Bis glycinate vs ascorbate

Clinical Trials result

1. 1
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Study No.: OTH114204
Title: A multicentre, randomized, laboratory-blinded, parallel-group study to
demonstrate the efficacy and tolerability of ferrous bisglycinate chelate in iron
deficiency anaemia and to compare these with those of ferrous ascorbate.

Rationale: Iron deficiency anaemia (Haemoglobin, Hb < 12gm/dl) is one of
India’s major public health problems particularly in women. Effective control of
iron deficiency anaemia decreases the incidence of fatigue, bodyache, headache,
lack of concentration and menstrual complications. Iron bisglycine chelate has
been used successfully to treat iron deficiency anaemia and is also a well
tolerated therapy. Use of ferrous bisglycinate chelate, one tablet daily as a
nutritional supplement is well established in India. For treatment of iron
deficiency anaemia, some women may need 1 tablet/day, while some may need
2tablets/day. In India, ferrous ascorbate, 1 tablet daily is a widely accepted form
of treatment for iron deficiency anaemia. The primary purpose of this study was
to demonstrate the efficacy and tolerability profile of ferrous bisglycinate chelate
to support the registration of this product as a ‘drug’ in India. We also compared
the efficacy and tolerability profile of ferrous bisglycinate chelate with ferrous
ascorbate in this study.


Phase: III
Study Period: 12 Oct 2010 to 17 Feb 2011
Study Design: This was a multicentre, randomized, laboratory-blinded, parallel-
group study. Randomization was stratified for each center in blocks of 6
subjects. Non pregnant women with iron deficiency anaemia were screened for
the study. Those who met the entry criteria were randomized to either ferrous
bisglycinate chelate, 60mg 1 tablet/day or 2 tablets/day or ferrous ascorbate,
100mg 1 tablet/day for 8 weeks. At fortnightly visits, blood was collected for Hb
(to evaluate efficacy), adverse events were documented (to evaluate tolerability),
and the investigational drugs were dispensed and reasons for non compliance
were recorded. The total study duration of the treatment period was 8-weeks and
included 6 clinic visits [Visit 0 (screening), Visit 1 (randomization, ≤ 5 days
from screening), Visit 2 (2 weeks ± 2 days), Visit 3 (4 weeks ± 2 days), Visit 4
(6 weeks ± 2 days), Visit 5 (8 weeks ± 2 days)].

Centres: Lucknow (2), Bareilly (1), Surat (1), Nagpur (1), Pune (1), Thane (1)
Indication: Iron deficiency anaemia
Treatment:
A: Ferrous bisglycinate chelate, 1 tablet of 60 mg once daily after dinner.
B: Ferrous bisglycinate chelate, 1 tablet each of 60mg, after breakfast and after
dinner.

2. 2
C: Ferrous ascorbate, 1 tablet of 100mg daily after dinner.

Objectives: Primary:
To estimate the mean rise in haemoglobin level in subjects with iron deficiency
anaemia after 8 weeks of treatment (vs. baseline) with ferrous bisglycinate
chelate (1 tablet and 2 tablets daily).
Secondary:
1. To compare the mean rise in haemoglobin in subjects with iron
deficiency anaemia after 8 weeks treatment with ferrous bisglycinate
chelate, 1 tablet and 2 tablets daily vs. ferrous ascorbate 1 tablet daily.
2. To compare the average rate of rise of haemoglobin during 8 weeks of
treatment with ferrous bisglycinate chelate 1 tablet daily, ferrous
bisglycinate chelate 2 tablets daily and ferrous ascorbate 1 tablet daily.
3. To compare the proportion of subjects who achieved a target Hb ≥
12gm/dl after 8 weeks of treatment with ferrous bisglycinate chelate 1
tablet daily, ferrous bisglycinate chelate 2 tablets daily and ferrous
ascorbate 1 tablet daily.
4. To compare the % incidence of gastrointestinal side effects during 8
weeks treatment with ferrous bisglycinate chelate 1 tablet daily, ferrous
bisglycinate chelate 2 tablets daily and ferrous ascorbate 1 tablet daily.

