Iron Supplements Effect on B-Phe Levels in PKU Patients During 3 Years Study

NCT06792240 | Completed Phase 2 DMC

• 1 other identifier: 43183/2019 - 2019/ST/142
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial study aims to Evaluate whether iron supplementation for 3 months may help reduce Phe blood concentration in PKU patients by enhancing the hydroxylation of Phe to tyrosine (Tyr). 84 patients affected by PKU with low Phe-controlled diet therapy (aged 3-25 years, both genders, 35 females and 49 males), were randomly enrolled in this 3 years study using Randomized Block Design. Patients were divided in two different groups: group (A) was treated with low Phe diet therapy and iron supplementation while group (B) was treated only with low Phe diet therapy. The duration of iron supplementation was 3 consecutive months for each patient in group (A). During this study, 3 hematological and clinical controls were performed at T0 (the enrolment day), T3 (3 months from T0), and T6 (6 months from T0) another TG was done at T1, T2, T4, and T5. During the clinical control blood samples for phenylalanine, and tyrosine were performed on all patients. A computer-generated block sequence balanced randomly assigned subjects to two different groups of 42 patients. The investigator who generated the randomization sequence was independent of the research staff. Energy calculation and diet preparation are according to the "Reference intake levels of nutrients and energy for the Italian population (LARN)" and RDA (USA- Recommended Daily Allowance). The patients were informed through the consent form about all study details. The researcher clarified that the iron supplementation was provided to patients for the purpose of studying "Phe" levels, oxidative stress, and inflammatory reactions, and not for treating Anemia before enrolling in this study. The amount of supplementary iron was decided for patients according to the daily requirement (8- 18 mg / day), according to LARN 2012 and (RDAs) for Iron. The number of patients in group A (42 patients) that consumed iron of 1 sac (14 mg/day) was 26 patients (61.9 %), of them 18 males and 8 females, in comparison with patients that consumption 1 sac an alternative day (14mg/every 2 days) = (7 mg/day- ½ sac/ day) was 16 patients (38.1%) of them 9 males and 7 females. Conclusions and Relevance:

• Our data suggests that regular iron supplementation could be needed to obtain better metabolic control in PKU patients, as it seems to be directly linked to lowering blood Phe levels. Thus, support that iron supplementation to PKU patients plays a relevant role for accurate function of PAH enzyme, probably represents one activator and it may can help to decrease the b-Phe value near to the normal range with - 46.7% of Phe, - 74.52% of Phe/Tyr ratio and increase 91.07% Tyr all with (P\<00.1) from the basal values
• It is also confirmed that oral iron supplementation with FERALGINE (FB + SA) to these patients could represent "as part of a comprehensive PKU management strategy" considering the high effectiveness and tolerability profile.
• additional study is required before the information should be used support our results The investigators declare that no conflict of interest.

Conditions

Phenylketonuria (PKU)

Keywords

PKU; Phe; Iron

Outcome Measures

Primary Outcomes (1)

• a significant decrease of Plasma Phe levels in Group A

  The outcome evidenced using Chi-square of di Pearson test a significant decrease (p\<0.001) - 46.7% of Phe, - 74.52% of Phe/Tyr ratio (population supplemented with Iron shows a significant metabolic improvement; in particular, Phe values. Used SPSS software and Prism software.

  The duration of iron supplementation lasted for 3 consecutive months for each patient in Group A. 3 clinical and hematological controls were performed at T0 (the enrolment day), T3 (3 months from T0) and T6 (6 months from T0).

Study Arms (2)

group (A)

EXPERIMENTAL

treated with low Phe diet therapy and iron supplementation

Dietary Supplement: iron supplementation

group (B)

OTHER

treated only with low Phe diet therapy

Dietary Supplement: control group

Interventions

iron supplementation DIETARY_SUPPLEMENT

The amount of supplementary iron was decided for patients according to the daily requirement (8- 18 mg / day), according to LARN 2012 and (RDAs) for Iron. (25) . This study took in consideration also, the recommendation of the National Institutes of Health iron dietary supplement fact of sheet as reference to calculate iron dose for our candidates because this dose isn't against LARN and more practical to applicate. The minimum RDA values is applied, which coincides within the LARN daily requirement limits. (7 mg-18 mg of iron per day). Applying the minimum recommended RDA dose, that can satisfy the daily iron requirement by age, approximating it to be adequate for the clinical dose administered orally once a day (e.g. 1.98 g ==\> 2 g, 1.53 g ==\> 1.5 g

group (A)

control group DIETARY_SUPPLEMENT

Non intervension: Only restricted low and controlled Phe diet therapy

group (B)

Eligibility Criteria

• Age: 3 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• The diagnosis of PKU must be made before 28 days of life, and confirmed genetically,
• At the diagnosis, patients' plasma Phe levels have at least two values ≥ 360 µmol/l.
• Phe low diet therapy started immediately after diagnosis confirmation.
• The age of participants, male or female, between 3-25 years old at scheduled Day one.
• Participants have no other diseases,
• Mean Phe levels should be between 120-360 µmol/l, within 3 months, before the Day 1.

