A Study to Demonstrate the Efficacy and Tolerability of Ferrous Bisglycinate Chelate in Iron Deficiency Anaemia and to Compare These With Those of Ferrous Ascorbate.

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 2 tablets/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 is to demonstrate the efficacy and tolerability profile of ferrous bisglycinate chelate to support the registration of this product as a 'drug' in India. Comparative data between ferrous bisglycinate chelate and ferrous ascorbate will also augment our existing knowledge, which will further support appropriate use of ferrous bisglycinate chelate for the treatment of iron deficiency anaemia. Study design and patient population: This will be a multicentre, randomized, laboratory-blinded, parallel- group study. It is projected that the study will randomize 270 women (90 subjects in each treatment arm) with iron deficiency anaemia (Hb 6-9 gm/dl + serum Ferritin \<15 μg/l) to either ferrous bisglycinate chelate 1 or 2 tablets/day, or ferrous ascorbate 1 tablet/day for 8 weeks. At fortnightly visits, blood will be collected for Hb (to evaluate efficacy), adverse events will be documented (to evaluate tolerability), the investigational drugs will be dispensed and reasons for non compliance will be recorded. Study endpoints: The primary endpoint is defined as the rise of Hb from baseline after 8 weeks of treatment in each ferrous bisglycinate chelate group (1 tablet/day and 2 tablets/day). The secondary endpoints include the difference in the average change in Hb, difference in the rate of rise of Hb, difference in the proportion of patients who achieve a target Hb ≥12gm/dl and difference in the % incidence of gastrointestinal side effects during 8 week therapy with 2 dosing regimens of ferrous bisglycinate chelate (1 tablet/day and 2 tablets/day) and ferrous ascorbate 1 tablet/day.

Rationale Iron deficiency is the most common form of malnutrition globally. In India, nearly 70% of women are estimated to be iron deficient. Iron deficiency anemia (IDA, Hb \<12gm/dl) is a very late manifestation of iron deficiency. IDA is a consequence of decreased iron intake, increased iron loss from the body or increased iron requirements Blood loss during menstruation can predispose women to have poor iron stores and the presence of excess menstrual bleeding can contribute to the development of IDA in women. Patients with IDA usually present with fatigue, headache, bodyache, paraesthesia and lack of concentration. IDA can cause menorrhagia, which in turn can aggravate IDA. With severe anemia, there may be amenorrhoea as well.

Iron deficiency anaemia is often treated with iron tablets such as ferrous sulphate, ferrous fumarate and ferrous gluconate. It usually takes about 6-10 weeks for Hb to return to normal after initiation of oral iron therapy. Although efficacious from a haematological point of view, most of these therapies are associated with limiting gastrointestinal side effects (e.g. nausea, vomiting, constipation, diarrhoea and abdominal pain), which eventually reduce patient compliance.

Among the recent alternatives, iron bisglycine chelate has been used successfully to treat iron deficiency anaemia and is also a well tolerated therapy.

Use of ferrous bisglycinate chelate (each tablet contains 60mg of elemental iron as ferrous bisglycinate chelate, 1 mg folic acid, 5 mcg cyanocobalamin and 15 mg zinc bis-glycinate), 1 tablet daily is well established as a nutritional supplement in India. However, for treatment of iron deficiency anaemia, some women may need 1 tablet/day, while some may need 2 tablets /day.

In India, ferrous ascorbate tablets (each tablet contains 100 mg elemental iron as ferrous ascorbate, with 1 mg folic acid) in the recommended dose of 1 tablet daily are a widely accepted form of treatment for iron deficiency anaemia.

The primary purpose of this study is to demonstrate the efficacy and tolerability profile of ferrous bisglycinate chelate to support the registration of this product as a 'drug' in India. Comparative data between ferrous bisglycinate chelate and ferrous ascorbate will also augment our existing knowledge, which will further support the use of ferrous bisglycinate chelate for the treatment of iron deficiency anaemia.

Objective(s)

Primary:

To estimate the mean rise in haemoglobin level in patients 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 patients 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 patients who achieve 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.

Study Design This will be a multicentre, randomized, laboratory-blinded, parallel-group study. It is projected that the study will randomize 270 women (90 subjects in each treatment arm) with iron deficiency anaemia (Hb 6-9 gm/dl + serum Ferritin \<15 μg/l) to either ferrous bisglycinate chelate 1 tablet/day, ferrous bisglycinate chelate 2 tablets/day or ferrous ascorbate 1 tablet/day for 8 weeks. At fortnightly visits, blood will be collected for Hb (to evaluate efficacy), adverse events will be documented (to evaluate tolerability), the investigational drugs will be dispensed and reasons for non compliance will be recorded.

The total study duration consists of an 8-week treatment period and will involve 6 clinic visits.

Study Endpoints/Assessments Primary Endpoint(s) Rise of haemoglobin from baseline to 8 weeks in each ferrous bisglycinate chelate group (1 tablet daily and 2 tablets daily).

Secondary Endpoint(s)

1. The difference in the average change in Hb from baseline to 8 weeks with ferrous bisglycinate chelate 1 and 2 tablets daily, and ferrous ascorbate 1 tablet daily.
2. The difference in the average rate of rise of Hb 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. The difference in proportion of patients who achieve 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. The difference in % 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.

Eligibility Criteria:
Inclusion Criteria

Subjects eligible for enrolment to the study must meet all of the following criteria:

1. Signed and dated written informed consent is obtained prior to participation.
2. Female outpatients between 18 to 55 years of age and using effective method of contraception if sexually active.
3. Non use of any iron supplement for 3 months prior to enrolment to the study.
4. Presence of iron deficiency anaemia: low haemoglobin (Hb 6-9 gm/dl) + low serum ferritin (\<15 μg/l).
5. No occult blood in stool.
6. Able to comply with the requirements of the protocol.
7. Subjects should have a valid telephone contact.

Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled to the study:

1. Pregnancy (confirmed by urine dipstick method)
2. Desire to conceive within the next 3 months including patients who are receiving treatment to facilitate conception.
3. Lactating women.
4. Medical history of current hematological disorders other than iron deficiency anaemia (e.g. aplastic anaemia, megaloblastic anaemia, sideroblastic anaemia, pernicious anaemia, thalassemia, sickle cell anaemia, etc.).
5. Medical history of thyroid dysfunction.
6. Medical history of chronic renal disease.
7. Medical history of malabsorption syndrome, haemochromatosis and haemosiderosis, hypochlorhydria, achlorhydria, gastrectomy, gastrojejunostomy.
8. Inability to withhold prohibited medication.
9. Obvious internal or external bleeding as documented by medical history and/or examination if considered clinically significant in the opinion of the investigator.
10. Clinically significant abnormality in laboratory reports and/or ECG.
11. Medical history of hepatitis B, hepatitis C and/or exposure to HIV.
12. Serious, uncontrolled disease (other than thyroid dysfunction and chronic renal disease) including serious psychological disorders likely to interfere with the study and/or likely to cause death within the study period.
13. Participation in another clinical trial in the last 8 weeks before entry to Visit 0.
14. Evidence of alcohol or drug abuse, that may, in the opinion of the investigator interfere with study compliance or prevent understanding of the objectives, investigational procedures or possible consequences of the study.
15. Known or suspected hypersensitivity to iron or any of the components of ferrous bisglycinate chelate or ferrous ascorbate tablets.