Do Iron And Vitamin B12 Injections Given Together, Improve Hemoglobin In Patients On Hemodialysis? (ALOHA)

The Role Of IV Iron (Ferric Carboxymaltose) And IM Vitamin B12 (Hydroxycobalamin) Supplementation In The Management Of Anaemic Prevalent Indian Hemodialysis Patients: A Parallel Group, Quadruple Blind, Placebo-Controlled, Pragmatic Randomized Control Trial With 2x2 Factorial Design

A parallel group, quadruple blind, placebo-controlled, randomized control trial with 2x2 factorial design to determine the effect of simultaneous IV ferric carboxymaltose and IM hydroxycobalamin supplementation in anemic Indian HD patients

Study Overview

• Status: Unknown
• Conditions: Iron Deficiency Anemia; B12 Deficiency Anemia
• Intervention / Treatment: Drug: Ferric carboxymaltose; Drug: Placebo; Drug: Placebo; Drug: Hydroxycobalamin

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anna T Valson, MD, DM; Phone Number: +91-416-2282683; Email: annavalson@cmcvellore.ac.in
• Study Contact Backup: Name: Rizwan Alam, MD; Phone Number: +91-416-2282053; Email: rizwangb0557@gmail.com

Study Locations

• India
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Recruiting
      • Christian Medical College, Vellore
      • Contact: Anna T Valson, MD, DM; Phone Number: +919894143677; Email: annavalson@cmcvellore.ac.in
      • Contact: Rizwan Alam, MD; Phone Number: +918130560297; Email: rizwangb0557@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All adult prevalent HD patients on HD for at least 3 months with hemoglobin < 11 g/dL

Exclusion Criteria:

• Blood transfusion, blood loss, infection, surgery or change in haemoglobin by > 1 g/dL in the last 1 month
• Hemoglobinopathy
• Cirrhosis
• Hematological malignancy or myeloproliferative disorder
• HIV, HBV or HCV infection
• Any chronic inflammatory disorder
• IV iron or oral/IM B12 received in the last 3 months
• Severe hyperparathyroidism (intact parathyroid hormone > 1,000 pg/mL)
• Pregnancy
• Age < 18 years
• History of asthma or eczema, any history of drug allergy, including allergy to iron preparations
• History of exposure to chemotherapy or cytotoxic drugs - 5-FU, hydroxyurea, hydroxycarbamide, methotrexate, trimethoprim, colchicine, azathioprine
• History of G-CSF use in the last 1 month
• General anaesthesia with nitrous oxide in the last 1 month