You may not qualify if:

• Diagnosed by any type of anemia, hematological, chronic or gastrointestinal diseases.
• If acute infection has been diagnosed the Day 1.
• Administration iron less than 3 months before the start the study.
• Known hypersensitivity to other approved formulations of Ferrous Bisglycinate.
• Current use of experimental or unregistered drugs that may affect the study outcomes.
• Inability to comply with study procedures or inability to tolerate oral intake.
• History of organ transplantation.

Sponsors & Collaborators

• ASST Santi Paolo e Carlo: lead
• Università Luigi Vanvitelli della Campania: collaborator

Study Sites (1)

ASST-Santi Paolo e Carlo

Milan, Lombardy, 20142, Italy

Location

Related Publications (23)

• Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc : a Report of the Panel on Micronutrients external link disclaimer. Washington, DC: National Academy Press; 2001

  BACKGROUND

• Chace DH, Hannon WH. Filter Paper as a Blood Sample Collection Device for Newborn Screening. Clin Chem. 2016 Mar;62(3):423-5. doi: 10.1373/clinchem.2015.252007. Epub 2016 Jan 21. No abstract available.

  PMID: 26797689 BACKGROUND

• Gervasi GB, Baldacci M, Bertini M. Feralgine® a new co-processed substance to improve oral iron bioavailability, taste and tolerability in iron deficiency patients. Arch Med. 2016;8:13-16. 25) LARN Livelli di Assunzione di Riferimento di Nutrienti ed energia per la popolazione Italiana ( https://sinu.it/tabelle-larn-2014/)

  BACKGROUND

• Baldacci M, Gervasi GB, Bertini M. Iron deficiency anemia (ida) and iron deficiency (id): are alginates a good choise to improve oral iron bioavailability and safety? J TranslSci. 2018;4:1-3. DOI: 10.15761/JTS.1000210

  BACKGROUND

• Allen LH. Advantages and limitations of iron amino acid chelates as iron fortificants. Nutr Rev. 2002 Jul;60(7 Pt 2):S18-21; discussion S45. doi: 10.1301/002966402320285047. No abstract available.

  PMID: 12141594 BACKGROUND

• Soldin OP, Bierbower LH, Choi JJ, Choi JJ, Thompson-Hoffman S, Soldin SJ. Serum iron, ferritin, transferrin, total iron binding capacity, hs-CRP, LDL cholesterol and magnesium in children; new reference intervals using the Dade Dimension Clinical Chemistry System. Clin Chim Acta. 2004 Apr;342(1-2):211-7. doi: 10.1016/j.cccn.2004.01.002.

  PMID: 15026283 BACKGROUND

• Bovell-Benjamin et al., 2000; Layrisse et al., 2000; García-Casal and Layrisse, 2001; Jeppsen, 2001

  BACKGROUND

• Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and materials in Contact with Food on a request from the Commission related to Ferrous bisglycinate as a source of iron for use in the manufacturing of foods and in food supplements. Question number EFSA-Q-2005-039 . Adopted on 6 January 2006 by written procedure. https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2006.299

  BACKGROUND

• Vargas CR, Wajner M, Sitta A. Oxidative stress in phenylketonuric patients. Mol Genet Metab. 2011;104 Suppl:S97-9. doi: 10.1016/j.ymgme.2011.07.010. Epub 2011 Jul 22.

  PMID: 21813309 BACKGROUND

• Guerra IMS, Ferreira HB, Neves B, Melo T, Diogo LM, Domingues MR, Moreira ASP. Lipids and phenylketonuria: Current evidences pointed the need for lipidomics studies. Arch Biochem Biophys. 2020 Jul 30;688:108431. doi: 10.1016/j.abb.2020.108431. Epub 2020 May 24.

