Study to Test the Hypothesis of Non-inferior Efficacy and Safety of Ferrum Lek® (Iron (III) Hydroxide Polymaltosate), 100 mg Chewable Tablets (Lek d.d., Slovenia), as Compared With MALTOFER® (Vifor S.A., Switzerland), in Subjects With Mild and Moderate Iron Deficiency Anemia.

• Sponsor: Sandoz (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03993288
• Collaborator: (none)
• Enrollment: 267
• Locations: 18
• Arms: 2
• Actual Duration (Months): 11.7
• Patients Per Site: 14.8
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate non-inferiority for efficacy and safety of Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia), compared to MALTOFER® (Vifor S.A., Switzerland), in the treatment of patients with mild and moderate iron-deficiency anaemia.

Condition or Disease	Intervention/Treatment	Phase
Mild and Moderate Iron-deficiency Anaemia	Drug: Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia); Drug: MALTOFER® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Vifor S.A., Switzerland)	Phase 3

Detailed Description

This was a multi-centric, open-label, randomized, prospective, comparative, parallel-group, active-controlled, phase III clinical trial (in the Russian Federation).

The purpose of this study was to evaluate non-inferiority for efficacy and safety of Ferrum Lek® (iron (III) hydroxide polymaltosate), compared to MALTOFER®, in the treatment of patients with mild and moderate iron-deficiency anaemia.

Participants underwent screening for up to 7 days. Eligible participants were randomized in 1:1 ratio to two treatment arms.

Subjects in Group 1 received 2 tablets per day (200 mg) of chewable tablets Ferrum Lek® during or immediately after meals; once daily.

Subjects in Group 2 (reference product) received 2 tablets per day (200 mg) of chewable tablets Maltofer® during or immediately after meals; once daily.

The subjects received the medicinal products daily for 12 weeks. After the last scheduled study site visit, a follow-up visit (by phone) was scheduled 14 days after the completion of the active treatment period (day 98±2) to record any delayed adverse events.

Study Design

• Study Type: Interventional
• Actual Enrollment: 267 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter, Open-label Active-controlled Randomized Study of Efficacy and Safety of Ferrum Lek® (Iron (III) Hydroxide Polymaltosate), 100 mg Chewable Tablets (Lek d.d., Slovenia) Compared With Maltofer® (Iron (III) Hydroxide Polymaltosate), 100 mg Chewable Tablets (Vifor S.A., Switzerland), in Treatment of Patients With Mild and Moderate Iron-deficiency Anaemia.
• Actual Study Start Date: Jun 27, 2019
• Actual Primary Completion Date: Jun 18, 2020
• Actual Study Completion Date: Jun 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ferrum Lek Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Drug: Ferrum Lek® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Lek d.d., Slovenia); Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks
Active Comparator: MALTOFER Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks	Drug: MALTOFER® (iron (III) hydroxide polymaltosate), 100 mg chewable tablets (Vifor S.A., Switzerland); Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Blood Hemoglobin Level (g/L) [Baseline and Week 12]

   Changes in blood hemoglobin level (g/L) after 12-weeks of iron-deficiency anaemia treatment, a non-inferiority comparison, as compared with the baseline value (screening visit) between Ferrum Lek® and MALTOFER® groups

Secondary Outcome Measures

1. Change From Baseline in Serum Iron [Baseline, Week 4, 8 and 12]

   Change in average values of iron metabolism parameter serum iron during the treatment period

2. Change From Baseline in Transferrin [Baseline, Week 4, 8 and 12]

   Change in average values of iron metabolism parameter transferrin during the treatment period

3. Change From Baseline in Percent Transferrin Saturation [Baseline, Week 4, 8 and 12]

   Change in average values of iron metabolism parameter percent transferrin saturation during the treatment period

4. Change From Baseline in Ferritin [Baseline, Week 4, 8 and 12]

   Change in average values of iron metabolism parameter ferritin during the treatment period

5. Number of Participants With Response to the Therapy [Baseline and Week 12]

   Response to the therapy is determined as an increase in hemoglobin level by 20 g/L and more after 12-weeks of treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The signed and dated written informed consent prior to participation in the study.

2. Men and women aged 18 and older (by the time of screening).

3. Outpatients.

4. Diagnosed iron-deficiency anemia, based on two criteria:

5. hemoglobin level below 110 g/L (in men and women), but above 80 g/L,

6. serum ferritin levels below 30 µg/L.

Exclusion Criteria:

1. Administration of any iron-containing drugs during the last 3 months.

2. History of erythropoietin drugs administration.

3. Hypersensitivity to iron therapy (both Oral and/or IV administration) and other components of the study drugs.

4. Hormone therapy (including the use of androgens/anabolic steroids) or administration of drugs that inhibit blood formation, less than 3 months before the start of the study.

