Browsing by Author "Mannstadt, Michael"

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    Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism
    (Oxford University Press, 2023-04-04) Watts, Nelson B.; Bilezikian, John P.; Bone, Henry G.; Clarke, Bart L.; Denham, Douglas; Levine, Michael A.; Mannstadt, Michael; Peacock, Munro; Rothman, Jeffrey G.; Vokes, Tamara J.; Warren, Mark L.; Yin, Shaoming; Sherry, Nicole; Shoback, Dolores M.; Medicine, School of Medicine
    Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.
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    OR30-1 Safety and Efficacy of Recombinant Human Parathyroid Hormone 1-84 for the Treatment of Adults with Chronic Hypoparathyroidism: Six-Year Results of the RACE Study
    (Oxford University Press, 2019-04-15) Bilezikian, John; Bone, Henry; Clarke, Bart; Denham, Douglas; Lee, Hak-Myung; Levine, Michael; Mannstadt, Michael; Peacock, Munro; Rothman, Jeffrey; Sherry, Nicole; Shoback, Dolores; Vokes, Tamara; Warren, Mark; Watts, Nelson; Medicine, School of Medicine
    RACE is an open-label study that assessed the long-term safety and efficacy of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for the treatment of hypoparathyroidism in adults (ClinicalTrials.gov identifier NCT01297309). Patients initially received 25 or 50 µg/day of rhPTH(1-84) subcutaneously, once daily, with stepwise dose adjustments of 25 µg (up or down) to a maximum of 100 µg/day. rhPTH(1-84) could be titrated and oral calcium (Ca) and calcitriol doses adjusted at any time during the study to maintain albumin-corrected serum Ca levels in the target range of 8.0-9.0 mg/dL. A composite efficacy endpoint was the proportion of patients who achieved at least a 50% reduction from baseline (BL) in oral Ca dose (or Ca ≤500 mg/day) and at least a 50% reduction from BL in calcitriol dose (or calcitriol ≤0.25 µg/day), while normalizing or maintaining albumin-corrected serum Ca compared with BL value and not exceeding the upper limit of normal for the central laboratory. Here, we present 6-year safety and efficacy data with descriptive summary statistics (mean ± SD). The study cohort consisted of 49 patients enrolled at 12 US centers (mean age, 48.1±9.78 years; 81.6% female); data from 34 patients (69.4%) who completed 72 months (M72) of treatment with rhPTH(1-84) as of July 17, 2018 are presented here. Oral Ca and calcitriol doses were reduced by 40.4% and 72.2% at M72, respectively, and albumin-corrected serum Ca levels were maintained within the target range (BL, 8.4±0.70 mg/dL; M72, 8.4±0.68 mg/dL). At M72, 22 of 34 patients (64.7%) achieved the composite efficacy endpoint. Urinary Ca excretion declined from above-normal at BL to within the normal range (BL, 356.7±200.37 mg/24 h; M72, 213.2±128.82 mg/24 h). Mean serum creatinine levels remained stable (BL, 1.0±0.21 mg/dL; M72, 0.9±0.21 mg/dL), as did estimated glomerular filtration rate (eGFR; BL, 77.7±17.67 mL/min/1.73 m2; M72, 79.4±18.39 mL/min/1.73 m2). Serum phosphorus levels declined from above-normal at BL to within normal range (BL, 4.8±0.58 mg/dL; M72, 4.0±0.62 mg/dL); calcium-phosphorus product levels also declined (BL, 42.1±6.35 mg2/dL2; M72, 33.7±5.01 mg2/dL2). Treatment-emergent adverse events and treatment-emergent serious adverse events were reported in 98.0% and 26.5% of patients, respectively; no new safety concerns were identified. Continuous use of rhPTH(1-84) over 6 years resulted in a favorable safety profile, was effective, and improved key measurements of mineral homeostasis, notably normalization of urinary calcium. Disclosures: All of the authors disclose a relationship with Shire: advisory board member, JPB, MAL, MM, DMS, TJV; consultant, JPB, BLC, MAL, MM, DMS, TJV; grant recipient, JPB, DD, MM, MP, DMS, MLW; employee, H-ML, NS; research investigator, JPB, HB, JR, DMS, TJV, MLW, NBW; speaker, JPB, HB, MLW, NBW. Funding: Shire
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    Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism
    (Endocrine Society, 2019-11-01) Mannstadt, Michael; Clarke, Bart L.; Bilezikian, John P.; Bone, Henry; Denham, Douglas; Levine, Michael A.; Peacock, Munro; Rothman, Jeffrey; Shoback, Dolores M.; Warren, Mark L.; Watts, Nelson B.; Lee, Hak-Myung; Sherry, Nicole; Vokes, Tamara J.; Medicine, School of Medicine
    CONTEXT: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. OBJECTIVE: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. DESIGN: Open-label extension study; 5-year interim analysis. SETTING: 12 US centers. PATIENTS: Adults (N = 49) with chronic hypoparathyroidism. INTERVENTION(S): rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. MAIN OUTCOME MEASURE(S): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. RESULTS: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. CONCLUSION: Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.