Bis glycinate vs ascorbate

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The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country.

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.

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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

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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):

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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)


Mean (95%CI)

8.4

(8.16, 8.54)*

8.4

(8.21, 8.59)

8.5

(8.31, 8.72)



Mean (95%CI)

0.6

(0.46, 0.69)*

0.6

(0.50, 0.78)

0.7

(0.57, 0.84)


Mean (95%CI)

9

(8.73, 9.25)

9.1

(8.82, 9.37)

9.2

(8.88, 9.45)



Mean (95%CI)

1.2

(0.98, 1.45)

1.3

(1.07, 1.61)

1.4

(1.10, 1.61)


Mean (95%CI)

9.6

(9.24, 9.93)

9.7

(9.34, 10.07)

9.7

(9.35, 10.05)



Mean (95%CI)

1.8

(1.46, 2.15)

1.9

(1.58, 2.32)

1.9

(1.56, 2.23)


Mean (95%CI)

10.4

(9.89, 10.81)

10.6

(10.13, 11.05)

10.4

(9.99, 10.90)



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

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.

Bis glycinate vs ascorbate

Healthcare

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