5. History of severe allergic reactions or drug intolerance.

6. Fructose intolerance, glucose-galactose malabsorption syndrome, and sucrase-isomaltase deficiency.

7. Pregnant or lactating women, or women intending to become pregnant during the study.

8. Failure of iron therapy for iron-deficiency anaemia in a subject's past medical history.

9. Heme metabolism disorders (e.g., sideroachrestic anaemia, lead anaemia, thalassaemia).

10. Iron overload including haemochromatosis and hemosiderosis

11. Other causes of anemia, apart from iron deficiency, including:

12. Haemolysis (determined as per analyses results at screening, or as per anamnestic data),

13. Vitamin B12 and folic acid deficiency (as per the screening data),

14. Chronic kidney disease (creatinine clearance at screening is below 90 ml/min (based on Cockcroft-Gault Formula)),

15. Systemic connective tissue diseases, chronic infectious diseases requiring regular therapy (as per the past medical history), and other conditions which may, in the investigator's opinion, be accompanied by anaemia of chronic diseases.

16. Dysfunction of the thyroid gland (based on the data obtained at screening).

17. Laboratory and clinical signs of an active inflammatory process for 10 days before screening.

18. AST, ALT, and total bilirubin levels exceeding the upper limit of normal 1.5 times and more.

19. Clinically apparent hypothyroidism, in the investigator's opinion.

20. Malignant diseases, including blood and lymphoid tissue disorders (leukemia, Hodgkin disease, myelodysplastic syndrome, myeloma, etc.) at screening or in the past medical history, provided that the remission was less than 5 years before screening.

21. Signs of bone marrow aplasia at screening or history of bone marrow aplasia.

22. The necessity of parenteral iron therapy, i.e. the following cases:

23. impaired absorption in case of an intestinal pathology (enteritis, coeliac disease, malabsorption, small intestinal resection, stomach resection, including the duodenum);

24. exacerbation of gastric or duodenal ulcer;

25. the necessity of quick iron saturation, e.g. in patients with iron-deficiency anaemia with upcoming surgery;

26. continuous vast blood loss and other causes, at the discretion of the investigator.

27. Known presence of an active infection caused by Helicobacter pylori. In case of presence of Helicobacter pylori, a subject may be enrolled after eradicative therapy.

28. Concomitant diseases and conditions, which, in the investigator's opinion, pose risk to a subject's safety in case of his/her participation in the study, or able to affect the safety data analysis in case of exacerbation of this disease/condition during the study, including:

29. Myocardial infarction or stroke within 6 months before screening.

30. Unstable angina;

31. Severe arrhythmia, not controlled by drug therapy;

32. Decompensated diabetes mellitus;

33. Nephrological disorders;

34. Other significant diseases, at the discretion of the investigator.

35. HIV infection (as per the screening data or the results of analysis performed within 6 months before screening).

36. Known or suspected drug or alcohol abuse for the last 2 years.

37. Suspected poor adherence of a subject (e.g., due to mental disorders).

38. Participation in any clinical drug studies less than 3 months before the study.

39. Blood donation / blood transfusion within 30 days prior to screening or planned blood transfusion at time of screening.

40. History of smoking, unless leave off smoking > 6 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sandoz Investigative Site	Krasnogorsk		Russian Federation	143408
2	Sandoz Investigative Site	Moscow		Russian Federation	119121
3	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	188643
4	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	191186
5	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	192177
6	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	193232
7	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	194354
8	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	194356
9	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	195197
10	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	196143
11	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	197706
12	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	198207
13	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	198328
14	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	199178
15	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	199226
16	Sandoz Investigative Site	Saint-Petersburg		Russian Federation	199406
17	Sandoz Investigative Site	Smolensk		Russian Federation	214019
18	Sandoz Investigative Site	Yaroslavl		Russian Federation	150003

Sponsors and Collaborators

• Sandoz

Investigators

• Study Director: Sandoz, Sandoz

Study Documents (Full-Text)

• Study Protocol - Mar 20, 2019
• Statistical Analysis Plan - Apr 6, 2020

More Information

Publications

None provided.

• Responsible Party: Sandoz
• ClinicalTrials.gov Identifier: NCT03993288
• Other Study ID Numbers: TE_005_FER_CHT
• First Posted: Jun 20, 2019
• Last Update Posted: Jul 12, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sandoz: Ferrum Lek® (iron (III) hydroxide polymaltosate); mild and moderate iron-deficiency anaemia
• Additional relevant MeSH terms: Anemia; Anemia, Iron-Deficiency; Deficiency Diseases; Iron

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from 18 sites in the Russian Federation.
Pre-assignment Detail	Participants were randomized in 1:1 ratio to two treatment arms.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Period Title: Overall Study
STARTED	133	134
Intention-to-treat (ITT) Population	123	129
Safety Analysis Set	133	134
COMPLETED	123	129
NOT COMPLETED	10	5

