Clinical trial NCT03324880: A Study to Learn if Recombinant Human Parathyroid Hormone [rhPTH(1-84)] Can Improve Symptoms and Metabolic Control in Adults With Hypoparathyroidism (BALANCE)
Official title: A Randomized, Double-blind, Placebo-controlled, Adaptive Study to Evaluate Symptom Improvement and Metabolic Control Among Adult Subjects With Symptomatic Hypoparathyroidism Treated With Recombinant Human Parathyroid Hormone [rhPTH(1-84)]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypoparathyroidism
Keywords: rhPTH[1-84)
Parathyroid hormone
Hypocalcemia
Hypoparathyroidism
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2017-10-30
Enrollment: 93
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Recombinant human parathyroid hormone, also known as if rhPTH(1-84), is a medicine to treat people with Hypothyroidism. The main aim of this study is to learn if rhPTH(1-84) can improve symptoms in adults with hypoparathyroidism.

In this study, participants will receive 1 of 2 treatments: rhPTH(1-84) or a placebo. A placebo looks like the medicine being studied but does not have medicine in it. In this study, the placebo will be a standard treatment which is either active Vitamin D, or active Vitamin D with calcium. Active Vitamin D is a form of vitamin D that has a faster effect on the body. These treatments will be given as a daily injection just under the skin. Participants will not know which treatment they received, nor will their study doctors. This is to help make sure the results are more reliable. All participants will also take active vitamin D and calcium supplements during treatment.

Participants will record their symptoms in a tool called the hypoparathyroidism symptom diary. This tool is used to assess symptoms and their impact and will give an overall score for each participant.

The study doctors will also check for side effects from the study treatments.

After treatment, researchers will check if there is any difference in the diary scores between the 2 treatment groups. A difference in score means there is a difference in symptoms and their impact. From this, researchers will learn if symptoms have improved for participants treated with rhPTH(1-84) compared with those treated with placebo.

Detailed description: 24 SEPTEMBER 2020: The temporary enrollment stop of new patients into this study due to the COVID-19 pandemic has been lifted in one or more countries, and the study is now again enrolling new patients. However, some countries/sites may still have paused the enrollment of new patients due to the pandemic.

20 APRIL 2020: Enrollment of new patients into this study has been paused due to the COVID-19 situation. The duration of this pause is dependent on the leveling and control of the COVID-19 pandemic.

Eligibility criteria: Inclusion Criteria:

* Has an understanding, ability, and willingness to fully comply with study procedures and restrictions.
* Is able to voluntarily provide a signed and dated informed consent form before any study-related procedures are performed.
* Is an adult male or female 18 to 85 years of age, inclusive.
* In participants 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) before randomization.
* 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.
* During the Week -3 screening visit, the participant 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).
* The participant must have a Hypoparathyroidism Symptom Diary (HPT-SD) symptom subscale Sum Score of greater than or equal to (\>=) 10 during the 14-day period immediately prior to the baseline (Week 0) visit (Day -14 to Day -1). In addition, the participant 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.
* 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.

  1. The participant must be taking \>= 0.5 microgram (mcg)/day of calcitriol or \>=1.0 mcg/day of alfacalcidol.
  2. If the participant is treated with a lower dose of active vitamin D the participant must also be taking calcium supplements of at least 800 milligrams per day (mg/day) of elemental calcium.
* Has serum thyroid-stimulating hormone (TSH) results within normal laboratory limits at screening for all participants not receiving thyroid hormone replacement therapy. For participants 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 normal range. A serum TSH level below the lower limit of the normal range but not undetectable in participant treated with thyroid hormone may be allowed if there is no anticipated need for a change in thyroid hormone dose during the trial.
* Has serum 25-hydroxyvitamin D levels \>=50 nmol/L (nanomoles per liter) (20 nanograms per milliliter \[ng/mL\]) and less than (\<) 1.5 times the upper limit of normal (ULN) for the central laboratory normal range.
* Has estimated glomerular filtration rate (eGFR) greater than (\>) 30 milliliter per minute per 1.73 square meters (ml/min/1.73m\^2).
* 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.
* 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.
* With regard to female participants: women who are postmenopausal (12 consecutive months of spontaneous amenorrhea and age \>= 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:

