The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics

Hypoparathyroidism is a rare endocrine disorder resulting from undetectable or inappropriately low circulating levels of parathyroid hormone (PTH), which is the principal regulator of calcium and phosphate homeostasis [1, 2]. The main biochemical abnormalities resulting from PTH deficiency are hypocalcemia and hyperphosphatemia [3]. The most common cause of hypoparathyroidism is neck surgery (approximately 75% of cases) [4, 5]. Guidelines from the European Society of Endocrinology; the First International Conference on the Diagnosis, Management, and Treatment of Hypoparathyroidism; and the Canadian-led international working group provide recommendations for the diagnosis, treatment, and monitoring of chronic hypoparathyroidism in adults [1, 4, 6]. Patients with chronic hypoparathyroidism who are treated with conventional therapy consisting of calcium and active vitamin D supplements may still be inadequately controlled and have symptoms and risks of complications and comorbidities [3, 7‐11]. In a 13-country patient and caregiver survey, the magnitude of symptom severity experienced by patients whose hypoparathyroidism was not adequately controlled despite receiving conventional therapy was associated with decreased health-related quality of life (HRQoL) and health status assessments and with increased caregiver burden [12]. Evaluation of HRQoL in patients with hypoparathyroidism has proved challenging because of variability of symptoms and differing types of study designs. Many but not all studies found there is a substantial burden of illness that adversely affects HRQoL in patients with chronic hypoparathyroidism [12‐21]. A spectrum of symptomatology varying from no symptoms to severe symptoms was reported by patients with chronic hypoparathyroidism; in 36-item Short Form Health Survey questionnaire (SF-36) data transformed on a 0−100 scale (lower scores indicating poorer health states) the scores ranged from 20 to >80 in different domains [12].

The recombinant human parathyroid hormone (1-84), rhPTH(1-84), is full-length PTH that is approved in the United States and Europe as adjunctive treatment for patients with chronic hypoparathyroidism [22, 23]. In Europe, rhPTH(1-84) is indicated as adjunctive treatment for patients with chronic hypoparathyroidism who cannot be adequately controlled with conventional therapy alone. In the United States, rhPTH(1-84) is indicated as an adjunct to calcium and vitamin D to control hypocalcemia and is recommended only for patients who cannot be well controlled with calcium supplements and active vitamin D alone. The safety and efficacy of rhPTH(1-84) in patients with chronic hypoparathyroidism were first shown in short-term placebo-controlled clinical studies in which the need for conventional therapy was reduced, serum calcium levels were maintained, serum phosphate decreased, and events of hypocalcemia were reduced [24, 25]. In longer-term, open-label clinical studies, no new safety concerns were observed, reductions in oral calcium supplements and active vitamin D were achieved, serum calcium remained within target range, serum phosphorus and calcium-phosphate product levels improved, and urinary calcium excretion normalized [26‐29].

Observational studies complement findings from interventional clinical trials and can provide real-world information on long-term outcomes of safety, effectiveness, and HRQoL across a broad population [30‐32]. Patient registries, in particular for rare diseases, can obtain natural disease or treatment response data over the long-term that would otherwise be limited if performed by individual centers [31].

The multinational PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry (NCT01922440, EUPAS register number: EUPAS16927) is an opportunity to obtain valuable real-world data beyond those reported for clinical trials in patients with chronic hypoparathyroidism by providing long-term data for the treatment of patients with chronic hypoparathyroidism with rhPTH(1-84). PARADIGHM also records data that will allow for the assessment of the overall disease course in patients under conditions of routine clinical practice. Herein we describe the protocol for PARADIGHM and report baseline demographic and clinical characteristics for the current participants.

This manuscript reports on the baseline patient demographic and clinical characteristics data collected for the overall analysis population and two adult patient cohorts predefined in the study design protocol: 1) patients prescribed rhPTH(1-84) after enrollment, and 2) patients receiving conventional therapy alone. Patients treated with rhPTH(1-34) were excluded, and patients who initiated treatment with rhPTH(1-84) prior to enrollment were excluded from specific analyses where this treatment could influence data reported at the time of enrollment (signs and symptoms of hypoparathyroidism reported within six months of enrollment; doctors’ office visits, ED visits, and overnight hospital admissions due to hypoparathyroidism; and HRQoL SF-36 questionnaire). Analysis exclusions are noted within each relevant Table footer. In addition, biochemical parameters excluded patients with outlier data that after review were considered clinically implausible for patients with serum total calcium <0.88 mmol/L, >5.00 mmol/L (<3.5 mg/dL, >20.0 mg/dL); serum phosphate <0.32 mmol/L, >2.58 mmol/L (<1.0 mg/dL, >8.0 mg/dL); serum creatinine <17.68 μmol/L, >884.00 μmol/L (<0.2 mg/dL, >10.0 mg/dL); or eGFR with negative values or values >200.0 mL/min/1.73 m².

