Pharmacy and Poisons Board
Protocol No: ECCT/20/11/04 Date of Protocol: 31-03-2020
Study Title:

Assessments of the EFficacy, the onset-of-Action and the Safety of Tot'héma® in adults with moderate iron deficiency anaemia

Not Amended.

Protocol Amendment 2

Dear Sir/Madam,

 

Following your approval for this study on 27th February 2021, we would like to submit the attached amendment to this protocol. We have listed below the amendments and their rationale and tracked the same in the body of the protocol.

 

1.       Selection and inclusion criteria update

We propose the modification of selection criterion #1 and inclusion criterion #2 in relation to the haemoglobin level in protocol V3.0 dated February 10, 2022 as follow:

a)      Selection criterion: Patient with moderate anaemia defined as 8 g/dL ≤ haemoglobin level (≤ 9

g/dL) ≤ 10 g/dL on the last hematological test performed within 7 days before screening visit

b)      Inclusion criteria: Patient with a confirmation of moderate anaemia defined as 8 g/dL ≤ haemoglobin level (≤ 9 g/dL) ≤ 10 g/dL on the last haematological test performed within 7 days before inclusion visit

After over a year of recruitment, the selection and inclusion criteria based on the haemoglobin level (8.0 g/dL ≤ Haemoglobin ≤ 9.0 g/dL) prove to be too restrictive for inclusion of patients in this study. Indeed, the number of patients with moderate iron deficiency anaemia between 8.0 g/dL and 9.0 g/dL and without any exclusion criteria is too limited in all involved countries. Only 5 patients have been included in the study in France, 19 in Bulgaria and 13 in Kenya, during the last 12 months. As a reminder, TOT'HEMA is contraindicated in patients with anaemia not resulting from a strict iron deficiency, therefore patients presenting with an inflammatory anaemia, haemolytic anaemia and megaloblastic anaemia are excluded.

 

The vast majority of patients identified with iron deficiency anaemia between 8.0g/dL and 9.0g/dL also presented with an associated inflammatory syndrome, cancerous pathology or active bleeding, and are therefore not part of the target population of the study.

Following discussions with the study coordinator and various investigators in France, Bulgaria and Kenya, and the reasons for non-inclusion reported, we propose in this protocol update, to expand this criterion with a haemoglobin level between 8.0 g/dL and 10.0 g/dL.

 

The modification of this selection and inclusion criteria does not modify patient safety, the other exclusion criteria remaining unchanged except the exclusion criterion #3 (described below). In addition, moderate anaemia remains the subject of the study given that according to the WHO classification, moderate anaemia corresponds to a haemoglobin level between 8 and 10 g/dL.

 

2.Exclusion criteria #3 update

We propose the update of the exclusion criterion #3 in the V3.0 protocol dated February 10, 2022.

  1. Patient with benign or malignant neoplastic tumour

 

The modification of this exclusion criterion aims to allow the inclusion of patients presenting with a non-malignant cancerous pathology that does not constitute a contraindication to treatment with oral iron.

 

3.Removal of stratification by gender and by geographical area

Due to the recruitment difficulties related to the selection, inclusion and exclusion criteria as well as the global health crisis, and in order to allow the recruitment of patients within an acceptable time frame, we propose the elimination of stratification by geographical area and by sex.

 

Based on the current inclusions, in 1 year, 37 patients were included, including 24 in France (5) and Bulgaria (19) and 12 in Kenya. Among these 37 patients, only 6 are men (i.e. 16%), against 34% initially anticipated.

 

The removal of stratification leads to update number of patients required for the evaluation of the primary endpoint. Based on the same initial statistical assumptions, the number of subjects is now estimated at 121 patients (including 20% of non-assessable).

 

This modification does not affect the validity of the study, however, the suppression of stratification by sex will no longer guarantee the minimum number of patients allowing a relevant analysis on the male population alone. However, the protocol provides a subgroup analysis if relevant.

 

4.Reference safety information update

The sponsor, Innotech International Laboratory, has updated the French SmPC of TOT'HEMA in OCT 2021. This update impacts several sections of the SmPC especially the section 4.8 adverse effects.

 

Following the update of the reference TOT'HEMA SmPC used for the study FAST, the reference safety information is also updated in the FAST study protocol.

 

5.Recruitment prolongation

Due to the recruitment difficulties encountered in 2021 due to the health situation and an overly restrictive inclusion criteria, we are proposing an extension of the recruitment period until the end of 2022.

The modification of the inclusion criteria mentioned above as well as the opening of 4 additional sites in Bulgaria should help to achieve the new recruitment objectives.

 

6. Protocol version updates

We have also updated both protocols from Version 2.0 to version 3.0 Site Specific Addendum 3.0 dated 09MAY2022

 

FAST Protocol 3.0 dated 10FEB2022  and Site Specific Addendum 3.0 dated 09MAY2022

We have uploaded all documents in the notification tab.