* History of hypoparathyroidism resulting from a known activating mutation in the CaSR gene or impaired responsiveness to PTH (pseudohypoparathyroidism).
* 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.
* 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.
* Blood calcium level above the ULN at the baseline (Week 0) visit. Results from a local laboratory may be used for this assessment.
* 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.
* 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.
* Use of other drugs known to influence calcium and bone metabolism, such as calcitonin, fluoride tablets, or cinacalcet hydrochloride, within the prohibited period.
* Use of oral bisphosphonates within the previous 6 months or intravenous bisphosphonate preparations within the previous 24 months before screening.
* Nonhypocalcemic seizure disorder with a history of a seizure within the previous 6 months before screening. Participants with a history of seizures that occur in the setting of hypocalcemia are allowed.
* The participant 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.
* Any disease or condition that, in the opinion of the investigator, may require treatment or make the participant 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.
* Pregnant or lactating women.
* Known or suspected intolerance or hypersensitivity to the investigational product, closely-related compounds, or any of the stated ingredients.
* History of diagnosed drug or alcohol dependence within the previous 3 years.
* Poorly controlled short bowel syndrome, bowel resection, tropical sprue, celiac disease, ulcerative colitis, and Crohn disease.
* 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).
* History of cerebrovascular accident.

Primary outcomes:
measure: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Subscale Score at Week 26
timeFrame: Baseline, Week 26
Secondary outcomes:
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Physical Component Summary (PCS) Derived From 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Subscale Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Items Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Anxiety (Item 8) Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Sadness or Depression (Item 9) Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Scores at Week 26
timeFrame: Baseline, Week 26
measure: Number of Participants With Response at Week 26 [Early Termination (ET)]
timeFrame: Baseline up to Week 26
measure: Change From Baseline in the Most Bothersome Symptom Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Perceived Cognitive Impairments (PCI) Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Impact on Quality of Life (QoL) Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Individual Domains of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Hypoparathyroidism (WPAI: Hypoparathyroidism) Score at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Severity (PGI-S) at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Change (PGI-C) at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in In-Clinic Neurocognitive Assessment Scores at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in At-Home Neurocognitive Assessment Scores at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in 24-hour Urine Calcium Excretion at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Serum Phosphate Level at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Doses of Active Vitamin D at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Doses of Calcium Supplements at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Albumin-corrected Serum Calcium Control at Week 26
timeFrame: Week 26
measure: Number of Participants Who Achieve Composite Criteria for Albumin-corrected Serum Calcium Concentration, Active Vitamin D Dose and Oral Elemental Calcium Supplement Dose at Week 26
timeFrame: Week 26
measure: Change From Baseline in Bone Turnover Marker Bone Specific Alkaline Phosphatase at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Bone Turnover Marker Type I Collagen C-Telopeptides at Week 26
timeFrame: Baseline, Week 26
measure: Change From Baseline in Bone Turnover Marker Osteocalcin and Procollagen 1 N-Terminal Propeptide at Week 26
timeFrame: Baseline, Week 26
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From start of study drug administration to 4 weeks post follow-up (up to Week 36)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Detroit
country: United States
facility: Michigan Bone and Mineral Clinic
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - PPDS
state: Minnesota
city: Greenville
country: United States
facility: Physicians East PA
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Gent
country: Belgium
facility: UZ Gent
state: Oost-Vlaanderen
city: Leuven
country: Belgium
facility: UZ Leuven
state: Vlaams Brabant
city: Halifax
country: Canada
facility: Nova Scotia Health Authority (Capital District Health Authority)
state: Nova Scotia
city: Oakville
country: Canada
facility: Bone Research and Education Centre
state: Ontario
city: Quebec
country: Canada
facility: CHU de Quebec-Universite Laval
city: Saint John's
country: Canada
facility: Eastern Health - Health Sciences Center- General Hospital
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital
state: Central Jutland
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Angers
country: France
facility: CHU Angers
city: Besançon
country: France
facility: Hopital Jean Minjoz
city: Le Kremlin-Bicêtre
country: France
facility: CHU Bicêtre
city: Lille
country: France
facility: CHRU Lille
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der TU Dresden
state: Sachsen
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
state: Lombardia
city: Firenze
country: Italy
facility: Universita di Firenze, Dipartimento di Chirurgia e Medicina Traslazionale (DCMT)
city: Roma
country: Italy
facility: Università Campus Bio Medico Di Roma
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
state: Noord-Holland
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Bergen
country: Norway
facility: Haukeland Universitetssykehus
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF Rikshospitalet
city: Oslo
country: Norway
facility: Oslo Universitetssykehus Aker
city: Coimbra
country: Portugal
facility: Centro Hospitalar E Universitário de Coimbra EPE
city: Matosinhos
country: Portugal
facility: Unidade Local de Saúde de Matosinhos SA
city: Porto
country: Portugal
facility: Centro Hospitalar de São João, E.P.E.
city: Cordoba
country: Spain
facility: C.H. Regional Reina Sofia - PPDS
state: Córdoba
city: Pozuelo De Alarcón
country: Spain
facility: Hospital Universitario Quironsalud Madrid
state: Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Gothenburg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Dundee
country: United Kingdom
facility: Ninewells Hospital - PPDS
state: Dundee City
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: Norfolk
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary - PPDS
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: