# rhPTH(1-84) for hypoparathyroidism: a randomized study of patient-reported outcomes.

M. L. Brandi, T. Vokes, N. M. Appelman-Dijkstra, O. Ayodele, B. Decallonne, R. de Jongh, M. Díaz-Curiel, W. Fraser, R. D. Finkelman, A. Heck, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

M. L. Brandi, T. Vokes, N. M. Appelman-Dijkstra, O. Ayodele, B. Decallonne, et al., rhPTH(1-84) for hypoparathyroidism: a randomized study of patient-reported outcomes., European Journal of Endocrinology, 2025, Eur J Endocrinol, 10.1093/ejendo/lvaf148. [https://doi.org/10.1093/ejendo/lvaf148](https://doi.org/10.1093/ejendo/lvaf148). [hal-05280507](https://hal HAL Id: hal-05280507)

Submitted on 24 Sep 2025

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<figure><img src="image_2.png" /></figure>
rhPTH(1-84) for hypoparathyroidism: a randomized study
of patient-reported outcomes

Maria Luisa Brandi,<fnref n="1" /> Tamara Vokes,<fnref n="2" /> Natasha M. Appelman-Dijkstra,<fnref n="3" /> Olulade Ayodele,<fnref n="4" />,\* ID

Brigitte Decallonne,<fnref n="5" /> Renate de Jongh,<fnref n="6" /> Manuel Díaz-Curiel,<fnref n="7" /> William Fraser,<fnref n="8" />,<fnref n="9" />,† ID

Richard D. Finkelman,<fnref n="10" /> Ansgar Heck,<fnref n="11" /> ID Steven W. Ing,<fnref n="12" /> Peter Kamenický,<fnref n="13" />,<fnref n="14" /> Aliya A. Khan,<fnref n="15" />

Christopher S. Kovacs,<fnref n="16" /> ID Bruno Lapauw,<fnref n="17" /> ID Graham Leese,<fnref n="18" /> Giovanna Mantovani,<fnref n="19" />,<fnref n="20" /> ID

Guillermo Martínez Díaz-Guerra,<fnref n="21" /> Laura Masi,<fnref n="22" /> Miguel Melo,<fnref n="23" /> ID Andrea Palermo,<fnref n="24" />,<fnref n="25" /> ID

Narendra L. Reddy,<fnref n="26" /> Lars Rejnmark,<fnref n="27" /> Elena Tokareva,<fnref n="4" /> Marie-Christine Vantyghem,<fnref n="28" />

Suwei Wang,<fnref n="4" /> Mark Warren,<fnref n="29" /> and Brian Yan<fnref n="4" />,‡

<footnote n="1">¹Fondazione Italiana Ricerca Sulle Malattie Dell'Osso, Fondazione Italiana Ricerca Sulle Malattie Dell'Osso, 50229 Florence, Italy</footnote>

<footnote n="2">²Section of Endocrinology, Diabetes and Metabolism, University of Chicago Medicine, Chicago, IL 60637, United States</footnote>

<footnote n="3">³Department of Internal Medicine, Leiden University Medical Center, 2333 Leiden, Netherlands</footnote>

<footnote n="4">⁴Takeda Development Center Americas, Inc., Cambridge, MA 02142, United States</footnote>

<footnote n="5">⁵Department of Endocrinology, University Hospitals Leuven, 3000 Leuven, Belgium</footnote>

<footnote n="6">⁶Department of Endocrinology and Metabolism, Amsterdam UMC Location Vrije Universiteit, 1081 HV Amsterdam, Netherlands</footnote>

<footnote n="7">⁷Metabolic Bone Diseases Unit, Fundación Jiménez Díaz, 28040 Madrid, Spain</footnote>

<footnote n="8">⁸Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, United Kingdom</footnote>

<footnote n="9">⁹Departments of Clinical Biochemistry and Endocrinology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, United Kingdom</footnote>

<footnote n="10">¹⁰Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA 02421, United States</footnote>

<footnote n="11">¹¹Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, N-0424 Oslo, Norway</footnote>

<footnote n="12">¹²Division of Endocrinology, Diabetes and Metabolism, Ohio State University Wexner Medical Center, Columbus, OH 43202, United States</footnote>

<footnote n="13">¹³Inserm, Physiologie et Physiopathologie Endocriniennes, Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France</footnote>

<footnote n="14">¹⁴Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate Hôpital Bicêtre AP-HP, 94270 Le Kremlin-Bicêtre, France</footnote>

<footnote n="15">¹⁵Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario L8N 3Z5, Canada</footnote>

<footnote n="16">¹⁶Faculty of Medicine—Endocrinology, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1C 5S7, Canada</footnote>

<footnote n="17">¹⁷Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium</footnote>

<footnote n="18">¹⁸Department of Molecular and Clinical Medicine, University of Dundee, Dundee DD1 4HN, United Kingdom</footnote>

<footnote n="19">¹⁹Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milan, Italy</footnote>

<footnote n="20">²⁰Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy</footnote>

<footnote n="21">²¹Department of Endocrinology and Nutrition, Instituto de Investigación Imas 12, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain</footnote>

<footnote n="22">²²Metabolic Bone Diseases Unit, University Hospital Florence—AOU Careggi, 50139 Florence, Italy</footnote>

<footnote n="23">²³Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal</footnote>

<footnote n="24">²⁴Unit of Metabolic Bone and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy</footnote>

<footnote n="25">²⁵Unit of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, 00128 Rome, Italy</footnote>

<footnote n="26">²⁶Department of Endocrinology, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, United Kingdom</footnote>

<footnote n="27">²⁷Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark</footnote>

<footnote n="28">²⁸Endocrinology-Diabetology-Metabolism and Nutrition Department, Inserm U1190 Centre Hospitalier Universitaire de Lille, Université de Lille, 59000 Lille, France</footnote>

<footnote n="29">²⁹Endocrinology Department, Physicians East, Greenville, NC 27834, United States</footnote>

<footnote>*Corresponding author: Takeda Development Center Americas, Inc., Lexington, MA 02142, USA. Email: lade.ayodele@takeda.com (O.A.)</footnote>

<footnote>† Professor William Fraser passed away prior to the submission of this manuscript. All co-authors affirm that Professor Fraser made significant contributions in accordance with International Committee of Medical Journal Editors and journal guidelines.</footnote>

<footnote>‡ During the study period.</footnote>
**Abstract**

**Objective:** To assess the impact of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] compared with placebo, in combination with conventional therapy with vitamin D and/or calcium supplements, on health-related quality of life (HRQoL) in patients with symptomatic chronic hypoparathyroidism (cHypoPT).

