Effects of PTH Replacement on Bone in Hypoparathyroidism

NCT00395538 | Terminated Phase 3 Results FDA Drug

• 2 other identifiers: 07001607-D-0016
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Hypoparathyroidism is a rare condition associated with a low level of parathyroid hormone (PTH) in the blood. Hypoparathyroidism can be genetic and show up in childhood, or it can occur later in life. If it occurs later, it is usually due to damage or removal of the parathyroid glands during neck surgery. PTH helps control the amount of calcium in blood, kidneys, and bones. Low levels of calcium in the blood can cause a person to feel sick. It can cause cramping or tingling in the hands, feet, or other parts of the body. A very low blood calcium can cause fainting or seizures. The standard treatment for hypoparathyroidism is a form of vitamin D (calcitriol) and calcium supplements. Keeping normal blood levels of calcium can be difficult. Sometimes there is too much calcium in the urine even if the calcium levels in the blood are low. High calcium in the kidneys and urine can cause problems such as calcium deposits in the kidney (nephrocalcinosis) or kidney stones. High levels of calcium in the kidney may keep the kidney from functioning normally. Treatment with PTH will replace the hormone you are missing. Your disease may be better controlled on PTH than on calcium and calcitriol. Researchers at the NIH have conducted prior studies to establish synthetic human parathyroid hormone 1-34 (HPTH) as a treatment for hypoparathyroidism. Other studies have shown that PTH may improve calcium levels in blood and urine. The primary purpose of this research study is to evaluate the effects of synthetic human parathyroid hormone 1-34 (HPTH) replacement therapy on bone in adults and teenagers with hypoparathyroidism. The study takes 5 (Omega) years to complete and requires 12 inpatient visits to the National Institutes of Health Clinical Center in Bethesda, MD. The first visit will help the study team decide whether you are eligible. This visit will last 2 to 3 days. After taking calcium and calcitriol for 1 - 7 months you will return to the NIH Clinical Center for the baseline visit. The baseline visit is the visit that you will start your PTH; you will also undergo a bone biopsy during the visit. The baseline visit may last 7 to 10 days. You will then take PTH twice a day for 5 years. You will be asked to return to the NIH clinical center every 6 months for 10 follow-up visits. During one of the follow-up visits, you will have a second bone biopsy taken from the other hip. That second biopsy will be done after 1 year, 2 years, or 4 years of taking PTH; the researchers will assign the timing of the second biopsy randomly. You will be asked to go to your local laboratory for blood and urine tests between each follow up visit. At first the blood tests will occur at least once a week. Later, you will need to go to your local laboratory for blood tests at least once a month and urine tests once every 3 months. The local laboratory visits and follow-up visits at the NIH Clinical Center will help the study team determine whether the HPTH treatment is controlling your hypoparathyroidism.

Conditions

Hypoparathyroidism; DiGeorge Syndrome

Keywords

Parathyroid; Bone Biopsy; Calcium-Sensing Receptor; Bone Density; Bone Turnover; Hypoparathyroidism

Outcome Measures

Primary Outcomes (8)

• Change in Bone Biopsy Cancellous Bone Volume (Cn.BV/TV)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, so the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.BV/TV is one of 8 primary endpoints measured from the bone biopsy. The changes in Cn.BV/TV outcome between two time-points are being reported. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Total Number of Cortical Pores Per mm^2 (Ct.Po.N)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, so the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ct.Po.N is a bone biopsy measure that assess the amount of holes in the cortical bone within a predetermined area of cortical bone. The changes in Cn.BV/TV outcome between two time-points are being reported. Cortical bone with a higher number of holes may be at greater risk of fracture. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Cancellous Bone Formation Rate Per Unit of Bone Surface (Cn.BFR/BS)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.BFR/BS, measured from the bone biopsy, is the cancellous bone formation rate per unit of bone surface where cancellous refers to the spongy structure of the bone. The changes in Cn.BFR/BS between two time-points are being reported. The unit of measure is a z-score. Z-scores are normed to standard populations to a mean of zero and a standard deviation of 1. The normal range for a z-score is from -2 to 2. Values above or below this normal range are considered worse outcomes.

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Cancellous Mineralizing Surface (Bone Surface Based)(Cn.MS/BS)

  Following their baseline bone biopsy, 5, 5, and 2 participants were randomized to receive their second bone biopsy at years 1, 2, and 4 after the start of HPTH therapy, respectively. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced in size due to withdrawal and the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Cn.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the cancellous bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Cn.MS/BS between two time-points are being reported.

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Endocortical Bone Formation Rate Per Unit of Bone Surface (Ec.BFR/BS)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.BFR/BS is measured from the bone biopsy. This measures the rate of new bone formation per day on the inner cortical (endocortical) surface in a predefined region of cortical bone. The changes in Ec.BFR/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Endocortical Mineralizing Surface (Bone Surface Based) (Ec.MS/BS)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ec.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the endocortical bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Ec.MS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Intracortical Bone Formation Rate Per Unit of Bone Surface (Ic.BFR/BS)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. However, because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.BFR/BS is measured from the bone biopsy. This measures the rate of new bone formation between the two cortical surfaces (intracortical) in a predefined region of cortical bone. The changes in Ic.BFR/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Intracortical Mineralizing Surface (Bone Surface Based) (Ic.MS/BS)

  Participants (in Cohorts 2 and 3) were randomized to receive their second bone biopsy at year 1, 2, or 4 after the start of HPTH therapy. For Cohort 2, the baseline bone biopsy was completed at the start of CC on the original protocol. For Cohort 3, the baseline biopsy was completed immediately prior to the first HPTH dose. Because the sample sizes for the 1-, 2- and 4-year biopsies are reduced due to the early termination of the study, the 2-, and 4-year biopsies were collapsed into one biopsy year group. Ic.MS/BS is measured from the bone biopsy. This measure demonstrates the percentage of the intracortical bone surface that is actively forming bone. The region of interest is the predefined area of total bone that is being measured. The changes in Ic.MS/BS between two time-points are being reported. The n's in the outcome measure table refer to the number of complete records (non-missing baseline and post-baseline measures).