 

 

Dear Sir/Madam,

 

Following your approval for this study on 27 Feb 2021, we would like to submit an amendment to this protocol.

 

  1. Protocol version updates

 We have updated protocol from V3.0 dated of 10-FEB-2022 based on Core Version 4.0 of dated 24 Jan 2022 to V4.0 dated of 21-NOV-2022 (based on Core Version 5.0 dated of 21-NOV-2022).

 

 This update include:

  1. Modification of the Sponsor’s contact details and of the CRO personnel on pages 2 and 5.
  2.  Total duration of the study postponed to Third quarter 2023 as already mentioned in the protocol clarification memo sent on 21 Dec 2022 on page 10.

Indeed, the recruitment in FAST study has encountered some difficulties, and the recruitment objectives are not yet achieved. On 31 Dec 2022 we were around 75% of recruitment objectives. In order to achieve the objectives in terms of recruitment we have updated the protocol to update the period of recruitment with a Last Patient Last Visit in October 2023.

 

  1.  Update of the SmPC dated of 15 Oct 2022 from SmPC dated 10 Aug 2022 as already mentioned and submitted in the protocol clarification memo submission on 21 Dec 2022 on pages 67 to 80. 

 

2. Attachment:

Please find enclosed:

 

  1. FAST_Protocol_BasedOnCoreV5.0_AdaptedToKE V4.0_20221121_ENG_signed.

 

  1. FAST_Protocol_BasedOnCoreV5.0_AdaptedToKE V4.0_20221121_ENG_TC version showing the modifications between Protocol V3.0 of 10Feb2022 and Protocol V4.0 of 21Nov2022.

 

  1. Ethics Committee approval dated 17 May 2023 for protocol version 4.0 dated 21 Nov 2022 based on core version 5.0 dated 21 Nov 2022

 

Please contact me if there are any further questions or clarifications needed. Thank you for your prompt and careful attention to our protocol.

 

Looking forward to your acknowledgement

 

Sincerely,

Dr Fredrick Odhiambo Otieno

Study Objectives:

Primary objective

To assess, in patients with moderate IDA, the Onset-of-Action of a daily treatment with Tot'héma®. The onset of action is defined as the time required for a mean increase of at least 0.5 g/dL from baseline in the haemoglobin level.

Secondary objectives

  1. Assessment, in patients with moderate IDA, of the Onset-of-Action of a daily treatment with Tot'héma® separately within each of the 2 geographic zones. The onset of action is defined as the time required for a mean increase of at least 0.5 g/dL from baseline in haemoglobin level.
  2. Assessment, in patients with moderate IDA, of the Onset-of-Action of a daily treatment with Tot'héma®, defined as the time required for a mean increase of at least 2 g/dL from baseline in the haemoglobin level.
  3. Assessment of the proportion of patients with moderate IDA treated with Tot'héma® achieving different levels of improvement and, ultimately, a normalization of haemoglobin level over time.
  4. Assessment of the time course of the increase and, ultimately, the normalization of haemoglobin level in patients with moderate IDA treated with Tot'héma®.
  5. Assessment of the evolution of biological markers of anaemia in patients with moderate IDA treated with Tot’héma®.
  6. Assessment of the evolution of the mean level of C-Reactive Protein (CRP) in patients with moderate IDA treated with Tot'héma®.
  7. Assessment of the evolution of fatigue in patients with moderate IDA treated with Tot'héma®.
  8. Assessment of the evolution of quality of life of patients with moderate IDA treated with Tot'héma®.
  9. Performance of conjunctival pallor for detecting anaemia and its evolution during treatment.
  10. Assessment of patient compliance with treatment.
  11. Assessment of treatment safety.
  12. Assessment of the overall level of investigators satisfaction with the treatment.
1 Not Amended.
Laymans Summary:

Iron Deficiency Anaemia is a condition whereby iron store depletion is associated with low blood volume in the body, i.e. a haemoglobin (Hb) concentration below an established cut-off value, consequently impairing the capacity of the blood to transport oxygen around the body. According to the World Health Organisation (WHO) about 30% of the world’s population suffers from anaemia.

Oral iron supplements are considered as safe, cheap, and effective in restoring iron balance. Side effects associated with iron supplementation are mostly gastrointestinal side effects including abdominal discomfort, nausea, vomiting, constipation, and dark colored stools.

With more than five decades of international use, the efficacy and the safety of Tot'héma® in the curative and prophylactic treatment of IDA has been well established. Several clinical trials conducted in different populations have supported the efficacy of Tot'héma® in IDA, showing normalization of biological parameters such as Hb and ferritin blood levels after treatment with Tot'héma®.

Iron supplementation has long been proven to be effective for the treatment of IDA and iron treatment is recommended by many international organizations (WHO) and national learned societies (UK, US, India).

