The primary objective is to test the hypothesis that rhPTH(1-84) treatment can result in superior improvements in the symptoms of hypoparathyroidism as assessed by the Hypoparathyroidism Symptom Diary (HPT-SD) symptom subscale compared with standard…
ID
Source
Brief title
Condition
- Endocrine and glandular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is to test the hypothesis that rhPTH(1-84) treatment can
result in superior improvements in the symptoms of hypoparathyroidism as
assessed by the Hypoparathyroidism Symptom Diary (HPT-SD) symptom subscale
compared with standard therapy.
Secondary outcome
The key secondary objectives are to test the hypotheses that rhPTH(1-84)
treatment can result in superior improvements in:
- Fatigue as assessed by the Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-Fatigue) compared with standard therapy.
- The physical component summary (PCS) derived from the 36-Item Short Form
Health Survey version 2 (SF-36v2) acute version compared with standard therapy.
Background summary
Chronic hypoparathyroidism is a rare disease characterized by hypocalcemia and
insufficient levels of parathyroid hormone (PTH).
Until recently, standard therapy for hypoparathyroidism consisted of calcium
and vitamin D supplementation, which only addresses the hypocalcemia
characteristic of this disorder. Other metabolic disorders associated with
hypoparathyroidism are not addressed by standard therapy.
The pivotal Phase 3 clinical study in the rhPTH(1 84) program demonstrated that
rhPTH(1-84) is effective in maintaining serum calcium levels and enabling
significant decreases in active vitamin D and oral calcium doses, when
administered subcutaneously once daily for 6 months. Long-term, open label
studies have supported these findings with subjects maintaining the physiologic
benefit derived from rhPTH(1-84) treatment .
A review of safety data across the hypoparathyroidism program indicated that
rhPTH(1 84) is safe for use for the treatment of hypoparathyroidism.
Study objective
The primary objective is to test the hypothesis that rhPTH(1-84) treatment can
result in superior improvements in the symptoms of hypoparathyroidism as
assessed by the Hypoparathyroidism Symptom Diary (HPT-SD) symptom subscale
compared with standard therapy.
Study design
This is a randomized, double-blind, placebo-controlled, 2-arm, adaptive study
in a minimum of 92 to no more than 150 adult subjects with symptomatic chronic
hypoparathyroidism on standard therapy. The study periods will be as follows: a
3-week screening period; a 16-week dose-titration period; a 10-week
maintenance-dosing period with minimal change in investigational product dose;
and a 4-week safety follow-up period that includes an end-of study contact for
all subjects 30 days following the last dose of investigational product. The
safety follow-up period includes weekly visits for subjects discontinuing
rhPTH(1-84) treatment after the end-of-treatment visit (Week 26) or early
termination visit. Subjects transferring to commercial rhPTH(1-84) who
experienced a treatment gap of >7 day after the EOT (Week 26) visit will
proceed with weekly follow-up visits for every week that there is an
interruption in rhPTH(1-84) dosing until receiving commercial rhPTH(1-84) or
until a maximum of 30 days has elapsed.
Immediately before dosing at the baseline visit (Week 0), eligible subjects
will be randomized in a 1:1 ratio to 1 of 2
treatment arms:
•rhPTH(1-84) as adjunctive treatment with active vitamin D and/or calcium
supplements
•*Placebo with active vitamin D and/or calcium supplements.
Investigational product [rhPTH(1-84) or placebo] will be administered each day
in the morning by SC injection into the thigh, alternating the left and right
thighs each day, via a multidose injection pen device. Subjects and site
personnel will remain blinded to the treatment assignments for the duration of
the study. Active vitamin D and calcium supplements will be provided by the
sponsor or designee or study site.
Dosing of investigational product and active vitamin D and calcium supplements
will be adjusted for each subject to
achieve specified biochemical target levels. Investigational product doses are
intended to remain stable during the last
12 weeks of the treatment period.
Serum calcium, albumin, phosphate, magnesium, 25-hydroxyvitamin D, and
1,25-dihydroxyvitamin D will be measured
at specified time points to assess efficacy and to provide information for
adjustment of investigational product and
supplement doses. Urine calcium, phosphate, magnesium, creatinine, sodium, and
citrate excretion, markers of bone
turnover, and bone mineral density will be measured at specified time points to
assess efficacy. Renal ultrasound
scans will be performed and fibroblast growth factor (FGF)-23 measured as
exploratory assessments of drug effect.