**Design:** Randomized, double-blind, placebo-controlled, phase 3b-4 study (ClinicalTrials.gov ID: NCT03324880).

**Methods:** Eligible patients with symptomatic cHypoPT were randomized to receive subcutaneous rhPTH(1-84) 25-100 µg/day or placebo. The primary endpoint was the change from baseline to week 26 in Hypoparathyroidism Symptom Diary (HypoPT-SD) symptom subscale score. Key secondary endpoints were changes from baseline to week 26 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and in 36-item Short Form Health Survey physical component summary (SF-36v2 PCS).

**Results:** In total, 93 patients were randomized to receive treatment: 45 received rhPTH(1-84) and 48 received placebo. Change from baseline to week 26 in HypoPT-SD symptom subscale score was significantly greater (improved) in the rhPTH(1-84) group than in the placebo group (difference in least-squares mean changes, -0.53; 95% confidence interval, -0.90 to -0.15, P = .003). Key secondary endpoints, changes between baseline and week 26 in the FACIT-Fatigue and SF-36v2 PCS scores were also significantly greater (improved) in the rhPTH(1-84) group than in the placebo group. The safety profile of rhPTH(1-84) was consistent with previous findings, and no new safety signals were identified.

**Conclusions:** rhPTH(1-84) alongside conventional therapy improved symptom burden (as measured by the HypoPT-SD) and HRQoL to a greater extent than conventional therapy alone in patients with symptomatic cHypoPT.

**Keywords:** human parathyroid hormone treatment, hypoparathyroidism, patient-reported outcomes, rhPTH(1-84)

**Significance**

Patients with chronic hypoparathyroidism (cHypoPT) often have lower health-related quality of life (HRQoL) than the general population, despite receiving conventional therapy. Observational studies have shown that treatment with recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] can improve HRQoL in patients with cHypoPT; however, this has not yet been demonstrated in a randomized clinical trial. This study assessed the impact of rhPTH(1-84) compared with placebo on symptoms and HRQoL as measured using the disease-specific Hypoparathyroidism Symptom Diary, as well as generic patient-reported outcome instruments, in patients with symptomatic cHypoPT who were receiving conventional therapy. Our findings demonstrate that treatment with rhPTH(1-84) significantly improves symptoms and HRQoL compared with placebo, irrespective of disease-specific improvements in biochemical parameters.

**Introduction**

Chronic hypoparathyroidism (cHypoPT) occurs following prolonged partial or total absence of parathyroid hormone (PTH), leading to hypocalcemia and, often, hyperphosphatemia.¹,² Patients can experience physical symptoms such as muscle cramps and spasms, paresthesia, numbness, and fatigue. In addition, patients may experience depression, anxiety, an inability to concentrate, cognitive decline, and memory loss.³,⁴

Conventional therapy with oral calcium and active forms of vitamin D does not replicate the function of PTH, adequately control symptoms, or improve quality of life in all patients with cHypoPT.⁵⁻⁷ Owing to the absence of PTH, conventional therapy may also worsen the progression of hypercalciuria and nephrocalcinosis, especially if serum calcium concentration is within the reference range.⁸

Several studies have demonstrated that patients with cHypoPT treated with conventional therapy have worse health-related quality of life (HRQoL) than matched control cohorts or the general population.⁹⁻¹¹ Symptom burden and inability to work have been identified as drivers of decreased HRQoL.⁴,¹²

Full-length recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] was approved as an adjunctive treatment to conventional therapy for patients with HypoPT in 2015 in the United States.¹³ The European Medicines Agency approved it 2 years later as an adjunctive treatment for adult patients with cHypoPT that is not adequately controlled by conventional therapy.¹⁴

In the 24-week REPLACE study, patients with cHypoPT treated with rhPTH(1-84) showed improvements in HRQoL scores compared with baseline, although differences in changes of HRQoL scores from baseline to week 24 between the rhPTH(1-84) and placebo groups were not statistically

significant.¹⁵ In an open-label study, patients with cHypoPT who received rhPTH(1-84) reported sustained improvements from baseline in HRQoL over 8 years.¹⁶ However, a 6-month placebo-controlled study of rhPTH(1-84) in patients with cHypoPT found no improvement in HRQoL for patients treated with rhPTH(1-84) compared with those receiving placebo.¹⁷

To our knowledge, with the exception of a study that evaluated an investigational prodrug of PTH [rhPTH(1-34)],¹⁸ the impact of treatment on HRQoL in patients with cHypoPT has only been measured in prospective studies using generic patient-reported outcome measures (PROMs).⁴,¹⁵⁻¹⁷,¹⁹ Recently, a disease-specific PROM, the Hypoparathyroidism Symptom Diary (HypoPT-SD), has been developed and validated using data from phase 3 and 4 studies.²⁰⁻²²

Our study aimed to assess the impact of rhPTH(1-84) treatment compared with placebo on symptom burden and HRQoL, as measured using the disease-specific HypoPT-SD and generic PROMs, in patients with symptomatic cHypoPT who were receiving conventional therapy.

**Materials and methods**

**Study design**

BALANCE (NCT03324880)²³ was a randomized, phase 3b-4, double-blind, placebo-controlled adaptive study carried out at 38 sites in Belgium, Canada, Denmark, France, Italy, the Netherlands, Norway, Portugal, Spain, Sweden, the United Kingdom, and the United States between January 24, 2018, and May 19, 2022. Study enrollment was temporarily paused between April 20, 2020, and September 24, 2020, owing to the COVID-19 pandemic.²³
Following a 3-week screening period, patients entered the intervention period comprising a 16-week titration phase and a 10-week maintenance phase. After the intervention period, the patients entered a 4-week safety follow-up period.

The study protocol, any protocol amendments, the final approved informed consent document, relevant supporting information, and all types of patient recruitment information were submitted by the investigators to an institutional review board or independent ethics committee, as applicable, and approved (as appropriate) before study initiation. The study was conducted in accordance with current applicable regulations, the principles of the declaration of Helsinki, International Council for Harmonisation guidelines, European Union Directive 2001/20/EC and its updates/revisions, and local ethical and legal requirements.

## Patients

Eligible patients were aged 18-85 years with a diagnosis of cHypoPT (defined as hypocalcemia in the setting of PTH concentrations below the lower limit of the reference range [1.87 mmol/L] for at least 12 months before enrollment). Additional inclusion criteria included a HypoPT-SD summed symptom subscale score of 10 or more during the 2-week period before the week 0 visit (patients were required to have at least four complete HypoPT-SD entries for both the first and the second 7-day period in the fortnight before the week 0 visit) and a history of two or more of the following symptoms in the 2-week period preceding the week 3 study visit: muscle cramps, muscle spasms or twitching, tingling, numbness, heaviness in the arms or legs, physical fatigue, or slowed or confused thinking.

Before screening, eligible patients had received treatment with active vitamin D (calcitriol or alfacalcidol) alone or in conjunction with calcium supplements for at least 4 months. Patients were required to be receiving calcitriol 0.5 µg/day or more, or alfacalcidol 1.0 µg/day or more. Patients who received lower doses of active vitamin D were required to have taken supplements containing at least 800 mg/day of elemental calcium. The intention-to-treat (ITT) set refers to all patients randomly assigned to active treatment or placebo, and the safety set includes all patients in the ITT set who received one or more doses of rhPTH(1-84) or placebo.

Exclusion criteria included albumin-adjusted serum calcium (AASC) concentrations below 1.87 mmol/L, or 2.97 mmol/L or higher; cHypoPT caused by activating mutations in the calcium-sensing receptor gene or PTH resistance; and the use of medications including loop and thiazide diuretics, phosphate binders (other than calcium carbonate), digoxin, lithium, methotrexate, or systemic corticosteroids, within predefined periods.

## Interventions

The treatment arm for each individual patient was determined by a randomization schedule; unique numbers were assigned to all patients when they consented to take part in the trial, and the individual patient's treatment arm was automatically assigned by interactive response technology.

Patients were randomized 1:1 to receive once-daily (QD) rhPTH(1-84), administered by subcutaneous (SC) injection into the thigh or mock-titrated, SC placebo. rhPTH(1-84) was administered at a dose of 25, 50, 75, or 100 µg QD with an individualized starting dose based on the patient's AASC and 24-hour urine calcium excretion concentrations.

Changes to the rhPTH(1-84) dose could be made every 4 weeks during the 16-week titration period in increments of 25 µg, up to a maximum dose of 100 µg QD.

Following the 16-week titration phase, the intention was to keep the rhPTH(1-84) dose stable during the 10-week maintenance phase. However, if the patient had not reached the optimal dose, adjustments could be made following discussion with the medical monitor. Changes could be made in increments of 25 µg—up to a maximum of 100 µg or down to a minimum of 25 µg—at any stage of the maintenance period if safety concerns arose. Dosing of active vitamin D and calcium supplements was adjusted during the titration and maintenance period for each patient to achieve prespecified biochemical target concentrations (AASC, 1.87-2.62 mmol/L).

## Outcomes

The primary endpoint was the change from baseline to week 26 in HypoPT-SD symptom subscale score. Lower scores on the HypoPT symptom subscale indicate lower cHypoPT symptom severity.²⁰

The key secondary endpoints were change from baseline to week 26 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and in 36-item Short Form Health Survey (SF-36v2) physical component summary (PCS) score. Higher scores on the FACIT-Fatigue scale indicate less fatigue.²⁴ Higher scores on the SF-36v2 PCS scale indicate better physical health status.²⁵

Other symptom burden and HRQoL secondary endpoints included the proportion of patients with at least 30% reduction (defined as a response) in HypoPT-SD symptom subscale score from baseline at week 26 and change from baseline to week 26 in (1) HypoPT-SD impact subscale score; (2) HypoPT-SD anxiety individual item score; (3) HypoPT-SD sadness or depression individual item score; (4) most bothersome HypoPT-SD symptom score; (5) Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) perceived cognitive impairment score;²⁶ (6) FACT-Cog impact of cognitive impairment on QoL score;²⁶ (7) SF-36v2 mental component summary; (8) Work Productivity and Activity Impairment (WPAI) questionnaire;²⁷ and (9) Patient Global Impression of Severity (PGI-S).²⁸

Secondary endpoints assessing metabolic parameters and supplement requirements included change from baseline to week 26 in (1) 24-hour urine calcium excretion; (2) proportion of patients with AASC between 1.87 mmol/L and the upper limit of normal (ULN; 2.62 mmol/L); (3) serum phosphate concentration; (4) active vitamin D and elemental calcium supplement doses; and (5) proportion of patients who achieved the composite endpoint, defined as meeting the criteria of AASC between 1.87 mmol/L and the ULN, prescribed active vitamin D dose decreased by at least 50%, and prescribed calcium supplement dose decreased by at least 50%. Unless otherwise specified, all efficacy analyses were carried out on the ITT set. Safety outcomes were also assessed.

## Assessments

The impact of cHypoPT was assessed using the HypoPT-SD, a 13-item disease-specific PRO measure that consists of a symptom subscale (items 1-7), single items for anxiety (item 8), and sadness or depression (item 9), and an impact subscale (items 10-13).²⁰,²¹ Scores are reported on a 5-point scale (0-4) for symptom subscale items, the anxiety item and the sadness or
depression item, and a 3-point scale (0-2) for impact subscale items. Lower scores represent lower symptom severity or a lower impact on daily life.²⁰,²¹ Generic PRO measures— FACIT-Fatigue, SF-36v2, FACT-Cog, WPAI, and PGI-S— have been described in detail previously.²⁴⁻²⁶,²⁸⁻³⁰ All patient-reported data were recorded using electronic devices.

## Statistical analyses

Sample size estimates were based on a mean change from baseline to week 26 in the HypoPT-SD symptom subscale of 0.4 units with a standard deviation (SD) of 0.6 units. A total of 39 completed patients per treatment group would provide 82.5% power to detect a treatment difference of 0.67 units between the rhPTH(1-84) and placebo treatment groups based on a 1-sided, 2-sample t-test at the 0.025 level of significance. An effect size of 0.67 was selected based on data from a psychometric analysis of the HypoPT-SD.

The original protocol enrollment target was 150 patients with symptomatic cHypoPT, which would provide adequate power and allow for a 21% dropout rate. However, the protocol was amended to reduce the enrollment target because study enrollment was terminated early by the sponsor when the active treatment was withdrawn from the market owing to a manufacturing issue.

A mixed-effect model for repeated measures (MMRM) analysis at post-baseline visits at weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, and 26 was used for the primary endpoint, with change from baseline in HypoPT-SD symptom subscale score as the outcome variable. The fixed effect factors were treatment group and visit, and the random effect factor was patients, with adjustments for baseline HypoPT-SD symptom subscale score. The class variable was visit (assuming an unstructured covariance matrix to model within-patient variability). The estimated difference between the rhPTH(1-84) and placebo group, standard errors (SEs), and 95% confidence intervals (CIs) were provided. In addition, least-squares means (LSMs) were estimated for each treatment group at every post-baseline visit, and the estimated treatment effect, along with SEs, 2-sided 95% CIs, and *P* values. Secondary efficacy endpoints were analyzed per the primary efficacy endpoint using an MMRM with adjustments for baseline FACIT-Figure and SF-36v2 PCS scores, respectively. To maintain study-wide type I error control, a hierarchical testing procedure was used in the comparisons between rhPTH(1-84) and placebo, with testing conducted in the following order: HypoPT-SD symptom subscale, FACIT-Fatigue, then SF-36v2 PCS. The null hypothesis was rejected if the statistical analysis resulted in a 1-sided *P* value of .025 for treatment at week 26. No multiplicity adjustment was performed for other efficacy endpoints in this study; therefore, the associated *P* values, if presented, are nominal.