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FCM + placebo; Ferric carboxymaltose: Single dose, 500 mg; Placebo: Single dose	Drug: Ferric carboxymaltose; Single dose of ferric carboxymaltose (Encicarb, Emcure Pharmaceuticals Ltd., Pune, India) 500 mg administered intravenously in 100 ml normal saline over 1 hour via the dialysis blood line immediately following HD; Drug: Placebo; Single dose of 1 ml of distilled water injected intramuscularly in the deltoid of the non-fistula arm immediately following HD; Drug: Placebo; Single dose of 100 ml normal saline administered intravenously over 1 hour via the dialysis blood line immediately following HD
Experimental: B12 + placebo; Hydroxycobalamine: Single dose, 1000 mcg; Placebo: Single dose	Drug: Placebo; Single dose of 1 ml of distilled water injected intramuscularly in the deltoid of the non-fistula arm immediately following HD; Drug: Placebo; Single dose of 100 ml normal saline administered intravenously over 1 hour via the dialysis blood line immediately following HD; Drug: Hydroxycobalamin; Single dose of hydroxycobalamine (Trineurosol Hp, Tridoss Laboratories, Mumbai, India) 1000 mcg administered intramuscularly in the deltoid of the non-fistula arm immediately following HD
Experimental: FCM +B12; Ferric carboxymaltose: Single dose, 500 mg; Hydroxycobalamine: Single dose, 1000 mcg	Drug: Ferric carboxymaltose; Single dose of ferric carboxymaltose (Encicarb, Emcure Pharmaceuticals Ltd., Pune, India) 500 mg administered intravenously in 100 ml normal saline over 1 hour via the dialysis blood line immediately following HD; Drug: Hydroxycobalamin; Single dose of hydroxycobalamine (Trineurosol Hp, Tridoss Laboratories, Mumbai, India) 1000 mcg administered intramuscularly in the deltoid of the non-fistula arm immediately following HD
Placebo Comparator: Placebo + placebo; Placebo: Single dose; Placebo: Single dose	Drug: Placebo; Single dose of 1 ml of distilled water injected intramuscularly in the deltoid of the non-fistula arm immediately following HD; Drug: Placebo; Single dose of 100 ml normal saline administered intravenously over 1 hour via the dialysis blood line immediately following HD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean haemoglobin	Mean haemoglobin measured 30 days after the intervention	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity and specificity of baseline automated red cell indices, peripheral smear red cell indices, and iron indices for diagnosis of iron deficiency	Sensitivity and specificity of baseline peripheral smear hypochromic RBCs >10%, peripheral smear red blood cell anisocytosis > 10%, percentage hypochromic mature red cells (%HYPOm) >6%, reticulocyte hemoglobin content (CHr) < 30 pg, transferrin saturation (TSAT), and serum ferritin, for the diagnosis of iron deficiency anemia. Iron deficiency anemia is defined by an increase in corrected reticulocyte index (reticulocyte % x hematocrit/40) >1% at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IV FCM in the FCM +placebo arm.	Baseline
Optimum cutoff for baseline automated red cell indices for the diagnosis of iron deficiency anemia using ROC curve analysis	Optimum cutoff of baseline %HYPOm and CHr for the diagnosis of iron deficiency anemia using ROC curve analysis. Iron deficiency anemia is defined by an increase in corrected reticulocyte index (reticulocyte % x hematocrit/40) >1% at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IV FCM in the FCM +placebo arm.	Baseline
Sensitivity and specificity of baseline peripheral blood smear hypochromia, peripheral blood smear anisocytosis and automated red cell indices for the diagnosis of iron deficiency anemia in participants with TSAT < 30% and TSAT > =30%.	Sensitivity and specificity of > 10% hypochromic red blood cells on peripheral blood smear, >10% red blood cell anisocytosis on peripheral blood smear, %HYPOm > 6%, and CHr < 30 pg measured at baseline, for the diagnosis of iron deficiency anemia in participants with baseline TSAT < 30% and TSAT > 30% respectively. Iron deficiency anemia is defined by an increase in corrected reticulocyte index (reticulocyte % x hematocrit/40) >1% at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IV FCM in the FCM +placebo arm.	Baseline
Sensitivity and specificity of baseline peripheral smear neutrophil hypersegmentation and cell population data for the diagnosis of B12 deficiency.	Sensitivity and specificity of baseline peripheral smear neutrophil hypersegmentation (>3 percent of neutrophils with ≥5 lobes or ≥1 neutrophil with ≥6 lobes per 100 neutrophils) and cell population data [mean neutrophil volume > 145 fl or mean monocyte volume > 168 fl] for the diagnosis of B12 deficiency. B12 deficiency is defined as an increase in corrected reticulocyte index > 1% (reticulocyte % x hematocrit/40) at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IM hydroxycobalamin in the B12 + placebo group.	Baseline
Optimum cutoff of cell population data for the diagnosis of B12 deficiency using ROC curve analysis	Optimum cutoff of baseline mean neutrophil volume and mean monocyte volume for the diagnosis of B12 deficiency using ROC curve analysis. B12 deficiency is defined as an increase in corrected reticulocyte index > 1% (reticulocyte % x hematocrit/40) at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IM hydroxycobalamin in the B12 + placebo group.	Baseline
Adverse effects of IV ferric carboxymaltose and IM hydroxycobalamin therapy	Any adverse events attributable to the use of IV ferric carboxymaltoise and/or IM hydroxycobalamin	Day 0

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Sensitivity and specificity of red cell anisochromia on peripheral smear for the diagnosis of iron deficiency anemia	Sensitivity and specificity of red cell anisochromia >=25% on the baseline peripheral smear for the diagnosis of iron deficiency anemia. Iron deficiency anemia is defined by an increase in corrected reticulocyte index (reticulocyte % x hematocrit/40) >1% at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IV FCM in the FCM +placebo arm.	Baseline
Optimal cutoff of baseline serum methylmalonic acid for the diagnosis of B12 deficiency	Optimal cutoff of baseline serum methylmalonic acid for the diagnosis of B12 deficiency. B12 deficiency is defined as an increase in corrected reticulocyte index > 1% (reticulocyte % x hematocrit/40) at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IM hydroxycobalamin in the B12 + placebo group. B12 deficiency is defined as an increase in corrected reticulocyte index > 1% (reticulocyte % x hematocrit/40) at 7 days and/or increase in hemoglobin by ≥1 g/dL 30 days after administration of IM hydroxycobalamin in the B12 + placebo group.	Baseline

Collaborators and Investigators

• Sponsor: Christian Medical College, Vellore, India
• Investigators: Study Director: Anna T Valson, MD, DM, Christian Medical College, Vellore, India; Principal Investigator: Rizwan Alam, MD, Christian Medical College, Vellore, India

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2020
• Primary Completion (Anticipated): March 1, 2021
• Study Completion (Anticipated): March 1, 2021

Study Registration Dates

• First Submitted: November 8, 2020
• First Submitted That Met QC Criteria: November 8, 2020
• First Posted (Actual): November 13, 2020

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Nutrition Disorders; Anemia, Hypochromic; Iron Metabolism Disorders; Malnutrition; Anemia, Iron-Deficiency; Anemia; Deficiency Diseases; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Vitamin B 12; Hydroxocobalamin
• Other Study ID Numbers: 12564 (INTERVEN) 29.01.2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All individual participant data (including data dictionaries) will be made available immediately after publication of the trial results for an indefinite time period.
• IPD Sharing Time Frame: Immediately after publication of the results, for an indefinite period
• IPD Sharing Access Criteria: IPD will be made available to investigators whose proposed use of the data has been approved by an independent review committee in order to achieve aims in the approved proposal. Proposals should be directed to annavalson@cmcvellore.ac.in. To gain access, data requestors will need to sign a data access agreement. Data will be made available at the third party website.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No