Subjects will be asked to complete neurocognitive assessment and
patient-reported outcome (PRO) instruments.
Healthcare utilization will also be recorded.
Safety measures will include adverse event (AE) recording, serum chemistry,
hematology, urinalysis, vital signs,
electrocardiograms (ECGs), physical examinations, and measurement of
parathyroid hormone (PTH) antibodies.
Subjects who discontinue treatment with rhPTH(1-84) (gap >7days) following
completion of the end-of-treatment (or early termination) visit and are not
immediately continuing treatment with commercial rhPTH(1-84) will enter a
weekly safety follow up period with serum calcium measurements until the
subject is able to begin outpatient rhPTH(1-84) treatment or until a maximum of
30 days has elapsed. All subjects will complete an EOS contact (Week 30 visit),
a safety follow up site visit who discontinued treatment with rhPTH(1-84) or is
a telephone call initiated by the site staff to document any serious adverse
events (SAEs), adverse events (AEs), and concomitant treatments for subjects
treated with commercial rhPTH(1-84).
Intervention
There is a chance of 50% that the patient will receive rhPTH(1-84) and a
chance of 50% of recieving placebo. Both groups will be taking calcium and
active vitamin D supplements during the study.
Study burden and risks
The study drug and study procedures are associated with certain risks. These
are described in the ICF. The study drug and the study procedures and the
combination thereof, can also lead to other unknown risks. The subjects are
carefully monitored. If necessary, the study drug dosage will be decreased of
administration will be stopped.
Shire Way 300
Lexington 02421
US
Shire Way 300
Lexington 02421
US
Listed location countries
Age
Inclusion criteria
1. Has an understanding, ability, and willingness to fully comply with study
procedures and restrictions.
2. Is able to voluntarily provide a signed and dated informed consent form
before any study-related procedures are performed.
3. Is an adult male or female 18 to 85 years of age, inclusive.
4. In subjects 18-25 years of age, has radiological evidence of epiphyseal
closure based on bone age X-ray (single posteroanterior X-ray of left wrist and
hand)
5. Has chronic hypoparathyroidism with onset 12 months or more before
screening. The diagnosis of hypoparathyroidism is established based on
hypocalcemia in the setting of inappropriately low serum PTH levels., 6. During
the Week -3 screening visit, the subject reports by history at least 2 of the
following symptoms related to hypoparathyroidism occurring within the 2 weeks
before Week -3 visit: muscle cramps, muscle spasms or twitching, tingling,
numbness, heaviness in arms or legs, physical fatigue, or slowed or confused
thinking (brain fog)., 7. The subject must have a Hypoparathyroidism Symptom
Diary (HPT-SD) symptom subscale Sum Score of >=10 during the 14-day period
immediately prior to the baseline (Week 0) visit (Day -14 to Day -1). In
addition, the subject must have at least 4 HPT-SD diaries completed in the
first 7 day period and at least 4 HPT-SD diaries completed in second 7 day
period. See Appendix 3 for the calculation of the sum score., 8. Must be
treated with active vitamin D (calcitriol or alfacalcidol) alone or in
conjunction with calcium supplements for at least 4 months prior to the
screening visit.
• The subject must be taking >=0.5 µg/day of calcitriol or >=1.0 µg/day of
alfacalcidol.
• If the subject is treated with a lower dose of active vitamin D the subject
must also be taking calcium supplements of at least 800 mg/day of elemental
calcium, 9. Has thyroid-stimulating hormone (TSH) results within normal
laboratory limits at screening for all subjects not receiving thyroid hormone
replacement therapy. For subjects on thyroid hormone replacement therapy, the
thyroid hormone dose must have been stable for at least 4 weeks before
screening, and serum TSH level must be within the central laboratory the normal
range. A serum TSH level below the lower limit of the normal range but not
undetectable in subjects treated with thyroid hormone may be allowed if there
is no anticipated need for a change in thyroid hormone dose during the trial.,
10. Has serum 25-hydroxyvitamin D levels >=50 nmol/L (20 ng/mL) and <1.5
times the upper limit of normal (ULN) for the central laboratory normal range.,
11. Has estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2., 12.
Prior to randomization, is able to perform daily SC self-injections of study
medication (or have a designee perform injection) via a multidose injection pen
into the thigh., 13. Willing to use oral active vitamin D and calcium
supplements provided for the study unless directed to remain on the supplements
used prior to enrollment in the current study by the investigator after
consultation with the medical monitor., 14. With regard to female subjects:
women who are postmenopausal (12 consecutive months of spontaneous amenorrhea
and age more than or equal to 51 years) and women who are surgically sterilized
can be enrolled. Women of childbearing potential must have a negative pregnancy
test at
randomization and be willing to comply with any applicable contraceptive
requirements of the protocol and pregnancy testing for the duration of the
study.
Exclusion criteria
1. History of hypoparathyroidism resulting from a known activating mutation in
the CaSR gene or impaired responsiveness to PTH (pseudohypoparathyroidism)., 2.
Any disease that might affect calcium metabolism or calcium-phosphate
homeostasis other than hypoparathyroidism, such as poorly controlled
hyperthyroidism; Paget disease; type 1 diabetes mellitus or poorly controlled
type 2 diabetes mellitus; severe and chronic cardiac, liver (Child-Pugh score
>9) (US FDA, 2003), or renal disease; Cushing syndrome; rheumatoid arthritis;
myeloma; active pancreatitis; malnutrition; rickets; recent prolonged
immobility; active malignancy (other than low-risk well differentiated thyroid
cancer); primary or secondary hyperparathyroidism; or documented parathyroid
carcinoma within the previous 5 years, acromegaly, or multiple endocrine
neoplasia types 1 and 2.
3. Very low or very high blood calcium level (eg, ACSC <1.87 mmol/L [<7.5
mg/dL] or >=2.97 mmol/L [>=11.9 mg/dL]) at the Week -3 screening visit. Results
from the central laboratory must be used for this assessment.
4. If the Blood calcium level is above the ULN at the baseline (Week 0) visit,
the analysis can be repeated another day as long as the next date is within the
visit window for the baseline visit. If the subject does not met exclusion #4
on the repeat measure the subject may be randomized., 5. Use of prohibited
medications, such as loop and thiazide diuretics, phosphate binders (other than
calcium carbonate), digoxin, lithium, methotrexate, or systemic
corticosteroids, within respective prohibited periods. See Section 5 (Prior and
Concomitant Treatment) for a list of prohibited and restricted medications, 6.
Participation in any other investigational study in which receipt of
investigational drug or device occurred within 6 months before screening for
this study. Prior treatment with PTH-like drugs (whether commercially available
or through participation in an, investigational study), including PTH(1-84),
PTH(1-34), or other N-terminal fragments or analogs of PTH or PTH-related
protein, within 3 months before screening., 7. Use of other drugs known to
influence calcium and bone metabolism, such as calcitonin, fluoride tablets, or
cinacalcet hydrochloride, within the prohibited period., 8. Use of oral
bisphosphonates within the previous 6 months or intravenous bisphosphonate,
preparations within the previous 24 months before screening., 9.
Nonhypocalcemic seizure disorder with a history of a seizure within the
previous 6 months before screening. Subjects with a history of seizures that
occur in the setting of hypocalcemia are allowed., 10. The subject is at
increased baseline risk for osteosarcoma, such as those with Paget*s disease of
bone or unexplained elevations of alkaline phosphatase, hereditary disorders
predisposing to osteosarcoma, or with a prior history of external beam or
implant radiation therapy involving the skeleton., 11. Any disease or condition
that, in the opinion of the investigator, may require treatment or make the
subject unlikely to fully complete the study, or any condition that presents
undue risk from the investigational product or procedures. For example, illness
that is anticipated to be chronic and not transient., 12. Pregnant or lactating
women., 13. Known or suspected intolerance or hypersensitivity to the
investigational product, closely-related compounds, or any of the stated
ingredients. Refer to the investigator*s brochure for the list of excipients.
14. History of diagnosed drug or alcohol dependence within the previous 3 years.
15. Poorly controlled short bowel syndrome, bowel resection, tropical sprue,
celiac disease, ulcerative colitis, and Crohn disease.
16. Chronic or severe cardiac disease including but not limited to heart
failure (according to the New York Heart Association classification Class II to
Class IV) (Dolgin and NYHA, 1994), arrhythmias, bradycardia (resting heart rate
<50 beats/minute).
17. History of cerebrovascular accident.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2017-000284-32-NL |
CCMO | NL62879.056.17 |