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Secondary Outcomes (58)

• Change in Trabecular Thickness (Tb.Th)

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Trabecular Number (Tb.N)

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Trabecular Separation (Tb.Sp)

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Change in Average Thickness of Inner and Outer Cortices (Ct.Th)

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

• Total Area of Inner and Outer Cortices (Ct.Ar)

  Baseline, 1 year bone biopsy, and combined 2 and 4 year bone biopsies

Study Arms (1)

Biopsy

OTHER

Subjects are randomized to have the second bone biopsy done 1,2, or 4 years after the start of PTH.

Drug: PTH 1-34

Interventions

PTH 1-34 DRUG

Given twice daily by subcutaneous

Also known as: HPTH

Biopsy

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age eligibility at screening:
• Premenopausal women: aged 18 to 45 years,
• Postmenopausal women: aged greater than or equal to 53 years to 70 years and 5 years since last menses. For women without a uterus, subjects must have a clinical history of menopause for at least 5 years and an FSH greater than 30 U/L.
• Men: aged 18 to 70 years,
• Physician-diagnosed hypoparathyroidism of at least 1-year duration, confirmed by medical record review. The investigators will confirm the diagnosis during the screening visit at which time the subject must have an intact PTH \< 30 pg/mL.

You may not qualify if:

• Moderate to severe hepatic disease defined as hepatic transaminases (ALT and AST) \> 2 times the upper limit of normal
• Severe renal insufficiency defined as a calculated GFR \< 25 mL/min/1.73 m(2), using the CKD-EPI equation(15).
• Allergy or intolerance to tetracycline antibiotics
• Pregnant or lactating or planning to become pregnant during the course of the study. (Women who are able to get pregnant must agree to use an effective form of birth control while in this study.).
• Perimenopausal defined by no menses for 6 months to 5 years and an FSH \> 20 U/L at the screening and/or baseline visits..
• Chronic diseases that might affect mineral metabolism such as diabetes, celiac disease, Crohn s disease, Cushing s syndrome, or adrenal insufficiency
• Concurrent treatment with doses of thyroid hormone intended to suppress thyroid stimulating hormone below the assay s detection limit or persistent thyroid cancer
• History of a skeletal disease unrelated to hypoparathyroidism, such as osteoporosis or low bone density (defined as a DXA Z-Score \< -2 in all subjects or T-score \< -2 in subjects greater than or equal to 20 year old), osteosarcoma, Paget s disease, alkaline phosphatase \> 1.5 times the upper limit of normal, or metastatic bone disease
• History of retinoblastoma or Li-Fraumeni syndrome
• History of treatment with bisphosphonates, calcitonin, tamoxifen, selective-estrogen receptor modulators, or directed skeletal irradiation
• Use of oral or intravenous corticosteroids or estrogen replacement therapy for more than 3 weeks within the last 6 months
• Use of depot medroxyprogesterone for contraception within the past 12 months
• Chronic inadequate biochemical control with conventional therapy and/or calcium infusion dependent
• Seizure disorder requiring antiepileptic medications
• Treatment with PTH for more than 2 weeks continuously at any time, prior to study entry

Sponsors & Collaborators

• National Institute of Dental and Craniofacial Research (NIDCR): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Chan JC, Young RB, Alon U, Mamunes P. Hypercalcemia in children with disorders of calcium and phosphate metabolism during long-term treatment with 1,25-dihydroxyvitamin-D3. Pediatrics. 1983 Aug;72(2):225-33. No abstract available.

  PMID: 6688127 BACKGROUND

• Chan JC, Young RB, Hartenberg MA, Chinchilli VM. Calcium and phosphate metabolism in children with idiopathic hypoparathyroidism or pseudohypoparathyroidism: effects of 1,25-dihydroxyvitamin D3. J Pediatr. 1985 Mar;106(3):421-6. doi: 10.1016/s0022-3476(85)80668-5.

  PMID: 3838346 BACKGROUND

• Christiansen C, Rodbro P, Christensen MS, Hartnack B, Transbol I. Deterioration of renal function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol. Lancet. 1978 Sep 30;2(8092 Pt 1):700-3. doi: 10.1016/s0140-6736(78)92702-2.

  PMID: 80633 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hypoparathyroidism; DiGeorge Syndrome

Interventions

Parathyroid Hormone

Condition Hierarchy (Ancestors)

Parathyroid Diseases; Endocrine System Diseases; 22q11 Deletion Syndrome; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Lymphatic Abnormalities; Lymphatic Diseases; Hemic and Lymphatic Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Robert James
• Organization: Rho, Inc

robert_james@rhoworld.com

(919) 595-6468

Study Officials

• Rachel I Gafni, M.D.

  National Institute of Dental and Craniofacial Research (NIDCR)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2006
• First Posted: November 3, 2006
• Study Start: October 30, 2006
• Primary Completion: September 30, 2017
• Study Completion: October 4, 2017
• Last Updated: August 28, 2019
• Results First Posted: January 8, 2019

Record last verified: 2019-08

Locations

US (1)