The baseline data reported herein is for the following parameters: patient demographics; clinical characteristics; concomitant medications; disease-reported signs and symptoms; hypoparathyroidism-relevant biochemical parameters measured as part of routine clinical practice for serum total calcium, serum phosphate, serum creatinine and eGFR; the number of doctors’ office visits, ED visits, and overnight hospital admissions in the 12 months before baseline; and HRQoL evaluated SF-36 questionnaires for adult patients.

As of 30 June 2019, the analysis population consisted of 737 patients (mean ± SD age, 49.1±16.45 years) from 64 centers in Europe and North America. The largest number of patients enrolled at a single center was 79, two centers had enrolled 47 patients, four centers had enrolled between 20 and 40 patients, and 57 centers had enrolled <20 patients. The number of patients enrolled at each center is shown in Additional file 1. The study protocol was approved by each participating site via Independent Ethics Committees, Research Ethics Boards, or Institutional Review Boards (IRBs). For approvals by IRBs, either an institution-specific (27 US sites) or a centralized service provider who was able to review and approve for multiple sites (1 UK, 4 Swedish, and 19 US sites) were used. The Institutional Review Board of the Mayo Clinic, Rochester, Minnesota, USA approved the protocol for use at that institution.

The baseline patient demographics and clinical characteristics of the 737 participants are shown in Table 3. Most physicians treating patients with chronic hypoparathyroidism were endocrinologists (n=660, 89.6%). In adult patients, the most frequently used concomitant medications are shown in Table 4. Active vitamin D and analogs were prescribed for 90.2%, calcium for 80.7%, and thyroid hormones for 73.3% of adult patients. Antidepressants were prescribed more frequently for patients who were subsequently prescribed rhPTH(1-84) than in the conventional therapy cohort.

The most commonly reported signs and symptoms of hypoparathyroidism in adult patients within the previous six months of enrollment are shown in Table 5. At enrollment, muscle twitching and muscle cramping were reported in 48.3% and 41.7% of patients who were subsequently prescribed rhPTH(1-84) (n=60) and 21.9% and 33.8% of patients who received conventional therapy (n=571), respectively. Fatigue and anxiety were reported in 51.7% and 26.7% of patients subsequently prescribed rhPTH(1-84) (n=60) and 40.1% and 20.7% of patients who received conventional therapy (n=571), respectively.

Hypoparathyroidism-relevant biochemical parameters measured as part of routine clinical practice included serum total calcium, serum phosphate, serum creatinine, and eGFR and were similar in adult patients in both groups (Table 6). Adult patients who were subsequently prescribed rhPTH(1-84) showed a trend for higher numbers of doctors’ office visits and ED visits in the 12 months before baseline versus those who received conventional therapy (Table 7). In addition, 45.0% of patients who were later prescribed rhPTH(1-84) and 14.5% of patients who received conventional therapy had ≥1 overnight hospital admission over the same time frame (Table 7).

At baseline, the mean ± SD SF-36 physical and mental component summary scores were 42±10.3 and 42±12.8 for patients in the subsequently treated rhPTH(1-84) cohort (n=60) and 46±10.4 and 48±10.8 for patients in the conventional therapy cohort (n=507), respectively. Reported outcome scores across individual SF-36 domains are illustrated in Table 8, which showed that scores at enrollment for patients subsequently treated with rhPTH(1-84) after enrollment trended lower in all domains than those who received conventional therapy.

Information gathered from the large number of patients with chronic hypoparathyroidism enrolled in PARADIGHM will provide extensive outcome data relevant to routine clinical practice in patients treated with conventional therapy or rhPTH(1-84). However, because of the observational study design, there may be unobserved and/or inaccurate data that may limit generalized interpretation of the study outcomes. Because the PARADIGHM registry is ongoing, activity continues within participating centers to reconcile all missing data. In addition, no formal statistical comparisons between cohorts were planned, and the registry is not powered for hypothesis testing to compare outcome variables between the two cohorts. Furthermore, relatively few patients with nonsurgical etiologies for chronic hypoparathyroidism have enrolled in PARADIGHM; as a result, information collected in the registry may be most relevant to patients with post-surgical hypoparathyroidism. Finally, because of the low prevalence of this disease, some participating clinical centers have enrolled only one or a few patients into the registry. The registry may be representative of patient populations in Europe and North America, which have a large number of centers with enrolled patients, but a broader demographic and regional representation could be achieved with additional global (ie, Asia, Australia, Africa, and South America) participation of centers treating patients with chronic hypoparathyroidism.

