- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01550705
Effect of Isoniazid on Protoporphyrin Levels in Erythropoietic Protoporphyria (INHEPP)
Quantification of the Effects of Isoniazid Treatment on Erythrocyte and Plasma Protoporphyrin IX Concentration and Plasma Aminolevulinic Acid in Patients With Erythropoietic Protoporphyria
In erythropoietic protoporphyria there is an accumulation of protoporphyrin IX (PPIX) in the plasma and liver. The reason it builds up is either the last step to make heme, insertion of iron into PPIX, is rate limiting or there is an increase in activity in the first step in the heme pathway.
It may be possible to decrease the amount of PPIX made and see a decrease in symptoms. The first step to make heme is the key step in the pathway and it uses vitamin B6 as a cofactor. If the investigators can limit the amount of vitamin B6 the investigators can possibly reduce the activity of this rate limiting step. With decreased activity of the enzyme it may be possible for the body to utilize all the PPIX that is made so that none builds up.
Study Overview
Status
Intervention / Treatment
Detailed Description
Clinically, both erythropoietic protoporphyria (EPP) and X-linked EPP (XLEPP) are characterized by painful, non-blistering cutaneous photosensitivity with onset in early childhood. EPP is the most common porphyria in children and the third most common in adults (after porphyria cutanea tarda and acute intermittent porphyria). Reports of prevalence vary between 5 and 15 cases per million population.
EPP is due in most cases to decreased activity of ferrochelatase (FECH), the enzyme that catalyzes the incorporation of ferrous iron into PPIX, the final step in the production of heme. The pattern of inheritance is autosomal recessive. However, homozygosity for a FECH mutation is rare. Rather, the decreased activity is a consequence of a combination of an inherited inactivating mutation affecting one FECH allele and an intronic polymorphism that alters splicing of the other allele. The alternative splice site, when used, produces a non-functional FECH messenger ribonucleic acid (mRNA). The alternative splice site is used approximately 40% of the time. Therefore, the polymorphic allele produces approximately 60% of normal FECH activity, and for this reason, is termed hypomorphic. When the hypomorphic FECH allele is in trans with the non-functional mutant allele the result is 30% or less of the normal FECH enzyme activity. This subnormal FECH activity becomes rate-limiting, resulting in accumulation of intracellular PPIX. Although the defect is presumably expressed in all tissues, the PPIX responsible for photosensitivity derives primarily from marrow reticulocytes.
Aminolevulinic acid synthase (ALAS), the first, and rate-limiting enzyme in the heme biosynthetic pathway, catalyzes the condensation of glycine and succinyl-Coenzyme A (succinyl-CoA) to form aminolevulinic acid (ALA), and requires pyridoxal 5'-phosphate as a cofactor. ALAS in mammalian cells is localized to the mitochondrial matrix. The enzyme is synthesized as a precursor protein in the cytosol and transported into mitochondria. Two separate ALA synthase genes encode housekeeping (tissue-nonspecific) and erythroid specific forms of the enzyme (ALAS1 and ALAS2, respectively). The gene for human ALAS1 is on 3p.21 and the locus for ALAS2 the X-chromosome, at Xp11.2.
The two forms of ALAS are differentially regulated, ALAS1 is a housekeeping gene expressed in all cells and ALAS2 is driven by erythroid specific transcription factors GATA1 and NF-E2. Additionally, ALAS2 mRNA contains an iron-responsive element (IRE) in its 5'-untranslated region, similar to mRNAs encoding ferritin and the transferrin receptor (in which the IRE is in the gene's 3' UTR). Gel retardation analysis showed that the iron-responsive element in ALAS2 mRNA is functional [as evidenced by binding to iron regulator protein 2 (IRP2)], indicating that translation of the erythroid-specific mRNA is directly linked to the availability of iron and heme in erythroid cells. In this case, when intracellular iron concentration is relatively high, it is available for binding to IRP2, a process that enhances ubiquitin-mediated degradation of IRP2. Under these conditions, IRP2 is unavailable for binding to the IRE element in ALAS2, clearing the message for efficient translation. Conversely, when intracellular iron is relatively low, IRP2 degradation is restricted, making the protein available for binding to the IRE and thereby blocking translation of ALAS2 mRNA.
Recently, a variant form of EPP, inherited in an X-linked pattern (XLEPP), was shown to be due to an ALAS2 gain-of-function mutation in exon 11. The mutation results in a truncated form of the protein that has supranormal specific activity as a result of less constrained enzyme-substrate interactions, resulting in overproduction of PPIX. This situation is in contrast to EPP with mutated FECH in which PPIX accumulates because of deficient heme formation.
ALAS1 and 2 use pyridoxal phosphate (PLP) as a cofactor. PLP is a modified form of vitamin B6. It has been shown that PLP complexes with isoniazid depleting the cofactor. This PLP depletion has been one of the causes of sideroblastic anemia.