Primary Outcome/Efficacy Variable: The primary endpoint was the rise in Hb
from baseline after 8 weeks of treatment in each ferrous bisglycinate chelate
group (1 tablet/day and 2 tablets/day).

Secondary Outcome/Efficacy Variable(s): The secondary endpoints were the
difference in the average change in Hb at 8 weeks, difference in proportion of
subjects who achieved a target Hb ≥12gm/dl at 8 weeks, and difference in the
rate of rise of Hb during 8 weeks therapy between 2 dosing regimens of ferrous
bisglycinate chelate (1 tablet/day and 2 tablets/day) and ferrous ascorbate 1
tablet/day. Safety endpoint was the difference in % incidence of gastrointestinal
side effects at 8 weeks between 2 dosing regimens of ferrous bisglycinate chelate
(1 tablet/day and 2 tablets/day) and ferrous ascorbate 1 tablet/day.

Statistical Methods: A sample size of 76 completed subjects in each treatment
group (i.e. total number = 76 x 3 = 228) was adequate to achieve the primary
objective in this study. With allowance for dropouts, suggested sample size was
90 per group (total 270). All efficacy analyses were done on per protocol (PP)
population (n=252, A = 82, B=83, C= 87 ) which was more than the required
number to achieve our primary objective. Safety analysis was done on intention
to treat (ITT) population (n=270). Statistical tests included the paired t-test with
95% CI, ANOVA, superiority and inferiority tests, Repeated Measure ANOVA
model, regression analysis, Chi-square test or Fisher’s exact test as appropriate.

Study Population: Female outpatients between 18 to 55 years of age, using an
effective method of contraception if sexually active, with iron deficiency

3. 3
anaemia whose Hb was 6-9 gm/dl, who had not received any hematinic for 3
months prior to enrollment and who had no desire to conceive for the next 3
months were screened for this study.
Subjects with obvious internal (e.g. stool test positive for occult blood) or
external bleeding that was clinically significant in the opinion of the investigator
were excluded from the study as these factors could affect the Hb levels and
response to therapy.
We excluded subjects with a medical history of current haematological
disorders, thyroid dysfunction, chronic renal disease, malabsorption syndrome,
haemochromatosis, haemosiderosis, hypochlorhydria, achlorhydria, gastrectomy
or gastrojejunostomy as these disorders could affect the response to the study
medication.

A B C
Number of Subjects:
Planned, N 90 90 90
Randomised, N 89 91 90
Completed, n (%) 87 (97.8) 88 (96.7) 89 (98.9)
Total Number Subjects Withdrawn, N (%) 2 (2.2) 3 (3.3) 1(1.1)
Withdrawn due to Adverse Events n (%) 0 1(33.3) 0
Withdrawn due to Lack of Efficacy n (%) 0 0 0
Withdrawn for other reasons n (%) 2 (100) 2 (66.7) 1(100)
Demographics A B C
N (ITT) 89 91 90
Females 89 91 90
Mean Age, years (SD) 33.2
(10.2)
34.8
(10.1)
34
(10)
Mean Height, cm (SD) 152.1
(7.4)
151.8
(5.9)
151.6
(4.9)
Mean Weight, kg (SD) 52
(7.6)
52.8
(8.2)
52.8
(6.4)
Mean Hb, gm/dl (SD) 7.7
(0.8)
7.7
(0.7)
7.8
(0.8)
Mean Serum ferritin, μg/L (SD) 9.9
(3.8)
10
(3.6)
9.9
(3.7)
Concomitant medication, n (%) 49 (55.1) 53 (58.2) 47 (52.2)
Primary Efficacy Results:
A B
Baseline Hb (gm/dl)
Mean (95%CI)
7.8
(7.61, 7.95)
7.8
(7.60, 7.91)

Hb (gm/dl) at Week 8
Mean (95%CI)
10.4
(9.89, 10.81)
10.6
(10.13, 11.05)

