Autoimmune Polyendocrine Syndrome Type 1, Autosomal Dominant Hypocalcemia Type 1 (ADH1), Hypocalcemia, Hypoparathyroidism
Conditions
Keywords
Parathyroid Hormone 1-34, Hypoparathyroidism, Hypocalcemia, APECED, CASR
Brief summary
This randomized crossover study will evaluate the safety, efficacy, and pharmacodynamics of synthetic human PTH 1-34 (PTH) delivered by an insulin pump (omnipod) compared with twice- daily subcutaneous injections. We predict pump delivery of PTH will simultaneously normalize blood and urine mineral levels with minimal or no fluctuations throughout the day, thus resulting in a more physiologic pharmacodynamic profile because this method of delivery mimics normal parathyroid gland function. Furthermore, we hypothesize that pump therapy will require lower PTH doses and will normalize markers of bone turnover. We anticipate the improved metabolic control when PTH is delivered by pump will be evident both in adults with surgically induced hypoparathyroidism and in children with more severe forms of hypoparathyroidism where there is an unmet need for improved therapy.
Detailed description
Prior studies (92-CH-0011) have been important in establishing synthetic human parathyroid hormone 1-34 (PTH) as a beneficial treatment for hypoparathyroidism, superior to conventional therapy with calcitriol and calcium. We are conducting a randomized crossover study comparing PTH delivered by an insulin pump vs twice-daily subcutaneous injections. We hypothesize that pump delivery of PTH 1-34, compared to injections, will provide smoother metabolic control of serum mineral levels with minimal fluctuations, normalization of urine mineral excretion and markers of bone turnover. The two arms will be divided into an inpatient and an outpatient phase. There will be three inpatient admissions at baseline, 3 months and 6 months which are separated by two 3-month outpatient periods. Patients between 10 and 70 years of age with chronic hypoparathyroidism for at least 1 year may be eligible for participation in this study. After the baseline evaluation, conventional therapy (calcitriol and calcium supplements) is discontinued and PTH delivered by an insulin pump (Omnipod) or by twice-daily subcutaneous injections is initiated, depending on randomization sequence. PTH is provided for the study (Clinical Center Pharmacy) in 200 mcg/mL vials. The initial PTH daily dose is 0.2 μg/kg/day for pump therapy and 0.5 μg/kg/day for the twice-daily injection therapy. Inpatient admissions consist of daily (early morning) blood collections for mineral levels, 1,25 OH vitamin D, and markers of bone turnover along with 24-h urine excretion measures of minerals to determine the optimal individualized dose. Titration of PTH dose continues during the outpatient phase with blood labs measured on a weekly basis and less often, when frequent changes are considered unnecessary. Study participants will cross over to the alternate PTH delivery method (PTH delivered by pump vs. injections) at the conclusion of the initial 3-month treatment period. At the conclusion of the third hospital admission, patients will return to the therapy they were receiving at study entry.
Interventions
DRUGSynthetic Human Parathyroid Hormone 1-34 pump
comparing two delivery modalities for PTH: insulin pump versus subcutaneous injections.
Sponsors
National Institutes of Health Clinical Center (CC)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized crossover design; all patients are their own controls. Comparing delivery of PTH 1-34 through an insulin pump (Omnipod) vs. PTH 1-34 by twice-daily subcutaneous injections.
Eligibility
Sex/Gender
ALL
Age
7 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: This study will include up to 24 patients of both genders (ages 7-70) with biochemically confirmed chronic hypoparathyroidism of at least one year duration. We will recruit adults with post-surgical hypoparathyroidism and children with genetic forms of hypoparathyroidism including autoimmune polyendocrine syndrome type 1 (APS-1) or hypocalcemia due to an activating mutation of the calcium sensing receptor.
