THALASSEMIA MAJORFertility thalNCT02308904
Reproductive Capacity and Iron Burden in Thalassemia
A study testing Blood Draw/Semen Exam, Retrospective data/Chart Review/Relevant Clinical Results and Pituitary MRI in people with THALASSEMIA MAJOR, run by UCSF Benioff Children's Hospital Oakland at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 12 years and olderHealthy volunteers can take part
- Conditions the study is for
- THALASSEMIA MAJOR
- What is being tested?
- Blood Draw/Semen Exam, Retrospective data/Chart Review/Relevant Clinical Results and Pituitary MRI
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2013to 1 Sep 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- Pregnant or lactating during study enrollment
- Unable to obtain liver iron concentration within 12 months prior or 6 months after study entry.
Trial locations and contacts
1 site in 1 country.
United States1 site
UCSF Benioff Children's Hospital Oakland
Oakland, California, 94609
About this study
Official title: Reproductive Capacity and Association to Iron Burden and Chelation Patterns in Thalassemia Major Patients
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
- Being tested
- Blood Draw/Semen Exam, Retrospective data/Chart Review/Relevant Clinical Results, Pituitary MRI
- Keywords
- Infertility, Thalassemia, Iron overload, Pituitary Iron Load, Oxidative Stress, REPRODUCTIVE CAPACITY AND ASSOCIATION TO IRON BURDEN AND CHELATION PATTERNS IN THALASSEMIA MAJOR PATIENTS
- Medical subject headings
- beta-Thalassemia, Infertility, Thalassemia, Iron Overload
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood Draw/Semen ExamOther
Also called Screening for biomarkers and correlations with iron load
Females:
- 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.
- 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.
- 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).
Retrospective data/Chart Review/Relevant Clinical ResultsOther
- 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.
- NTBI will be accessed using a mobilizer ligand to collect NTBI from all pools as Fe-NTA which is then measured by HPLC.
- 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.
- 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).
- Assessment of time for pubertal development, assessment of menstrual history and need for treatment with gonadal hormone replacement.
Pituitary MRIOther
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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 Receives: 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. Receives: Other: Pituitary MRI |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
We will evaluate potential associations using Pearson correlations of each measure: Mean LIC with each of the fertility hormone levels and with pituitary volume and height. Mean ferritin with each of the fertility hormone levels and with pituitary volume and height. NTBI with each of the fertility hormone levels and with pituitary volume and height. Oxidative measures (Vit C, Vit E, GSH/GSSG) with each of the fertility hormone levels and with pituitary volume and height. Regression analysis will be utilized to assess correlation of pituitary iron, LIC and cardiac iron. We will compute descriptive statistics for all measures by group. We will assess differences between the 2 groups using Student's t-test for continuous data and chi-square or Fisher's exact for categorical. A detailed retrospective analysis of LIC and chelation patterns (type of chelator and average dose) on these 2 groups will also be performed and fertility measures will be compared.
Measured: Up to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2014 (estimated)
- Study start1 Jun 2013
- Primary completion1 Sep 2020
- Study completion1 Sep 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for THALASSEMIA MAJORStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- UCSF Benioff Children's Hospital Oakland
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Sylvia T Singer, MD, Principal investigator, UCSF Benioff Children's Hospital Oakland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02308904
- Sponsor's protocol ID
- CICL670AUS46T
- Acronym
- Fertility thal
- Status last verified
- Dec 2020
- First submitted
- 25 Nov 2014
- Last updated
- 23 Dec 2020
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reproductive Capacity and Association to Iron Burden and Chelation Patterns in Thalassemia Major Patients
- ClinicalTrials.gov ID
- NCT02308904
- Acronym / sponsor ID
- Fertility thal / CICL670AUS46T
- 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
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 59 participants (actual)
- Lead sponsor
- UCSF Benioff Children's Hospital OaklandUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Study start
- 1 Jun 2013 (actual)
- Primary completion
- 1 Sep 2020 (actual)
- Study completion
- 1 Sep 2020 (actual)
- First posted
- 4 Dec 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Laboratory Studies for Pituitary-Gonadal Function | Other | Other: Blood Draw/Semen ExamFemales: 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. |
| Data on iron burden and chelation history | Other | Other: Retrospective data/Chart Review/Relevant Clinical ResultsRetrospective 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 |
| Pituitary MRI | Other | Other: Pituitary MRIMRI has been shown to demonstrate well the changes related to iron toxicity in the pituitary gland. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (2 listed)
- Pregnant or lactating during study enrollment
- Unable to obtain liver iron concentration within 12 months prior or 6 months after study entry.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Blood Draw/Semen ExamAlso: Screening for biomarkers and correlations with iron loadFemales: 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). | Other | Laboratory Studies for Pituitary-Gonadal Function |
| Retrospective data/Chart Review/Relevant Clinical Results1. 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. | Other | Data on iron burden and chelation history |
| Pituitary MRIMRI 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. | Other | Pituitary MRI |
Primary outcome
Laboratory studies for pituitary and gonadal function and for iron level measures
Time frame: Up to 12 months
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.
1 secondary outcome
Retrospective analysis of annual LIC and of type and dose of iron chelation agent in the parallel time period
Time frame: Up to 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Dec 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sylvia T Singer, MD principal investigator
UCSF Benioff Children's Hospital Oakland
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Blood Draw/Semen Exam, Retrospective data/Chart Review/Relevant Clinical Results and Pituitary MRI in people with THALASSEMIA MAJOR, run by UCSF Benioff Children's Hospital Oakland at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Laboratory studies for pituitary and gonadal function and for iron level measures (time frame: Up to 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Dec 2020.