## Study reporting

The reporting of the results from this clinical trial adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.³¹

## Results

### Baseline characteristics and demographics

Following randomization, 45 patients received rhPTH(1-84) and 48 received placebo, of whom 39 (86.7%) and 46 (95.8%) completed the study, respectively (Figure S1). The ITT and safety analysis set both comprised 93 patients; 38

<table><caption>**Table 1.** Patient characteristics and demographics at baseline (safety analysis set).</caption><thead><tr><th>Demographic/ characteristic</th><th>Placebo (N = 48)</th><th>rhPTH(1-84) (N = 45)</th></tr></thead><tbody><tr><td>Mean age, years (range)</td><td>49.2 (24-76)</td><td>47.8 (23-66)</td></tr><tr><td>Female, n (%)</td><td>40 (83.3)</td><td>42 (93.3)</td></tr><tr><td>Ethnicity, n (%)</td><td></td><td></td></tr><tr><td>Hispanic or Latino</td><td>4 (8.3)</td><td>3 (6.7)</td></tr><tr><td>Not Hispanic or Latino</td><td>39 (81.3)</td><td>31 (68.9)</td></tr><tr><td>Not reported</td><td>2 (4.2)</td><td>5 (11.1)</td></tr><tr><td>Unknown</td><td>3 (6.3)</td><td>6 (13.3)</td></tr><tr><td>Race, n (%)</td><td></td><td></td></tr><tr><td>Asian</td><td>1 (2.1)</td><td>2 (4.4)</td></tr><tr><td>White</td><td>47 (97.9)</td><td>43 (95.6)</td></tr><tr><td>Weight, kg (range)</td><td>75.15 (43.6-139.6)</td><td>76.40 (47.2-123.6)<sup>a</sup></td></tr><tr><td>Mean albumin-adjusted serum calcium, mmol/L (SD)</td><td>2.08 (0.19)</td><td>2.06 (0.15)</td></tr><tr><td>Mean serum phosphate, mmol/L (SD)</td><td>1.31 (0.215)</td><td>1.335 (0.2077)</td></tr><tr><td>Mean eGFR, mL/min/1.73 m<sup>2</sup> (SD)</td><td>87.9 (21.2)</td><td>93.5 (18.6)</td></tr><tr><td>Mean elemental calcium dose, mg/day (SD)</td><td>1934 (1588)</td><td>2187 (2596)</td></tr><tr><td>Mean active vitamin D dose, µg/day (SD)<sup>b,c</sup></td><td>9.80 (44.80)</td><td>1.21 (1.26)</td></tr><tr><td>Mean native vitamin D dose, µg/day (SD)<sup>d</sup></td><td>25.26 (39.81)</td><td>201.82 (1063.07)</td></tr><tr><td>Mean 25-hydroxyvitamin D3, nmol/L (SD)</td><td>86.1 (25.5)</td><td>86.3 (25.7)</td></tr><tr><td>Patients receiving levothyroxine sodium, n (%)</td><td>37 (77.1)</td><td>39 (86.7)</td></tr><tr><td>Patients with post-surgical cHypoPT, n (%)</td><td>39 (81.3)</td><td>39 (86.7)</td></tr><tr><td>Patients with autoimmune cHypoPT, n (%)</td><td>1 (2.1)</td><td>3 (6.7)</td></tr><tr><td>Mean HypoPT-SD symptom subscale score (SD)</td><td>2.23 (0.54)<sup>e</sup></td><td>2.56 (0.73)</td></tr><tr><td>Mean FACIT-Fatigue score (SD)</td><td>20.0 (9.9)<sup>f</sup></td><td>17.0 (11.3)<sup>g</sup></td></tr><tr><td>Mean SF-36v2 PCS score (SD)</td><td>37.3 (7.8)<sup>g</sup></td><td>33.6 (8.4)<sup>a</sup></td></tr></tbody></table>

patients in the rhPTH(1-84) group and 30 patients in the placebo group were included in the week-26 primary analysis. Baseline characteristics and demographics are shown in Table 1. The majority of patients were female. Baseline mean AASC (SD) was 2.06 (0.15) mmol/L in the rhPTH(1-84) group and 2.08 (0.19) mmol/L in the placebo

<footnote>a$n=43$.</footnote>

<footnote>bAlfacalcidol or calcitriol.</footnote>

<footnote>cIncorrectly high doses of active vitamin D were reported for eight patients; all data related to vitamin D should be treated with caution.</footnote>

<footnote>dCholecalciferol and calcifediol.</footnote>

<footnote>eITT set, $n=47$.</footnote>

<footnote>fITT set, $n=41$.</footnote>

<footnote>gITT set, $n=42$.</footnote>

<footnote>Values are median unless otherwise stated.</footnote>

<footnote>Abbreviations: cHypoPT, chronic hypoparathyroidism; eGFR, estimated glomerular filtration rate; FACIT, Functional Assessment of Chronic Illness Therapy; HypoPT-SD, Hypoparathyroidism Symptom Diary; ITT, intention-to-treat; PCS, physical component summary; rhPTH(1-84), recombinant human parathyroid hormone (1-84); SD, standard deviation; SF-36v2, 36-item Short Form Health Survey.</footnote>
group. More than 50% of patients had baseline AASC below 2.00 mmol/L. Mean (SD) doses of calcium were 2187 (2596) mg/day in the rhPTH(1-84) group and 1934 (1588) mg/day in the placebo group.

At baseline, 21 patients were not taking calcium supplements, 15 of whom had AASC concentrations within the reference range (2.10-2.20 mmol/L), and 6 had AASC concentrations between 2.00 and 2.10 mmol/L. Baseline mean (SD) HypoPT-SD symptom subscale scores in the rhPTH(1-84) and placebo groups were 2.56 (0.73) and 2.23 (0.54), respectively. Mean FACIT-Fatigue scores (SD) in the rhPTH(1-84) and placebo groups were 17.0 (11.3) and 20.0 (9.9), respectively, and mean (SD) SF-36v2 PCS scores were 33.6 (8.4) and 37.3 (7.8), respectively. Mean adherence rates during the overall treatment period were similar in both groups (93.1% in the rhPTH(1-84) group and 93.8% in the placebo group).

## Primary and key secondary endpoints

Improvements from baseline to week 26 in HypoPT-SD symptom subscale score were significantly greater in the rhPTH(1-84) group than in the placebo group (difference in LSM change, -0.53; 95% CI, -0.90 to -0.15, *P* = .003; Figure 1A). The LSM changes between baseline and week 26 in the FACIT-Fatigue, and SF-36v2 PCS scores were significantly larger (indicating greater improvement) in the rhPTH(1-84) group than in the placebo group (differences in LSM change: 10.5, 95% CI 5.1-15.9, *P* < .001 in FACIT-Fatigue and 4.2, 95% CI 0.4-8.1, *P* = .015 in SF-36v2 PCS; Figures 1B and 1C).

## Other secondary endpoints: HRQoL

Improvements between baseline and week 26 in the scores for the HypoPT-SD impact subscale, FACT-Cog cognitive impairment, FACT-Cog cognitive impact on quality of life, SF-36v2 mental component summary (MCS), and PGI-S were numerically greater in the rhPTH(1-84) group than in the placebo group (*P* ≤ .024 in all cases; Table 2). Baseline scores are available in Table S1.

Changes in the scores for WPAI owing to cHypoPT were numerically higher in the rhPTH(1-84) group than in the placebo group for impairment while working, overall work impairment, and activity impairment (*P* ≤ .031 in all cases; Table 2).

## Other secondary endpoints: metabolic

No meaningful differences between groups were observed in baseline to week 26 changes in the proportion of patients with AASC concentrations between 1.87 mmol/L and the ULN and 24-hour urine calcium excretion. Serum phosphate concentration decreased between baseline and week 26 in the rhPTH(1-84) group but increased in the placebo group (difference in LSM between groups, -0.175 mmol/L; 95% CI -0.097 to -0.254; *P* < .001; Table 3). Between baseline and week 26, the supplemental dose of calcium required decreased to a greater extent in the rhPTH(1-84) group than in the placebo group (difference in LSM, -331 mg; 95% CI -595 to -68; *P* = .007; Table 3).

Data on the proportion of patients who achieved the composite endpoint at week 26 (AASC between 1.87 mmol/L and the ULN, reduction in active vitamin D dose of 50% or

more, and reduction in calcium dose of 50% or more) and changes to week 26 in active vitamin D dose required are summarized in Table S2.

## Safety

During the study, 338 treatment-emergent adverse events (TEAEs) were reported in 41 patients (91.1%) in the rhPTH(1-84) group, and 275 TEAEs were reported in 46 patients (95.8%) in the placebo group (Table 4). Of these events, 107 (22 patients [48.9%]) in the rhPTH(1-84) group and 27 (15 patients [31.3%]) in the placebo group were considered related to treatment (Table 4).

In both groups, the majority of TEAEs were mild or moderate. The number of serious events occurring in the rhPTH(1-84) group and placebo group was 7 (in 6 patients [13.3%]) and 15 (in 6 patients [12.5%]), respectively (Table 4). Hypocalcemia was considered to be the cause of 30 adverse events in 15 patients (33.3%) in the rhPTH(1-84) group and 41 events in 21 patients (43.8%) in the placebo group (Table 4).

The most common TEAEs in the rhPTH(1-84) group were headache, nausea, and arthralgia (31.1%, 24.4%, and 17.8% of patients, respectively; Table S3). The most frequently reported treatment-related TEAEs in the rhPTH(1-84) group were nausea and headache (10 events in 8 patients [17.8%] and 15 events in 6 patients [13.3%], respectively). TEAEs related to cHypoPT are presented in Table S4.

## Discussion

Our study showed that rhPTH(1-84) significantly improved HRQoL and symptom burden compared with placebo in patients with symptomatic cHypoPT who were receiving conventional therapy.

Studies have shown that rhPTH(1-84) can improve HRQoL from baseline as measured by generic PROMs such as the SF-36v2.¹⁵,¹⁶ In the Phase 3 REPLACE study, however, the differences between the rhPTH(1-84) and placebo groups were not significant for the SF-36v2 summary or individual domain scores.¹⁵ It should be noted that the study authors suggested that imbalances between baseline HRQoL parameters observed in patients at Hungarian sites may have affected the PROM findings.¹⁵ In contrast, improvements in the SF-36v2 PCS and MCS scores were significantly greater in the rhPTH(1-84) group than in the placebo group in our study.

Patients in the rhPTH(1-84) group in this study had numerically greater improvements from baseline scores for all PROMs assessed, except the WPAI missed work due to HypoPT. Scores for this subcategory increased (got worse) in both arms, with a larger increase from baseline reported in the rhPTH(1-84) group. In contrast, WPAI scores suggested a greater reduction in impairment while working, overall work impairment, and activity impairment in the rhPTH(1-84) group. Patient numbers were low for work-related outcomes, and it is likely that many patients in this trial were not working.

In general, PROM scores improved from baseline in the placebo group; this could be attributed to the tight control of serum calcium concentration during this study and the increased level of healthcare professional interaction that occurs during clinical trials.
<figure><img src="image_3.png" /></figure>

<table><thead><tr><th rowspan="2"></th><th colspan="2">Placebo</th><th colspan="2">rhPTH(1-84)</th></tr><tr><th>n</th><th>Mean HypoPT-SD score (SD)</th><th>n</th><th>Mean HypoPT-SD score (SD)</th></tr></thead><tbody><tr><th>Baseline</th><td>47</td><td>2.23 (0.54)</td><td>45</td><td>2.56 (0.73)</td></tr><tr><th>Week 26</th><td>39</td><td>1.34 (0.92)</td><td>30</td><td>1.14 (0.85)</td></tr><tr><th>Change</th><td>38</td><td>-0.83 (0.72)</td><td>30</td><td>-1.42 (1.04)</td></tr></tbody></table>

<figure><img src="image_4.png" /></figure>

<table><thead><tr><th rowspan="2"></th><th colspan="2">Placebo</th><th colspan="2">rhPTH(1-84)</th></tr><tr><th>n</th><th>Mean SF-36v2 PCS score (SD)</th><th>n</th><th>Mean SF-36v2 PCS score (SD)</th></tr></thead><tbody><tr><th>Baseline</th><td>42</td><td>37.3 (7.8)</td><td>43</td><td>33.6 (8.4)</td></tr><tr><th>Week 26</th><td>33</td><td>41.4 (9.0)</td><td>29</td><td>41.7 (10.3)</td></tr><tr><th>Change</th><td>29</td><td>3.7 (8.0)</td><td>29</td><td>8.4 (8.6)</td></tr></tbody></table>