Exclusion criteria
Subjects who meet any of the following criteria are not eligible for study entry: * Presence of significant hepatic or kidney disease * Pregnancy * Patients who are calcium infusion dependent. * Seizure disorder requiring antiepileptic medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Serum Calcium in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum calcium level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Calcium in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum calcium level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine Calcium Excretion in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine calcium excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children and young adults. |
| Mean Urine Calcium Excretion in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine calcium excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Serum Phosphorus in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum phosphorus level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Phosphorus in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum phosphorus level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine Phosphorus Excretion in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine phosphorus excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children and young adults. |
| Mean Urine Phosphorus Excretion in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine phosphorus excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated. |
| Mean Serum Magnesium in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum magnesium level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Magnesium in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum magnesium level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine Magnesium Excretion in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine magnesium excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children and young adults. |
| Mean Urine Magnesium Excretion in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine magnesium excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated. |
| Mean Serum Alkaline Phosphatase in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum alkaline phosphatase level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Alkaline Phosphatase in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum alkaline phosphatase level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Bone-specific Alkaline Phosphatase in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum bone-specific alkaline phosphatase level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum 1,25-hydroxyvitamin D3 in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum 1,25-hydroxyvitamin D3 level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum 1,25-hydroxyvitamin D3 in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum 1,25-hydroxyvitamin D3 level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum 25-hydroxyvitamin D3 in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum 25-hydroxyvitamin D3 level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum 25-hydroxyvitamin D3 in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum 25-hydroxyvitamin D3 level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine Creatinine Clearance Excretion in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine creatinine clearance excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children and young adults. |
| Mean Urine Creatinine Clearance Excretion in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine creatinine clearance excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated. |
| Mean Serum Osteocalcin in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum osteocalcin level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Osteocalcin in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean fasting serum osteocalcin level at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine N-terminal Telopeptide Level in Children and Young Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine N-terminal telopeptide of type 1 collagen excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children and young adults. |
| Mean Urine N-terminal Telopeptide Level in Adults | Day 1-3 of inpatient evaluation at the conclusion of 13 weeks of PTH 1-34 delivered by pump or injection | Mean 24-hour urine N-terminal telopeptide of type 1 collagen excretion at the end of week 13. After 13 weeks of PTH 1-34 administration, participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated. |
| Mean Blood Mineral Levels - Calcium, Phosphorus, Magnesium | Day 1-3 of baseline initial inpatient evaluation | Mean fasting serum calcium, phosphorus, and magnesium levels first three days of initial baseline inpatient admission. Participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine Mineral Excretion - Calcium, Phosphorus, Magnesium | Day 1-3 of baseline initial inpatient evaluation | Mean 24-hour urine calcium, phosphorus, and magnesium excretion first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children and young adults. |
| Mean Serum Alkaline Phosphatase | Day 1-3 of baseline initial inpatient evaluation | Mean fasting serum alkaline phosphatase level first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Bone Specific Alkaline Phosphatase in Children and Young Adults | Day 1-3 of baseline initial inpatient evaluation | Mean fasting serum bone specific alkaline phosphatase level first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum 1,25-hydroxyvitamin D3 | Day 1-3 of baseline initial inpatient evaluation | Mean fasting serum 1,25-hydroxyvitamin D3 level first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Serum Bone Minerals - 25-hydroxyvitamin D3 and Osteocalcin | Day 1-3 of baseline initial inpatient evaluation | Mean fasting serum 25-hydroxyvitamin D3 and osteocalcin levels first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and fasting blood sample was collected each morning (6-8 am) for three days. Mean value for the three days was calculated. |
| Mean Urine Creatinine Clearance Excretion | Day 1-3 of baseline initial inpatient evaluation | Mean 24-hour urine creatinine clearance excretion first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children. |
| Mean Urine N-terminal Telopeptide Level | Day 1-3 of baseline initial inpatient evaluation | Mean 24-hour urine N-terminal telopeptide of type 1 collagen excretion first 3 days of initial baseline inpatient admission. Participants were admitted for five to seven days and 24 hour urine sample was collected each day for three days. Mean value for the three days was calculated with values corrected for body surface area in children. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKaren K Winer, M.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Participant flow
Pre-assignment details
One participant withdrew prior to randomization
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized >= 21 years | 8 Participants |
| Age, Customized 7-20 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 3 / 20 | 4 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
None listed