Reproductive Capacity and Iron Burden in Thalassemia

NCT02308904 | Completed

• 1 other identifier: CICL670AUS46T
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

Brief Summary

The improved long-term survival of thalassemia major (TM) patients has resulted in increased focus on the ability to preserve fertility. While the association of iron toxicity with vital organ dysfunction, heart and liver, has been extensively investigated, the correlation of reproductive capacity and extent of iron overload is not well understood. Despite remarkable progress in methodology for prediction of reproductive status and intervention for preserving fertility, implementation in thalassemia is lacking. The investigators hypothesize that iron toxicity to the anterior pituitary occurring in the process of transfusional iron loading is directly associated with a decline in gonadal function. The investigators expect pituitary MRI measurements of iron deposition as well as markers of oxidative damage to correlate with the functional studies of pituitary-gonadal axis performed in this study. This cross sectional study will examine the relation of pituitary iron deposition and pituitary volume; serum iron and oxidative stress measures, liver iron concentration (LIC), cardiac iron and chelation adequacy with pituitary and gonadal reproductive hormone levels (and spermatogenesis in adult male patients), in order to better define the association of iron burden and chelation patterns with fertility potential, in thalassemia patients with iron overload. The study will assess whether the current chelation treatment regimens, in particular during the pubertal developmental age, are adequate for preserving fertility and could lead to improved chelation routines for preventing the high prevalence of compromised fertility. In addition, by utilizing state-of-the-art markers for fertility status, findings from this study may improve current methods for screening for hypogonadism and reproductive potential and allow earlier intervention. The investigators propose to examine 26-30 patients, 12 years and older, with measures of fertility potential, and correlate them to their current iron burden parameters and to the cumulative iron effect as indicated by past iron overload patterns and chelation history.

Conditions

THALASSEMIA MAJOR

Keywords

Infertility; Thalassemia; Iron overload; Pituitary Iron Load; Oxidative Stress; REPRODUCTIVE CAPACITY AND ASSOCIATION TO IRON BURDEN AND CHELATION PATTERNS IN THALASSEMIA MAJOR PATIENTS

Outcome Measures

Primary Outcomes (1)

• Laboratory studies for pituitary and gonadal function and for iron level measures

  Each patient's pituitary iron and pituitary volume will be correlated with each hormone levels: LH, FSH, estrogen and AMH (Females), testosterone Inhibin B and (males). We will then evaluate potential associations using Pearson correlations. Univariate analyses on all variables and it's relation with iron, will also be conducted.

  Up to 12 months

Secondary Outcomes (1)

• Retrospective analysis of annual LIC and of type and dose of iron chelation agent in the parallel time period

  Up to 12 months

Other Outcomes (1)

• Pituitary MRI and Male: Semen analysis

  Up to 12 months

Study Arms (3)

Laboratory Studies for Pituitary-Gonadal Function

OTHER

Females: We expect to enroll approximately 15 females ages 12 years and older. Males: We expect to enroll approximately 15 males ages 12 years and older.

Other: Blood Draw/Semen Exam

Data on iron burden and chelation history

OTHER

Retrospective data, as listed in this section, will be obtained from chart review and results of relevant clinical data. 1. Iron burden data 2. Assay for non-transferrin bound iron (NTBI) 3. Chelation data 4. Oxidant stress 5. History or presence of hypogonadism

Other: Retrospective data/Chart Review/Relevant Clinical Results

Pituitary MRI

OTHER

MRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland.

Other: Pituitary MRI

Interventions

Retrospective data/Chart Review/Relevant Clinical Results OTHER

1. 1\. Documentation of liver iron from SQUID or MRI. 2. Transfusion data on age at onset of regular transfusions, transfusion frequency over the previous five years, and years of chronic transfusion therapy (defined as 8 or more per year). 3. Data on cardiac iron as indicated by T2\* MRI. 4. Ferritin levels. 2. NTBI will be accessed using a mobilizer ligand to collect NTBI from all pools as Fe-NTA which is then measured by HPLC. 3. 1\. Age at onset of chelation 2. Estimated periods of known or recalled non-compliance with regular chelation. 3. Listing of all chelation drugs previously used including dose and time period. 4. 1\. Vitamins E and C, at time closest to obtaining reproductive hormone levels. 2. Measuring the ratio of reduced gluthatione (GSH) to oxidized gluthatione (GSSG). 5. Assessment of time for pubertal development, assessment of menstrual history and need for treatment with gonadal hormone replacement.

Data on iron burden and chelation history

Blood Draw/Semen Exam OTHER

Females: 1\. Obtain levels of LH/FSH, Estradiol, and AMH in all enrolled women. Males: We expect to enroll approximately 15 males ages 12 years and older. 1. Levels of FSH/LH and testosterone will be obtained. In addition, we will examine the association of the hormone inhibin B with mean fertility measures. Inhibin B levels were shown to correlate with azospermia and could demonstrate better prediction of reproductive potential. 2. Semen exam for determination of volume, sperm count, motility and sperm DNA integrity will be determined for interested adult thalassemia males (age ≥18 years and older).

Also known as: Screening for biomarkers and correlations with iron load

Laboratory Studies for Pituitary-Gonadal Function

Pituitary MRI OTHER

MRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland. An MRI protocol was optimized at Children's Hospital and Research Center Oakland (CHRCO) and Texas Children's Hospital. Utilizing 1.5 T clinical scanner to evaluate the iron accumulation in the anterior pituitary. The total data acquisition time is approximately 32 minutes. No sedation will be given. MRI data will be sent to Dr. Wang, department of Radiology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas. Quantification of R2, pituitary height and volume will be conducted.

Pituitary MRI

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Transfusion-dependent\* females and males with thalassemia (any genotype) who are 12 to 45 years of age.
• History of at least 5 years of chronic transfusion (defined as ≥ 8 transfusions/year) (Age of initiation of transfusions does not matter)
• Any pubertal stage.
• Liver iron evaluated by SQUID, MRI or liver biopsy within 12 months prior to enrollment in the study.
• Need to be able to stop hormonal therapy for 3 weeks (males) and one month (females) prior to study enrollment.

You may not qualify if:

• Pregnant or lactating during study enrollment
• Unable to obtain liver iron concentration within 12 months prior or 6 months after study entry.

Sponsors & Collaborators

• UCSF Benioff Children's Hospital Oakland: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

UCSF Benioff Children's Hospital Oakland

Oakland, California, 94609, United States

Location

MeSH Terms

Conditions

beta-Thalassemia; Infertility; Thalassemia; Iron Overload

Interventions

Mass Screening; Biomarkers

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genital Diseases; Urogenital Diseases; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diagnostic Techniques and Procedures; Diagnosis; Health Surveys; Surveys and Questionnaires; Data Collection; Epidemiologic Methods; Investigative Techniques; Diagnostic Services; Preventive Health Services; Health Services; Health Care Facilities Workforce and Services; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health; Public Health Practice; Biological Factors

Study Officials

• Sylvia T Singer, MD

  UCSF Benioff Children's Hospital Oakland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2014
• First Posted: December 4, 2014
• Study Start: June 1, 2013
• Primary Completion: September 1, 2020
• Study Completion: September 1, 2020
• Last Updated: December 23, 2020

Record last verified: 2020-12

Locations

US (1)