<figure><img src="image_5.png" /></figure>

<table><caption>**Figure 1.** Changes from baseline to week 26 in (A) HypoPT-SD symptom score, (B) FACIT-fatigue score, and (C) SF-36v2 PCS score (ITT set). LSM (SEM) change and LSM difference (95% CI) were derived from an MMRM, with fixed effects for treatment group and visit, random effect factor for patients, and adjustments made for baseline score values. CI, confidence interval; FACIT, Functional Assessment of Chronic Illness Therapy; HypoPT-SD, Hypoparathyroidism Symptom Diary; LSM, least-squares mean; PCS, physical component summary; rhPTH(1-84), recombinant human parathyroid hormone (1-84); SD, standard deviation; SEM, standard error of the mean; SF-36v2, 36-item Short Form Health Survey.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Placebo</th><th colspan="2">rhPTH(1-84)</th></tr><tr><th>n</th><th>Mean FACIT-Fatigue score (SD)</th><th>n</th><th>Mean FACIT-Fatigue score (SD)</th></tr></thead><tbody><tr><th>Baseline</th><td>41</td><td>20.0 (9.9)</td><td>42</td><td>17.0 (11.3)</td></tr><tr><th>Week 26</th><td>34</td><td>25.8 (12.1)</td><td>29</td><td>30.4 (12.7)</td></tr><tr><th>Change</th><td>29</td><td>5.0 (8.2)</td><td>28</td><td>14.6 (15.1)</td></tr></tbody></table>

AASC concentration within the target range was an inclusion criterion in this study, and vitamin D and calcium supplementation were optimized throughout to maintain AASC concentrations in both groups. It is not surprising, therefore, that with the exception of serum phosphorus concentrations, rhPTH(1-84) did not induce any meaningful changes in biochemical parameters. However, the contribution that

hormone replacement made to maintaining AASC levels was reflected by the marked reduction in calcium supplementation required in the rhPTH(1-84) group observed during the treatment period. Safety findings were in line with previous studies.

As expected, based on the inclusion criteria, baseline PROM scores in this study were worse than those observed in other cHypoPT patient populations. The SF-36v2 PCS and MCS
<table><caption>**Table 2.** Change from baseline to week 26 in symptoms and HRQoL-related secondary endpoints (ITT set).</caption><thead><tr><th rowspan="2">Secondary endpoint</th><th colspan="2">Placebo (N = 48)</th><th colspan="2">rhPTH(1-84) (N = 45)</th><th rowspan="2">Difference (95% CI)<sup>a</sup></th><th rowspan="2">P value<sup>a</sup></th></tr><tr><th>n</th><th>LSM change (95% CI)</th><th>n</th><th>LSM change (95% CI)</th></tr></thead><tbody><tr><td>HypoPT-SD impact subscale score</td><td>38</td><td>-0.36 (-0.51 to -0.21)</td><td>30</td><td>-0.69 (-0.85 to -0.52)</td><td>-0.32 (-0.55 to -0.10)</td><td>.002</td></tr><tr><td>Proportion of patients with ≥ 30% reduction in HypoPT-SD symptom subscale score,<sup>b</sup> %</td><td>38</td><td>63.2</td><td>32</td><td>78.1</td><td>14.9 (6 to 36)</td><td>.173</td></tr><tr><td>Most bothersome HypoPT-SD symptom score</td><td>38</td><td>-0.87 (-1.18 to -0.56)</td><td>26</td><td>-1.77 (-2.12 to -1.43)</td><td>-0.90 (-1.37 to -0.43)</td><td>&lt; .001</td></tr><tr><td>FACT-Cog score in perceived cognitive impairment</td><td>29</td><td>6.4 (1.3 to 11.4)</td><td>28</td><td>17.5 (12.3 to 22.8)</td><td>11.2 (3.9 to 18.5)</td><td>.002</td></tr><tr><td>FACT-Cog score in impact on quality of life</td><td>29</td><td>2.7 (1.2 to 4.2)</td><td>28</td><td>4.8 (3.3 to 6.4)</td><td>2.1 (0.0 to 4.3)</td><td>.024</td></tr><tr><td>SF-36v2 MCS</td><td>29</td><td>4.3 (1.1 to 7.5)</td><td>29</td><td>12.6 (9.4 to 15.8)</td><td>8.3 (3.8 to 12.8)</td><td>&lt; .001</td></tr><tr><td>WPAI: cHypoPT score, %</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Missed work</td><td>15</td><td>2.3 (-10.5 to 15.1)</td><td>11</td><td>5.4 (-9.1 to 20.0)</td><td>3.1 (-16.3 to 22.6)</td><td>.627</td></tr><tr><td>Impairment while working</td><td>14</td><td>-11.7 (-21.5 to -2.0)</td><td>9</td><td>-26.3 (-38.0 to -14.6)</td><td>-14.6 (-29.9 to 0.7)</td><td>.031</td></tr><tr><td>Overall work impairment</td><td>13</td><td>-11.2 (-19.0 to -3.3)</td><td>9</td><td>-26.1 (-35.8 to -16.35)</td><td>-14.9 (-27.4 to -2.4)</td><td>.011</td></tr><tr><td>Activity impairment</td><td>29</td><td>-10.2 (-18.1 to -2.3)</td><td>27</td><td>-23.3 (-31.6 to -14.9)</td><td>-13.0 (-24.5 to -1.5)</td><td>.014</td></tr><tr><td>PGI-S</td><td>34</td><td>-0.8 (-1.1 to -0.5)</td><td>29</td><td>-1.4 (-1.7 to -1.0)</td><td>-0.5 (-1.0 to -0.1)</td><td>.010</td></tr></tbody></table>

<sup>a</sup>P values are nominal because secondary endpoints other than the key secondary endpoints were not adjusted for multiplicity.

<sup>b</sup>Proportion of patients who achieved a ≥ 30% reduction between baseline and week 26.

Abbreviations: cHypoPT, chronic hypoparathyroidism; CI, confidence interval; FACT-Cog, Functional Assessment of Cancer Therapy-Cognitive Function; HRQoL, health-related quality of life; HypoPT-SD, Hypoparathyroidism Symptom Diary; ITT, intention-to-treat; LSM, least-squares mean; MCS, mental component summary; n, number of patients with data available; PGI-S, Patient Global Impression of Severity; rhPTH(1-84), recombinant human parathyroid hormone (1-84); SF-36v2, 36-item Short Form Health Survey; WPAI, Work Productivity and Activity Impairment.