  PMID: 32461102 BACKGROUND

• Gropper SS, Yannicelli S, White BD, Medeiros DM. Plasma phenylalanine concentrations are associated with hepatic iron content in a murine model for phenylketonuria. Mol Genet Metab. 2004 May;82(1):76-82. doi: 10.1016/j.ymgme.2004.01.017.

  PMID: 15110326 BACKGROUND

• Mackler B, Person R, Miller LR, Finch CA. Iron deficiency in the rat: effects on phenylalanine metabolism. Pediatr Res. 1979 Sep;13(9):1010-1. doi: 10.1203/00006450-197909000-00012.

  PMID: 503651 BACKGROUND

• Bodley JL, Austin VJ, Hanley WB, Clarke JT, Zlotkin S. Low iron stores in infants and children with treated phenylketonuria: a population at risk for iron-deficiency anaemia and associated cognitive deficits. Eur J Pediatr. 1993 Feb;152(2):140-3. doi: 10.1007/BF02072491.

  PMID: 8444222 BACKGROUND

• Robin A Williams, et al (Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. Vogelstein B, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw- Hill; 2001. p. 1667-724).

  BACKGROUND

• Navarro G, Gomez-Autet M, Morales P, Rebassa JB, Llinas Del Torrent C, Jagerovic N, Pardo L, Franco R. Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling. Pharmacol Res. 2024 Oct;208:107363. doi: 10.1016/j.phrs.2024.107363. Epub 2024 Aug 22.

  PMID: 39179054 BACKGROUND

• Knox WE. Retrospective study of phenylketonuria: relation of phenylpyruvate excretion to plasma phenylalanine. PKU newsletter 1970;2

  BACKGROUND

• Hanley WB, Linsao L, Davidson W, Moes CA. Malnutrition with early treatment of phenylketonuria. Pediatr Res. 1970 Jul;4(4):318-27. doi: 10.1203/00006450-197007000-00002. No abstract available.

  PMID: 5447890 BACKGROUND

• Lichter-Konecki U, Vockley J. Phenylketonuria: Current Treatments and Future Developments. Drugs. 2019 Apr;79(5):495-500. doi: 10.1007/s40265-019-01079-z.

  PMID: 30864096 BACKGROUND

• Blau N, et al. Disorders of phenylalanine and tetrahydrobiopterin metabolism. In: Blau N, Hoffmann GF, Leonard J, Clarke JTR, editors. Physician's guide to the treatment and follow-up of metabolic diseases. Berlin: Springer; 2006. p. 25-34

  BACKGROUND

• Fitzpatrick PF. Mechanism of aromatic amino acid hydroxylation. Biochemistry. 2003 Dec 9;42(48):14083-91. doi: 10.1021/bi035656u. No abstract available.

  PMID: 14640675 BACKGROUND

• Nenad Blau. Phenylketonuria and BH4 deficiencies- UNI-MED 2010. ISBN: 978-1-84815-162-8

  BACKGROUND

• Matthew M. Phenylketonuria: Defects in Amino Acid Metabolism. South Carolina Journal of Molecular Medicine (SCJMM) 5:57-61; 2004

  BACKGROUND

• Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev. 2008 Feb;29(1):31-41.

  PMID: 18566668 BACKGROUND

Related Links

• Reference range of ferritin

MeSH Terms

Conditions

Phenylketonurias

Interventions

Control Groups

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Raed Selmi, MD-PhD

  ASST Santi Paolo e Carlo

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: A computer-generated block sequence balanced randomly assigned subjects to two different groups of 42 patients. The investigator who generated the randomization sequence was independent of the research staff.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: DR

Model Details: Cohort stydy. The duration of iron supplementation lasted for 3 consecutive months for each patient in Group A. 3 clinical and hematological controls were performed at T0 (the enrolment day), T3 (3 months from T0) and T6 (6 months from T0). This study contains of 84 children (A= 42) Iron Group and (B= 42) control group. As our active protocol at the Metabolic Centre, the patient must do one blood sample / Guthrie card each month to measure only Phe, Tyr levels, and Phe/Tyr Ratio with standardized methods. That allow the researcher to add 4 blood drop samples gathered by Guthrie card (T1, T2, T4, and T5) per each patient during long the study. It is clear now that each participant underwent blood sample collections at T0, T3, and T6 and blood drop sample collections at T1, T2, T4, and T5 using the Guthrie card (TG).

Study Record Dates

• First Submitted: January 1, 2025
• First Posted: January 24, 2025
• Study Start: January 7, 2020
• Primary Completion: January 9, 2023
• Study Completion: April 3, 2023
• Last Updated: January 24, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)