Baseline Characteristics

Arm/Group Title	Ferrum Lek	MALTOFER	Total
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks	Total of all reporting groups
Overall Participants	133	134	267
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	39.68	38.16	38.92
Sex: Female, Male (Count of Participants)
Female	124 93.2%	125 93.3%	249 93.3%
Male	9 6.8%	9 6.7%	18 6.7%
Race/Ethnicity, Customized (Count of Participants)
Asian	2 1.5%	2 1.5%	4 1.5%
Caucasian	131 98.5%	132 98.5%	263 98.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Blood Hemoglobin Level (g/L)
Description	Changes in blood hemoglobin level (g/L) after 12-weeks of iron-deficiency anaemia treatment, a non-inferiority comparison, as compared with the baseline value (screening visit) between Ferrum Lek® and MALTOFER® groups
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population included all randomized participants who were administered at least one dose of the investigational product or comparator and who had hemoglobin level data both before and after treatment with the investigational product and the reference product.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Measure Participants	123	129
Mean (Standard Deviation) [g/L]	18.33 (15.05)	18.52 (14.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ferrum Lek, MALTOFER
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was considered confirmed if the upper bound of the two-sided 95% confidence interval for the mean value calculated by the least squares method did not exceed the predetermined boundary of non-inferiority of 5 g/L
Statistical Test of Hypothesis	p-Value	0.0032
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -4.86 to 4.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Serum Iron
Description	Change in average values of iron metabolism parameter serum iron during the treatment period
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population included all randomized participants who were administered at least one dose of the investigational product or comparator and who had hemoglobin level data both before and after treatment with the investigational product and the reference product.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Measure Participants	123	129
Week 4	1.76 (7.35)	3.42 (6.57)
Week 8	4.09 (9.62)	4.34 (9.19)
Week 12	5.16 (9.56)	6.12 (8.28)

3. Secondary Outcome

Title	Change From Baseline in Transferrin
Description	Change in average values of iron metabolism parameter transferrin during the treatment period
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population included all randomized participants who were administered at least one dose of the investigational product or comparator and who had hemoglobin level data both before and after treatment with the investigational product and the reference product.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Measure Participants	123	129
Week 4	-0.15 (0.31)	-0.14 (0.38)
Week 8	-0.22 (0.41)	-0.22 (0.41)
Week 12	-0.24 (0.41)	-0.25 (0.43)

4. Secondary Outcome

Title	Change From Baseline in Percent Transferrin Saturation
Description	Change in average values of iron metabolism parameter percent transferrin saturation during the treatment period
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population included all randomized participants who were administered at least one dose of the investigational product or comparator and who had hemoglobin level data both before and after treatment with the investigational product and the reference product.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Measure Participants	123	129
Week 4	2.46 (5.82)	4.44 (8.04)
Week 8	8.25 (12.54)	5.47 (9.45)
Week 12	7.27 (12.02)	8.03 (10.14)

5. Secondary Outcome

Title	Change From Baseline in Ferritin
Description	Change in average values of iron metabolism parameter ferritin during the treatment period
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population included all randomized participants who were administered at least one dose of the investigational product or comparator and who had hemoglobin level data both before and after treatment with the investigational product and the reference product.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Measure Participants	123	129
Week 4	3.48 (11.2)	7.35 (33.76)
Week 8	4.9 (14.72)	4.49 (15.42)
Week 12	7.62 (20.24)	6.55 (15.87)

6. Secondary Outcome

Title	Number of Participants With Response to the Therapy
Description	Response to the therapy is determined as an increase in hemoglobin level by 20 g/L and more after 12-weeks of treatment
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) population included all randomized participants who were administered at least one dose of the investigational product or comparator and who had hemoglobin level data both before and after treatment with the investigational product and the reference product.

Arm/Group Title	Ferrum Lek	MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks	Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
Measure Participants	123	129
Count of Participants [Participants]	59 44.4%	56 41.8%

Adverse Events

Time Frame	Adverse Events were collected for 14 weeks (12 weeks treatment period plus 2 weeks follow up).
Adverse Event Reporting Description	Any signs or symptoms that occurred for 14 weeks (12 weeks treatment period plus 2 weeks follow up).
Arm/Group Title	Ferrum Lek		MALTOFER
Arm/Group Description	Participants received Ferrum Lek® 2 tablets daily (200 mg) for 12 weeks		Participants received MALTOFER® 2 tablets daily (200 mg) for 12 weeks
All Cause Mortality
	Ferrum Lek		MALTOFER
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/133 (0.8%)		0/134 (0%)
Serious Adverse Events
	Ferrum Lek		MALTOFER
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/133 (1.5%)		0/134 (0%)
Nervous system disorders
Encephalopathy	1/133 (0.8%)		0/134 (0%)
Reproductive system and breast disorders
Menometrorrhagia	1/133 (0.8%)		0/134 (0%)
Other (Not Including Serious) Adverse Events
	Ferrum Lek		MALTOFER
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/133 (40.6%)		47/134 (35.1%)
Gastrointestinal disorders
Constipation	8/133 (6%)		7/134 (5.2%)
Diarrhoea	13/133 (9.8%)		9/134 (6.7%)
Stool discoloration	26/133 (19.5%)		20/134 (14.9%)
Dyspepsia	6/133 (4.5%)		7/134 (5.2%)
Abdominal pain	9/133 (6.8%)		6/134 (4.5%)
Nausea	7/133 (5.3%)		5/134 (3.7%)
Infections and infestations
Nasopharyngitis	4/133 (3%)		8/134 (6%)
Nervous system disorders
Headache	5/133 (3.8%)		8/134 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.