<table><caption>**Table 3.** Change from baseline to week 26 in biochemical parameters and dosing of conventional therapy (ITT set).</caption><thead><tr><th rowspan="2">Endpoint</th><th colspan="2">Placebo (N = 48)</th><th colspan="2">rhPTH(1-84) (N = 45)</th><th rowspan="2">Difference (95% CI)</th><th rowspan="2">P value<sup>a</sup></th></tr><tr><th>n</th><th>LSM change (95% CI)</th><th>n</th><th>LSM change (95% CI)</th></tr></thead><tbody><tr><td>Proportion of patients with AASC between 1.87 mmol/L and ULN, %</td><td>47</td><td>95.7</td><td>40</td><td>90.0</td><td>-5.7 (-16.7 to 5.2)</td><td>.292</td></tr><tr><td>24-hour urine calcium excretion, mmol/day</td><td>43</td><td>-1.99 (-3.13 to -0.85)</td><td>33</td><td>0.11 (-1.19 to 1.40)</td><td>2.09 (0.36 to 3.83)</td><td>.991</td></tr><tr><td>Serum phosphate concentration, mmol/L</td><td>47</td><td>0.03 (-0.02 to 0.08)</td><td>40</td><td>-0.145 (-0.202 to -0.087)</td><td>-0.175 (-0.254 to -0.097)</td><td>&lt; .001</td></tr><tr><td>Elemental calcium supplement dose, mg/day</td><td>47</td><td>-44 (-225 to 137)</td><td>40</td><td>-376 (-567 to -184.5)</td><td>-331 (-595 to -68)</td><td>.007</td></tr></tbody></table>

<sup>a</sup>P values are nominal, secondary endpoints related to efficacy were not adjusted for multiplicity.

Abbreviations: AASC, albumin-adjusted serum calcium; CI, confidence interval; ITT, intention-to-treat; LSM, least-squares mean; rhPTH(1-84), recombinant human parathyroid hormone (1-84); ULN, upper limit of normal.

scores at baseline in this study were approximately 10 points lower (worse) than scores reported for patients in the REPLACE study.¹⁵ The findings may not be generalized to all patients with cHypoPT, owing to the symptomatic study population.

rhPTH(1-84) is no longer being manufactured; however, the findings of this study suggest that PTH replacement as a treatment modality could improve quality of life and reduce the symptom burden in patients with symptomatic cHypoPT. Further trials will be needed to confirm this benefit for other PTH replacement products.

## Strengths

To our knowledge, this is the first prospective, randomized, placebo-controlled study designed specifically to assess the impact of treatment on PROs in patients with HypoPT, using a disease-specific instrument. The study also included an eligibility criterion based on the HypoPT-SD score, which enabled symptomatic patients to be identified for enrollment.

## Limitations

Findings of this study should be considered in the context of the following limitations. The proportion of randomized patients for whom data were available at week 26 was low and not balanced across the study arms. The small sample sizes could be related to the number of questionnaires that patients needed to complete. In addition, the electronic mode of completion may have led to the exclusion of some patients with cognitive dysfunction or those who were unwilling to use electronic devices.

Baseline scores for the HypoPT-SD symptom subscale, FACIT-Fatigue scale, and SF-36v2 survey were worse in the rhPTH(1-84) group than in the placebo group. These differences were, however, small and accounted for within the MMRM model.

Native vitamin D supplementation data did not distinguish between cholecalciferol and calcifediol. Similarly, measurement of active vitamin D supplementation did not distinguish between alfacalcidol and calcitriol. In addition, incorrect vitamin D data were reported for eight patients across six sites. The doses recorded were considerably higher than the doses
<table><caption>**Table 4.** Treatment-emergent adverse events (safety analysis set).</caption><thead><tr><th rowspan="2">Category</th><th colspan="2">Placebo (N = 48)</th><th colspan="2">rhPTH(1-84) (N = 45)</th></tr><tr><th>Number of events</th><th>Number (%) of patients</th><th>Number of events</th><th>Number (%) of patients</th></tr></thead><tbody><tr><td>Any TEAE</td><td>275</td><td>46 (95.8)</td><td>338</td><td>41 (91.1)</td></tr><tr><td>Hypocalcemia</td><td>41</td><td>21 (43.8)</td><td>30</td><td>15 (33.3)</td></tr><tr><td>Treatment-related TEAEs</td><td>27</td><td>15 (31.3)</td><td>107</td><td>22 (48.9)</td></tr><tr><td>TEAEs leading to withdrawal of study drug</td><td>0</td><td>0</td><td>3</td><td>2 (4.4)</td></tr><tr><td>TEAEs by highest severity</td><td></td><td></td><td></td><td></td></tr><tr><td>Mild</td><td>196</td><td>23 (47.9)</td><td>246</td><td>14 (31.1)</td></tr><tr><td>Moderate</td><td>73</td><td>20 (41.7)</td><td>81</td><td>22 (48.9)</td></tr><tr><td>Severe</td><td>6</td><td>3 (6.3)</td><td>11</td><td>5 (11.1)</td></tr><tr><td>Serious TEAEs</td><td>15</td><td>6 (12.5)</td><td>7</td><td>6 (13.3)</td></tr><tr><td>Serious TEAEs by relationship to study drug</td><td></td><td></td><td></td><td></td></tr><tr><td>Not related</td><td>12</td><td>3 (6.3)</td><td>5</td><td>4 (8.9)</td></tr><tr><td>Related</td><td>3</td><td>3 (6.3)</td><td>2</td><td>2 (4.4)</td></tr><tr><td>Serious TEAEs by highest severity</td><td></td><td></td><td></td><td></td></tr><tr><td>Mild</td><td>2</td><td>2 (4.2)</td><td>0</td><td>0</td></tr><tr><td>Moderate</td><td>8</td><td>2 (4.2)</td><td>4</td><td>3 (6.7)</td></tr><tr><td>Severe</td><td>5</td><td>2 (4.2)</td><td>3</td><td>3 (6.7)</td></tr><tr><td>TEAEs leading to death</td><td>0</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>

Abbreviations: rhPTH(1-84), recombinant human parathyroid hormone (1-84); TEAE, treatment-emergent adverse event.

that were administered. All data related to vitamin D reported in the manuscript should, therefore, be treated with caution.

## Conclusions

PTH replacement, alongside conventional therapy, significantly improved symptom burden and HRQoL to a greater extent than conventional therapy alone in a population of patients with cHypoPT who were receiving conventional therapy, but did not alleviate all symptoms. Our findings reinforce the importance of looking beyond biochemical parameters when assessing disease control in patients with cHypoPT.

## Supplementary material

Supplementary material is available at *European Journal of Endocrinology* online.

## Funding

This work was funded by Takeda Development Center Americas, Inc., Lexington, Massachusetts, United States.

## Acknowledgments

We thank the patients who participated in this study and Dr Pernille Hermann for their contributions. Under the direction of the authors, medical writing support was provided by Joseph Hawkins, PhD, of Oxford PharmaGenesis, Oxford, UK, and was funded by Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States, in

accordance with Good Publication Practice (GPP 2022) guidelines (www.ismpp.org/gpp-2022).