However, only few studies have demonstrated an increase in the Hb level and in biological parameters associated with IDA at early stages of treatment by iron supplementation.  A significant increase in Hb level was already observed after 1 week of iron supplementation in a study conducted on women with severe postpartum anaemia. In a study conducted on chronic kidney disease patients with IDA, the increase in Hb level was significant after 3 weeks of iron treatment. An analysis of pooled data from 5 randomized trials identified patients with an increase of Hb ≥ 1 g/dL at 14 days of treatment as responders to iron supplementation.

The purpose of this study is to obtain data on the biological parameters associated with IDA at the very early stages of treatment (3rd, 5th, 7th days) to assess the Onset-of-Action of an Iron gluconate liquid formulation (Tot'héma®). The efficacy and the safety of Tot'héma®, administered according to the summary of product characteristics (SmPC) recommendations, will also be evaluated regularly during the scheduled 12 weeks of treatment for the study.

The IP is registered in kenya. Registration number in Kenya is n°H2009/19801/578

 
4 i) Modification of the Sponsor’s contact details and of the CRO personnel on pages 2 and 5. ii) Total duration of the study postponed to Third quarter 2023 as already mentioned in the protocol clarification memo sent on 21 Dec 2022 on page 10.
Abstract of Study:

Iron Deficiency Anaemia is a condition whereby iron store depletion is associated with low blood volume in the body, i.e. a haemoglobin (Hb) concentration below an established cut-off value, consequently impairing the capacity of the blood to transport oxygen around the body. According to the World Health Organisation (WHO) about 30% of the world’s population suffers from anaemia.

Oral iron supplements are considered as safe, cheap, and effective in restoring iron balance. Side effects associated with iron supplementation are mostly gastrointestinal side effects including abdominal discomfort, nausea, vomiting, constipation, and dark colored stools.

With more than five decades of international use, the efficacy and the safety of Tot'héma® in the curative and prophylactic treatment of IDA has been well established. Several clinical trials conducted in different populations have supported the efficacy of Tot'héma® in IDA, showing normalization of biological parameters such as Hb and ferritin blood levels after treatment with Tot'héma®.

Iron supplementation has long been proven to be effective for the treatment of IDA and iron treatment is recommended by many international organizations (WHO) and national learned societies (UK, US, India).

However, only few studies have demonstrated an increase in the Hb level and in biological parameters associated with IDA at early stages of treatment by iron supplementation.  A significant increase in Hb level was already observed after 1 week of iron supplementation in a study conducted on women with severe postpartum anaemia. In a study conducted on chronic kidney disease patients with IDA, the increase in Hb level was significant after 3 weeks of iron treatment. An analysis of pooled data from 5 randomized trials identified patients with an increase of Hb ≥ 1 g/dL at 14 days of treatment as responders to iron supplementation.

The purpose of this study is to obtain data on the biological parameters associated with IDA at the very early stages of treatment (3rd, 5th, 7th days) to assess the Onset-of-Action of an Iron gluconate liquid formulation (Tot'héma®). The efficacy and the safety of Tot'héma®, administered according to the summary of product characteristics (SmPC) recommendations, will also be evaluated regularly during the scheduled 12 weeks of treatment for the study.

Primary objective

To assess, in patients with moderate IDA, the Onset-of-Action of a daily treatment with Tot'héma®. The onset of action is defined as the time required for a mean increase of at least 0.5 g/dL from baseline in the haemoglobin level.

Secondary objectives

  1. Assessment, in patients with moderate IDA, of the Onset-of-Action of a daily treatment with Tot'héma® separately within each of the 2 geographic zones. The onset of action is defined as the time required for a mean increase of at least 0.5 g/dL from baseline in haemoglobin level.
  2. Assessment, in patients with moderate IDA, of the Onset-of-Action of a daily treatment with Tot'héma®, defined as the time required for a mean increase of at least 2 g/dL from baseline in the haemoglobin level.
  3. Assessment of the proportion of patients with moderate IDA treated with Tot'héma® achieving different levels of improvement and, ultimately, a normalization of haemoglobin level over time.
  4. Assessment of the time course of the increase and, ultimately, the normalization of haemoglobin level in patients with moderate IDA treated with Tot'héma®.
  5. Assessment of the evolution of biological markers of anaemia in patients with moderate IDA treated with Tot’héma®.
  6. Assessment of the evolution of the mean level of C-Reactive Protein (CRP) in patients with moderate IDA treated with Tot'héma®.
  7. Assessment of the evolution of fatigue in patients with moderate IDA treated with Tot'héma®.
  8. Assessment of the evolution of quality of life of patients with moderate IDA treated with Tot'héma®.
  9. Performance of conjunctival pallor for detecting anaemia and its evolution during treatment.
  10. Assessment of patient compliance with treatment.
  11. Assessment of treatment safety.
  12. Assessment of the overall level of investigators satisfaction with the treatment.

 
4

Total duration of the study postponed to Third quarter 2023 as already mentioned in the protocol clarification memo sent on 21 Dec 2022 on page 10