Hyperinsulinism-Hyperammonemia Syndrome
Conditions
Keywords
hyperinsulinism, hyperammonemia, hypoglycemia, vitamin e
Brief summary
Investigators will assess the tolerability of oral Vitamin E supplementation in subjects with congenital hyperinsulinism (HI) and hyperammonemia (HA) syndrome.
Detailed description
Congenital hyperinsulinism (HI) is a rare disorder of pancreatic beta cell insulin secretion that causes persistent and severe hypoglycemia starting at birth. Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital HI and is caused by activating mutations in glutamate dehydrogenase (GDH). Patients with HI/HA exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia, hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. These effects result from abnormal GDH activity in the beta cells, liver and kidney cells, neurons, and astrocytes. The only available treatment for HI/HA syndrome is diazoxide, which acts on the beta cells to decrease insulin secretion but has no effect on GDH activity itself or on other cell types. Thus, there remains a significant unmet need for improved therapies for this disorder. Preliminary data show that Vitamin E (alpha-tocopherol) inhibits GDH activity in cell lines and improves hypoglycemia in a GDH HI mouse model. Based on these preclinical studies, Investigators hypothesize that Vitamin E will inhibit GDH activity and may impact hyperinsulinemic hypoglycemia and hyperammonemia in subjects with HI/HA syndrome. This hypothesis will be tested in a future study. In this initial pilot study, investigators will assess the tolerability of oral Vitamin E supplementation in subjects with HI/HA syndrome.
Interventions
DIETARY_SUPPLEMENTVitamin E
Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if \>17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive \<600 IU daily, or for any subjects who prefer liquid medication to capsules.
Sponsors
University of Pennsylvania
Lawson Wilkins Pediatric Endocrine Society
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Elizabeth A Rosenfeld
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
This open-label tolerability and feasibility pilot clinical study will use a before-and-after design, with blood tests and fasting oral protein tolerance test performed prior to and after 2 weeks of daily oral Vitamin E supplementation in individuals with HI/HA syndrome.
Eligibility
Sex/Gender
ALL
Age
1 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Individuals age ≥12 months and ≤40 years * Diagnosis of HI/HA syndrome * On diazoxide therapy for treatment of hypoglycemia * Females ≥11 years of age or menstruating must have a negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study. * Informed consent for participants ≥18 years. Parental/guardian permission (informed consent) and, if appropriate, child assent for participants \<18 years.
Exclusion criteria
* Individuals age \<12 months or \>40 years * Individuals who have experienced an allergic reaction to Vitamin E * Individuals with a known allergy to dairy, whey, or soy * On concurrent therapy with a medication known to be metabolized by the CYP3A pathway * Individuals with a known increased risk of bleeding (bleeding disorder or on antiplatelet or anticoagulation therapy) * Vitamin E supplementation within 30 days prior to enrollment, including multivitamins containing Vitamin E * Severe hypoglycemia (plasma glucose \<50 mg/dL on repeat checks using home glucose meter) more than once weekly within 30 days prior to enrollment. * Evidence of a medical condition that might alter results or compromise the interpretation of results, including active infection, kidney failure, severe liver dysfunction, severe respiratory or cardiac failure. * Evidence of severe hematologic abnormality including severe anemia and/or thrombocytopenia. * Any investigational drug use within 30 days prior to enrollment. * Pregnant or lactating females. * Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures. * Unable to provide informed consent (e.g. impaired cognition or judgment). * Parents/guardians or subjects with limited English proficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline | 2 weeks | The following symptoms will be scored as either none (did not occur)=0, mild (minimal symptoms, no treatment needed)=1, moderate (symptoms requiring treatment at home or as an outpatient=2, or severe (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Delta-plasma Glucose Concentration | 2 weeks | change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Fasting Plasma Glucose Concentration | 2 weeks | change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Nadir Plasma Glucose Concentration | 2 weeks | change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Fasting Plasma Insulin Concentration | 2 weeks | change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Plasma Alpha-tocopherol Concentration | 2 weeks | change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Delta-plasma Insulin Concentration | 2 weeks | change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Fasting Plasma Ammonia Concentration | 2 weeks | change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Delta-plasma Ammonia Concentration | 2 weeks | change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Hypoglycemia Frequency | 2 weeks | change in frequency of hypoglycemia (plasma glucose \<70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
| Peak Plasma Insulin Concentration | 2 weeks | change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\]) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vitamin E Supplementation Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if \>17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive \<600 IU daily, or for any subjects who prefer liquid medication to capsules. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Vitamin E Supplementation |
|---|---|
| Age, Continuous | 8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 2 | 0 / 5 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 9 / 14 | 1 / 2 | 2 / 5 | 3 / 3 | 3 / 4 |
| serious Total, serious adverse events | 0 / 14 | 0 / 2 | 0 / 5 | 0 / 3 | 0 / 4 |
Outcome results
Primary
Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline
The following symptoms will be scored as either none (did not occur)=0, mild (minimal symptoms, no treatment needed)=1, moderate (symptoms requiring treatment at home or as an outpatient=2, or severe (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.
Time frame: 2 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin E Supplementation | Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline | 2 Participants |
Secondary
Delta-plasma Ammonia Concentration
change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: The 2 week (visit 2) plasma ammonia at 60 minutes was not obtained in 1 participant in whom the visit 2 oral protein tolerance test was performed, yielding n=5 for analysis of this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Delta-plasma Ammonia Concentration | -3.4 micromolar | Standard Deviation 15.5 |
Secondary
Delta-plasma Glucose Concentration
change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Delta-plasma Glucose Concentration | 1.1 mg/dL | Standard Deviation 8.3 |
Secondary
Delta-plasma Insulin Concentration
change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Delta-plasma Insulin Concentration | -5.2 uIU/mL | Standard Deviation 16.5 |
Secondary
Fasting Plasma Ammonia Concentration
change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Fasting Plasma Ammonia Concentration | 1.0 micromolar | Standard Deviation 31.6 |
Secondary
Fasting Plasma Glucose Concentration
change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Fasting Plasma Glucose Concentration | -0.3 mg/dL | Standard Deviation 6.5 |
Secondary
Fasting Plasma Insulin Concentration
change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Fasting Plasma Insulin Concentration | -2.4 uIU/mL | Standard Error 4.4 |
Secondary
Hypoglycemia Frequency
change in frequency of hypoglycemia (plasma glucose \<70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: Home glucose meter testing was not performed by 3 participants, yielding n=10 analyzed for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Hypoglycemia Frequency | 0.6 Hypoglycemia events | Standard Deviation 2.3 |
Secondary
Nadir Plasma Glucose Concentration
change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Nadir Plasma Glucose Concentration | 0.01 mg/dL | Standard Deviation 9.46 |
Secondary
Peak Plasma Insulin Concentration
change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Peak Plasma Insulin Concentration | -6.3 uIU/mL | Standard Deviation 18.2 |
Secondary
Plasma Alpha-tocopherol Concentration
change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Population: The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin E Supplementation | Plasma Alpha-tocopherol Concentration | 18.6 micromolar | Standard Deviation 12.5 |