Average rise in Hb (gm/dl)
from baseline up to Week 8
Mean (95%CI)
2.6
(2.12, 3.03)
2.8
(2.36, 3.31)


p-value <0.0001 <0.0001
Secondary Outcome Variable(s):

4. 4
A B C
Baseline Hb (gm/dl)
Mean (95%CI)
7.8
(7.61, 7.95)
7.8
(7.60, 7.91)
7.8
(7.63, 7.98)
Hb (gm/dl) at Week 2
Mean (95%CI)
8.4
(8.16, 8.54)*

8.4
(8.21, 8.59)

8.5
(8.31, 8.72)

Average rise in Hb (gm/dl)
from baseline up to Week 2
Mean (95%CI)
0.6
(0.46, 0.69)*
0.6
(0.50, 0.78)
0.7
(0.57, 0.84)
Hb (gm/dl) at Week 4
Mean (95%CI)
9
(8.73, 9.25)

9.1
(8.82, 9.37)

9.2
(8.88, 9.45)

Average rise in Hb (gm/dl)
from baseline up to Week 4
Mean (95%CI)
1.2
(0.98, 1.45)
1.3
(1.07, 1.61)
1.4
(1.10, 1.61)
Hb (gm/dl) at Week 6
Mean (95%CI)
9.6
(9.24, 9.93)

9.7
(9.34, 10.07)

9.7
(9.35, 10.05)

Average rise in Hb (gm/dl)
from baseline up to Week 6
Mean (95%CI)
1.8
(1.46, 2.15)
1.9
(1.58, 2.32)
1.9
(1.56, 2.23)
Hb (gm/dl) at Week 8
Mean (95%CI)
10.4
(9.89, 10.81)
10.6
(10.13, 11.05)
10.4
(9.99, 10.90)
Average rise in Hb (gm/dl)
from baseline up to Week 8
Mean (95%CI)
2.6
(2.12, 3.03)
2.8
(2.36, 3.31)

2.6
(2.19, 3.09)

Proportion of subjects who achieved a target
Hb ≥ 12 gm/dl after 8 weeks of treatment, N
(%)
28
(34.2%)
30
(36.1%)
29
(33.3%)
*N=81
An on therapy adverse event (AE) or serious adverse event (SAE) was defined as
an AE with onset on or after the start date of study medication but not later than
one day after the last date of study medication.



A B C
Most Frequent Adverse Events – On-Therapy n (%) n (%) n (%)
Subjects with any AE(s), n (%) 8/89
(9%)
12/91
(13.2%)
12/90
(13.3%)
Gastrointestinal disorders 6/89
(6.7%)
9/91
(9.9%)
10/90
(11.1%)
Infections and infestations 1/89
(1.1%)
1/91
(1.1%)
2/90
(2.2%)
General disorders and administration site
conditions
1/89
(1.1%)
1/91
(1.1%)
1/90
(1.1%)

5. 5
Musculoskeletal and connective tissue disorders 1/89
(1.1%)
1/91
(1.1%)
0
Reproductive system and breast disorders 1/89
(1.1%)
0 0
Respiratory, thoracic and mediastinal disorders 1/89
(1.1%)
0 0
Serious Adverse Events - On-Therapy
A B C
Subjects with non-fatal SAEs, n (%) 0 0 0
Subjects with fatal SAEs, n (%) 0 0 0

Conclusion:
There was no statistical difference between ferrous bisglycinate chelate 60mg/day and
ferrous bisglycinate chelate 120mg/day for the primary efficacy variable. In the ferrous
bisglycinate chelate 60mg/day treatment group, 8 subjects reported adverse events, in the
ferrous bisglycinate chelate 120mg/day treatment group, 12 subjects reported adverse
events and in the ferrous ascorbate 100mg/day treatment group, 12 subjects reported
adverse events. The most frequently reported adverse event was gastrointestinal disorders
in all the three treatment groups.