The investigators will test the hypothesis that depletion of PLP will lead to decreased activity of ALAS.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Utah
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Salt Lake City, Utah, United States, 84132
- University of Utah School of Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- All subjects will be enrolled in the Longitudinal Study of the Porphyrias.
In patients with EPP the inclusion criteria are based on
- clinical features
- biochemical findings, as documented by laboratory reports of porphyria-specific testing performed after 1980
- molecular findings documenting the identification of a mutation in FECH or ALAS2 genes (molecular evidence of EPP is required for inclusion in the study).
These data will be obtained from the Porphyria Rare Disease Clinical Research Consortium Longitudinal Study (RDCRN Protocol 7201). An individual must be willing to give written informed consent and be 18 years of age or greater.
Autosomal EPP (EPP) and X-linked protoporphyria (XLEPP)
Clinical features - a or b required
- A history of non-blistering cutaneous photosensitivity, usually with early age of onset.
- A diagnosis of EPP or XLEPP in a relative.
Biochemical findings
- A marked increase in erythrocyte protoporphyrin [total erythrocyte protoporphyrin >200 ug/dL, or more than 1.5-fold increase relative to upper limit of normal of 80 ug/dL, with a predominance of free protoporphyrin (85-100% in EPP and 50-85% in XLEPP). Note: Methods in some laboratories for measuring free erythrocyte protoporphyrin (FEP) actually measure zinc protoporphyrin, so these results cannot be relied upon for diagnosis or characterizing the phenotype in EPP and XLEPP.
- Increased plasma porphyrins with a fluorescence emission peak at ~634 nm.
- Normal urinary porphyrins (except in patients with hepatobiliary impairment), and normal ALA and porphobilinogen (PBG).
Molecular findings - one of the following:
- A disease causing FECH mutation trans to the IVS3-48C>T low expression FECH allele (aEPP)
- Two disease-causing FECH mutations (EPP, recessive variant)
- A gain-of-function ALAS2 C-terminal deletion/exon 11 mutation (XLEPP)
Exclusion Criteria:
- Patients with a diagnosis of EPP that cannot be documented by DNA testing.
- Patients with evidence of active liver injury as defined by serum transaminase concentrations greater than three times the upper limit of normal, those with a history of recent (within 3 months of enrollment) or ongoing alcohol abuse, those with diabetes mellitus requiring therapy, renal insufficiency (serum creatinine >2.0 mg/ml) or evidence of malnutrition (based on subnormal plasma concentration of transthyretin) will be ineligible for participation in the study.
- Pregnant and/or lactating women will be excluded from the study.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Isoniazid
Subjects will receive isoniazid daily for 2 months.
Subjects will be seen every 2 weeks to obtain lab samples and health check.
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Isoniazid 5 mg/Kg up to 300 mg per day.
Oral tablets. 2 months.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Plasma Protoporphyrin IX Level
Time Frame: Baseline and 3 Months
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Plasma Protoporphyrin IX will be measured at baseline and at 3 months
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Baseline and 3 Months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Participants With Increased Sun Sensitivity
Time Frame: Baseline and 3 Months
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Study participants were asked to report after 3 months if they had experienced an increase in subjective measures of sun sensitivity during the trial.
Reported outcome is the number of study participants who reported increased sun sensitivity
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Baseline and 3 Months
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: John D Phillips, PhD, University of Utah
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Metabolic Diseases
- Skin Diseases
- Liver Diseases
- Genetic Diseases, Inborn
- Skin Diseases, Genetic
- Porphyrias, Hepatic
- Porphyrias
- Protoporphyria, Erythropoietic
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antimetabolites
- Hypolipidemic Agents
- Lipid Regulating Agents
- Anti-Bacterial Agents
- Antitubercular Agents
- Fatty Acid Synthesis Inhibitors
- Isoniazid
Other Study ID Numbers
- UTINH
- U54DK083909 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Erythropoietic Protoporphyria (EPP)
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Mitsubishi Tanabe Pharma America Inc.CompletedErythropoietic Protoporphyria (EPP)United States
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University of Alabama at BirminghamPorphyria Rare Disease Clinical Research ConsortiumCompletedErythropoietic Protoporphyria (EPP)United States
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Icahn School of Medicine at Mount SinaiNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Rare... and other collaboratorsCompletedErythropoietic Protoporphyria | EPP | XLP | X-Linked Protoporphyria | XLPP | X-Linked Dominant Erythropoietic Protoporphyria | XLEPP | XLDPUnited States
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Icahn School of Medicine at Mount SinaiNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)CompletedErythropoietic Protoporphyria | EPP | X-linked Protoporphyria | XLPUnited States
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Mitsubishi Tanabe Pharma America Inc.Active, not recruitingEPP | XLPUnited States, Germany, Japan, Spain, Italy, Sweden, Australia, Canada, Norway, United Kingdom
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Mitsubishi Tanabe Pharma America Inc.CompletedEPP | XLPSpain, United States, Germany, Norway, Italy, Australia, Canada, Japan, Sweden, United Kingdom
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Brigham and Women's HospitalCompleted
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