Because hypoparathyroidism is a rare disease, this multinational registry will enroll more patients with chronic hypoparathyroidism than is feasible for any single center or clinical trial. The design of the study protocol enables the collection of robust real-world data and informative disease-relevant parameters. It is expected that findings from PARADIGHM will increase the understanding of the course of hypoparathyroidism, provide insight into treatment effects in the patient populations, and stimulate further international effort and cooperation that may improve current clinical practices.

In this first report of the PARADIGHM registry, in addition to describing the protocol, we analyzed the baseline characteristics of the currently enrolled patient population. Despite serum calcium levels being maintained within the normal range, signs and symptoms of hypocalcemia, including paresthesia and muscle twitching, can persist in patients with chronic hypoparathyroidism that contribute toward the burden of illness, suggesting that the disease is not adequately controlled in these patients [9, 38]. At enrollment, the cohort of patients who were later prescribed rhPTH(1-84) showed a trend for increased reporting of symptoms related to chronic hypoparathyroidism, including paresthesia and muscle twitching, versus patients who received conventional therapy alone. Chronic hypoparathyroidism is associated with a range of physical, emotional, and mental health symptoms that impact the quality of life of patients, and which also impacts their caregivers [12, 14, 39]. At baseline, use of antidepressants was numerically higher in patients who were later prescribed rhPTH(1-84) than in the conventional therapy cohort, and SF-36 scores across all domains were numerically lower for patients who were later prescribed rhPTH(1-84) than for patients who received conventional therapy. These data suggest that at baseline, patients enrolled in the rhPTH(1-84) group may have had a higher burden of symptoms than those in the conventional therapy group. The data presented in this publication predate any interruption of data collection due to the recall of rhPTH(1-84) in the United States. Any patient who would discontinue rhPTH(1-84) treatment for any reason, including temporary product recall, is eligible for continued follow-up in the registry. Any change in therapy, from rhPTH(1-84) to conventional therapy or from conventional therapy to rhPTH(1-84), for any reason and at any time during the study is consistent with the registry protocol design and would be accounted for in data analysis according to the statistical analysis plan. Continuing assessment of biochemical and other parameters related to health status over the longer term will allow any differences in disease progression to be evaluated.

Information collected in PARADIGHM for patients with hypoparathyroidism encompasses areas of specific interest that are also included in other real-world registries, but there are a number of features that differentiate PARADIGHM from other national registries. The Danish National Patient Registry (DNPR) is a population-based administrative registry that has collected data from all Danish hospitals with complete coverage since 1978 [40]. An aim of the DNPR registry is to monitor the frequency of various diseases and treatments, whereas PARADIGHM collects detailed information on biochemical parameters and overall health status of patients with chronic hypoparathyroidism. The DNPR includes administrative data, diagnoses, treatment, and examinations that provide a sampling resource for longitudinal population-based clinical research. Patients with hypoparathyroidism in PARADIGHM had similar characteristics and etiology to those in the DNPR and Canadian National Hypoparathyroidism Registry (CNHR) that was formed in 2014. Although patient characteristics in PARADIGHM overall were similar to those in the CNHR, 81% of patients were reported to be receiving calcium and 74% were receiving calcitriol in PARADIGHM compared with 100% receiving calcium supplements and 82.2% receiving calcitriol in the CNHR [41].

Despite the noted limitations, the real-world data gathered by PARADIGHM integrate patient demographics, clinical characteristics, biochemical data, and comorbidity data with symptom burden and impact of chronic hypoparathyroidism on quality of life that goes beyond that of other registries and clinical studies [12, 24‐28, 42‐45]. The added value in the data will also come from the intended long follow-up period and data that will be captured for both adult and pediatric patients, including the opportunity to collect data for pediatric patients as they transition to adulthood.

In summary, PARADIGHM is expected to become a valued information resource about the clinical course of hypoparathyroidism, whether patients are treated with conventional therapy or rhPTH(1-84). PARADIGHM will also provide valuable longitudinal data on the safety and effectiveness of rhPTH(1-84) and may assist clinicians in the future management of patients with chronic hypoparathyroidism.