be continuously regenerated,[14] have been used in Korean medicine as Cervi parvum cornu based on their great tonifying effects. They are considered relatively safe because of their long history of use. However, as much as it has strong efficacy, there are also concerns about side effects that may occur if not used properly. In particular, there are significant changes in the pharmacokinetics of drugs in children as they grow and develop continuously. As the dose extrapolated from adults does not show the same response in children,[15] the reaction to herbal medicine intake should be observed more carefully. However, clinical studies on the safety of deer antlers in humans are scarce. Moreover, especially in the pediatric population, information on the safety of deer antlers is relatively more lacking because of difficulties in conducting clinical research. Therefore, this clinical study was conducted to accumulate a study base for DAE safety in children.
One hundred participants who passed the screening were randomly assigned to either the DAE or control group. Although the proportion of boys was higher in both groups, the difference was not significant. There were no significant differences between the groups in other demographic details and baseline data.
All classifications of causality, except “definitely not related,” were included in determining ADRs. Although the DAE group had a slightly higher incidence of ADR, there was no significant difference between the 2 groups. The ADRs were further classified based on the MedDRA system organ class. In both groups, ADRs categorized into “gastrointestinal disorders” or “skin and subcutaneous tissue disorders” were reported.
The gastrointestinal and skin-related symptoms observed in this study also appeared as ADRs in several other studies.[16,17] In a study that analyzed AEs in children and adults in various countries,[18] skin reactions were reported to be significantly higher in children than in adults. This may be due to differences in skin physiology between children and adults, and the fact that symptoms can be checked superficially. In addition, because drugs administered orally are absorbed into the body through the gastrointestinal tract, the associated symptoms are thought to be the most common. However, it cannot be ruled out that most people who report ADRs in pediatric patients are caregivers, and the types of reported clinical symptoms may be limited due to the patient lack of expressive ability.[19] The severity of ADRs during this study period was all mild, completely cured without sequelae, and there were no SADRs.
Depending on the individual characteristics of a child, laboratory test results may vary within the normal range or close to normal, which is clinically insignificant.
In the CBC, the baseline results for WBC, neutrophils, lymphocytes and basophils showed significant differences between the 2 groups, and basophils also showed differences at week 12. WBC, neutrophils, basophils, and lymphocytes can be influenced by factors such as infection, inflammation, surgery or trauma, stress, drugs, and nutritional status.[20] There was a statistically significant difference between groups in hematocrit at week 12, and factors including anemia and dehydration can affect hematocrit levels.[20] However, despite these differences, no clinical symptoms or abnormalities in other blood markers were observed. Both the baseline and 12-week results were within the normal range or a clinically insignificant range, suggesting that the differences observed in these specific parameters may not hold significant clinical importance.
In the biochemistry test, only total bilirubin had a significant difference within the normal range between the 2 groups at baseline. Total bilirubin may increase in liver disease, obstructive jaundice, hemolytic anemia and Gilbert syndrome.[20] However, by the end of the study, there was no difference between the groups.
Estradiol, a hormone marker, there was no significant difference between the 2 groups at both baseline and week 12. Elevated serum estradiol levels, which are associated with gonadotropin suppression, can be an indicator of peripheral precocious puberty caused by disorders such as ovarian cysts or tumors.[21] However, the findings of the present study provide evidence that the DAE does not increase the risk of peripheral precocious puberty regarding estradiol.
Urinalysis revealed no significant differences between the groups at baseline and week 12 for any of the markers. However, some participants reported proteinuria or hematuria above trace levels. Abnormal urine findings can be found in 1% to 14% of healthy students.[22] Hematuria appears in 0.5 to 2% of school-age children[23] and temporary hematuria can often be caused by fever, exercise, urinary tract infection, or trauma without any pathological significance.[24] Proteinuria may be a transient, functional finding in healthy children or a major indicator of an underlying renal disease. Generally, fever, physical labor, emotional stress, congestive heart failure, seizures, or hyperthyroidism do not indicate renal disease.[25]
One participant was found to have proteinuria over the trace level at both baseline and week 12; however all other blood and urine test markers were normal, and there were no symptoms suggestive of glomerular disease. When proteinuria and hematuria occur together, consultation with a pediatric kidney specialist is required, especially if there are signs of nephritis syndrome or systemic disease.[26] But nobody showed hematuria and proteinuria simultaneously. In addition, most participants with significant test results were found one-time only at baseline or week 12. Therefore, it is difficult to conclude whether the DAE affected the urine test results.
Therefore, the laboratory test results of the safety analysis set were normal or out of normal but within a clinically insignificant range. There was no significant difference between the 2 groups, and even when the parameters were found to be different, they were considered clinically insignificant.
To the best of our knowledge, this is the first clinical trial to assess the safety of DAE alone in pediatric populations. The significance of this study is even greater considering the difficulties of clinical research in children. The safety data for DAE obtained in this study will provide evidence to support subsequent studies.
This study has some limitations. First, all the participants in the DAE group were administered the same dose of DAE without considering their age and weight. Although safety was verified in all participants regarding ADRs and laboratory tests results under the conditions studied, the fact that the dosage was adjusted considering various factors in actual clinical settings was not reflected. Secondly, it is difficult to infer the safety of herbal medicines containing DAE, as DAE is often taken as a mixture of other herbal medicines. The accurate information on their interactions and potential toxicities is unknown.
5. Conclusion
In this study, DAE was found to be safe in terms of ADRs and laboratory parameters. Further studies are required to accumulate safety data on DAE dosage adjustment, interactions with other medicines.
Author contributions
Conceptualization: Gyu Tae Chang, Jin Yong Lee, Sun Haeng Lee.
Data curation: Hye Yeon Kim, Hae Sun Seo, Hee Ae Seo.
Investigation: Hye Yeon Kim, Hae Sun Seo, Tae Yun Doh, Sun Haeng Lee.
Methodology: Tae Yun Doh.
Project administration: Gyu Tae Chang, Sun Haeng Lee.
Visualization: Hee Ae Seo.
Supervision: Jin Yong Lee.
Writing – original draft: Hye Yeon Kim.
Writing – review & editing: Hye Yeon Kim, Hae Sun Seo, Hee Ae Seo, Tae Yun Doh, Gyu Tae Chang, Jin Yong Lee, Sun Haeng Lee.
Abbreviations:
- ADR
- adverse drug reaction
- AE
- adverse event
- CBC
- complete blood cell
- DAE
- deer antler extract
- IRB
- institutional review board
- PT
- preferred term
- SOC
- system organ class
- WBC
- white blood cell
This research was supported by the Korea Ginseng Co., Ltd., Daejeon, Republic of Korea [grant number: KGCANTLER2021].
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
How to cite this article: Kim HY, Seo HS, Seo HA, Doh TY, Chang GT, Lee JY, Lee SH. Safety of deer antler extract in children: A 12-week randomized controlled clinical trial. Medicine 2024;103:18(e37970).
Contributor Information
Hye Yeon Kim, Email: khyean1008@gmail.com.
Hae Sun Seo, Email: dmleh19@naver.com.
Hee Ae Seo, Email: dmleh19@naver.com.
Tae Yun Doh, Email: lbboy0420@naver.com.
Gyu Tae Chang, Email: gtchang@khu.ac.kr.
Jin Yong Lee, Email: civil011@khu.ac.kr.
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