## Authors' contributions

Maria Brandi (Investigation [equal], Writing—review & editing [lead]), Tamara Vokes (Conceptualization [equal], Data curation [equal], Formal analysis [supporting], Writing—review & editing [equal]), N Appelman-Dijkstra (Investigation [equal], Writing—review & editing [equal]), Olulade Ayodele (Investigation [supporting], Methodology [supporting], Supervision [supporting], Writing—original draft [equal], Writing—review & editing [equal]), Brigitte Decallonne (Investigation [equal], Supervision [equal], Visualization [equal], Writing—review & editing [equal]), Renate de Jongh (Investigation [equal], Resources [equal], Writing—review & editing [equal]), Manuel Diaz-Curiel (Investigation [equal], Writing—review & editing [equal]), William Fraser (Investigation [equal], Writing—review & editing [equal]), Richard D Finkelman (Methodology [equal], Writing—review & editing [equal]), Ansgar Heck (Investigation [equal], Writing—review & editing [equal]), Steven Ing (Investigation [equal], Writing—review & editing [equal]), Peter Kamenicky (Investigation [equal], Writing—review & editing [equal]), Aliya A. Khan (Investigation [equal], Writing—review & editing [equal]), Christopher Kovacs (Investigation [equal], Resources [equal], Supervision [equal], Writing—original draft [equal], Writing—review & editing [equal]), Bruno Lapauw (Investigation [equal], Resources [equal], Writing—review & editing [equal]), G. Lees (Investigation [equal], Writing—review & editing [equal]), Giovanna Mantovani (Investigation [equal], Validation [equal], Visualization [equal], Writing—review & editing [equal]), Guillermo MartC3ADnez DC3ADaz-Guerra (Validation [equal], Visualization [equal], Writing—review & editing [equal]), Laura Masi (Investigation [equal], Resources [equal], Writing—review & editing [equal]), Miguel Melo (Investigation [equal], Writing—review & editing [equal]), Andrea Palermo (Investigation [equal], Writing—review & editing [equal]), Narendra Reddy (Investigation [equal], Writing—review & editing [equal]), Lars Rejnmark (Investigation [equal], Writing—review & editing [equal]), Elena Tokareva (Conceptualization [equal], Project administration [equal], Supervision [equal], Writing—review & editing [equal]), Marie Vantyghem (Investigation [equal], Validation [equal], Writing—review & editing [equal]), Suwei Wang (Methodology [supporting], Writing—review & editing [supporting]), Mark Warren (Investigation [equal], Writing—review & editing [equal]), and Brian Yan (Data curation [supporting], Formal analysis [lead], Methodology [equal], Resources [equal], Validation [equal], Visualization [equal], Writing—review & editing [equal]).

All authors have contributed to this study to meet the International Committee of Medical Journal Editors authorship criteria. All authors have seen, approved, and are fully conversant with the contents of the manuscript. All authors are responsible for the accuracy of the manuscript.

## Conflict of interest

M.L.B. has received honoraria from Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, and UCB; and grants and/or speaker fees from Abiogen Pharma, Alexion, Amgen,
Bruno Farmaceutici, Echolight, Kyowa Kirin, Lilly, and Theramex.

T.V. serves as a consultant, research investigator, and advisory board member for and has received consulting fees and research support from Takeda Pharmaceuticals U.S.A., Inc. and Ascendis Pharma U.S.A.

N.M.A.D. has received speaker fees from Amgen and UCB, and research funding from Kyowa Kirin and UCB.

O.A. is employed by Takeda Development Center Americas, Inc. and holds stock/stock options in Takeda.

B.D. has served on advisory boards for Takeda Belgium NV.

M.D.C. has lectured for LabAlter.

W.F. has received honoraria/speaker fees and unrestricted grants from Amgen, IDS Ltd., Lilly, Merck Sharp and Dohme, Novartis, NPS Pharma, Roche, Siemens, Sandoz, and Shire.

R.D.F. was employed by Takeda Pharmaceuticals U.S.A., Inc. at the time of the study and now acts as a consultant for Takeda Pharmaceuticals U.S.A., Inc.

A.H. has received speaker fees from Kyowa Kirin, Novo Nordisk, Recordati, and Roche, and is a data monitoring committee member for Amolyt Pharma.

S.W.I. has received research grants paid to his institution from Alexion, Amgen, Amolyt Pharma, Calcilytix, Radius, Takeda, and Ultragenyx, and has served on advisory boards and/or as a consultant for Amgen, the Bone Health & Osteoporosis Foundation, Virginia, United States, Extend Biosciences, Radius, and the Soft Bones Foundation, New Jersey, United States.

P.K. has received honoraria from Amolyt Pharma, Kyowa Kirin, and Pfizer, support for travel to and/or attending meetings from Amolyt Pharma, Pfizer, and Recordati, and has served on advisory boards for Ascendis Pharma and Kyowa Kirin.

A.A.K. served as a research investigator for Takeda Pharmaceuticals U.S.A., Inc.

C.S.K. has no conflicts of interest to report apart from being an investigator in this study.

G.M.D.G. has served on advisory boards for Amgen, Ascendis Pharma, Italfármaco, Kyowa Kirin, Takeda, and UCB, is a scientific adviser for Takeda, and has received travel grants from Theramex.

L.M. has received speaker fees from Abiogen Pharma, Theramex, and Takeda.

M.M. has received consultant and speaker fees from Shire Ltd.

A.P. served as research investigator for Ascendis Pharma and Takeda and has received speaker fees from Abiogen Pharma, Amgen, and UCB.

N.L.R. has served on advisory boards, and is a research investigator for and has received research support from Amolyt Pharma, Ascendis Pharma, and Takeda Pharmaceuticals.

L.R. has served on advisory boards, and is a research investigator and speaker for and has received research support from Amolyt Pharma, Ascendis Pharma, Calcilytix Therapeutics, and Takeda Pharmaceuticals U.S.A., Inc.

E.T. is employed by Takeda Development Center Americas, Inc. and holds stock/stock options in Takeda.

S.W. is employed by Takeda Development Center Americas, Inc. and holds stock/stock options in Takeda.

M.W. has served as a speaker for and has received honoraria and research support from Ascendis Pharma and Takeda Pharmaceuticals U.S.A., Inc., and has received research support from Amolyt Pharma.

B.Y. was employed by Takeda Development Center Americas, Inc. during the study period, and holds stock/stock options in Takeda.

R.d.J., B.L., G.L., G.M., and M.C.V. have received research support from Takeda for this study.

## Data availability

The data sets, including the redacted study protocol, redacted statistical analysis plan, and individual patients' data supporting the results reported in this article, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.

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