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Safety and Efficacy of Oral Human Parathyroid Hormone (1-34) in Hypoparathyroidism: An Open-Label Study.

ABSTRACT: The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

SUBMITTER: Ish-Shalom S

PROVIDER: S-EPMC8252608 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract 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

Project description:BackgroundFexinidazole has been reported as an effective oral monotherapy against non-severe gambiense human African trypanosomiasis in a recent trial in adults. We aimed to assess the safety and efficacy of fexinidazole in children across all disease stages of gambiense human African trypanosomiasis.MethodsWe did a multicentre, single-arm, open-label, phase 2-3 trial at eight district hospitals in the Democratic Republic of the Congo. We recruited children with a Karnofsky score of more than 50, those aged 6 years to younger than 15 years, weighing 20 kg or more, and with confirmed gambiense human African trypanosomiasis (any stage). Children weighing 20 kg or more and less than 35 kg received oral fexinidazole of 1200 mg (two × 600 mg tablets) once per day for 4 days (days 1-4) followed by 600 mg (one × 600 mg tablet) once per day for 6 days (days 5-10). Children weighing 35 kg or more received oral fexinidazole of 1800 mg (three × 600 mg tablets) once per day for 4 days (days 1-4), followed by 1200 mg (two × 600 mg tablets) once per day for 6 days (days 5-10). The primary endpoint was fexinidazole treatment success rate 12 months after end of treatment. A rate greater than 80% was deemed acceptable and a target value of 92% was aimed for. Safety was assessed through routine monitoring. This study is completed and registered with ClinicalTrials.gov, number NCT02184689.FindingsBetween May 3, 2014, and Nov 22, 2016, we screened a total of 130 paediatric patients, of whom 125 (96%) received at least one dose of fexinidazole. All 125 patients (69 [55%] patients with stage 1, 19 [15%] with early stage 2, and 37 [30%] with late stage 2 gambiense human African trypanosomiasis) completed the 10-day treatment. Treatment success rate at 12 months was 97·6% (95% CI 93·1-99·5; 122 of 125 patients). The primary endpoint was met and the targeted value of 92% was exceeded. Treatment success at 12 months was elevated across all disease stages: 98·6% (95% CI 92·2-99·9; 68 of 69 patients) in stage 1, 94·7% (74·0-99·9; 18 of 19 patients) in early stage 2, and 97·3% (85·8-99·9; 36 of 37 patients) in late stage 2 gambiense human African trypanosomiasis. No new safety issues were observed beyond those found in adult trials. Overall, 116 (93%) of 125 patients reported 586 treatment-emergent adverse events, mainly mild or moderate. The most frequently reported treatment-emergent adverse events of interest during hospital admission were vomiting (86 [69%] of 125) and headache (41 [33%]). Seven (6%) of 125 patients had severe malaria, which was often accompanied by anaemia that was unrelated to fexinidazole. One patient died following dyspnoea and injury due to traumatic aggression 172 days after end of treatment, which was considered unrelated to fexinidazole or gambiense human African trypanosomiasis.InterpretationOral fexinidazole is a safe and effective first-line treatment option across all gambiense human African trypanosomiasis disease stages in paediatric patients.FundingThrough the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation (USA), the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (Netherlands), the Norwegian Agency for Development Cooperation (Norway), the Federal Ministry of Education and Research through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the human African trypanosomiasis campaign.TranslationFor the French translation of the abstract see Supplementary Materials section.

Project description:Abstract Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States. The MPOWERED trial (NCT02685709) showed that OOC were noninferior to injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide) in maintenance of biochemical control in patients previously responding to both treatments, as well as demonstrated improvements in patient-reported outcomes among patients receiving OOC. Objective Report long-term safety and efficacy outcomes with OOC from the open-label extension (OLE) of MPOWERED. Methods Patients were eligible for and could voluntarily enroll into the OLE if they had completed the 15-month core treatment phase of MPOWERED (6-month Run-in phase plus 9-month randomized controlled treatment [RCT] phase or, for OOC nonresponders during/at end of Run-in at participating sites, combination sub-study evaluating OOC in combination with cabergoline) and were adequately biochemically controlled per investigator assessment. Maintenance of response (definition: IGF-I <1.3×ULN; single timepoint) was assessed in each year of the OLE in patients responding at the start of that year. Additional analyses were performed on patients switching to OOC in the OLE from iSRLs in the core study. Results Sixty patients elected to enroll in the OLE (35 who received OOC and 19 who received iSRLs in the RCT phase, 6 from the combination sub-study). Median and maximal OOC exposure durations in the OLE were 2.2 and 3.5 years, respectively. A total of 94%, 90%, and 93% of patients receiving OOC monotherapy maintained biochemical response at the end of years 1, 2, and 3 of the OLE, respectively (using last observation carried forward imputation). Of patients switching from iSRLs to OOC during the OLE, 79% reported very good (47%) or excellent (32%) symptom control at the end of the OLE, compared with 47% (42% very good, 5% excellent) at the end of the RCT phase while receiving iSRLs. Patients switching from iSRLs also experienced significant improvements in the treatment convenience and treatment satisfaction domains (both P<0.05) of the Acromegaly Treatment Satisfaction Questionnaire. Median OOC compliance rate during the OLE was 99%. OOC safety during the OLE was consistent with that observed during the core study, with no new safety signals observed with long-term exposure. Conclusions The OLE of MPOWERED demonstrated a high percentage (≥90%) of patients maintaining biochemical response while receiving OOC monotherapy with a favorable long-term safety profile of OOC. Those who switched from iSRLs to OOC demonstrated improvements in symptom control, treatment convenience, and treatment satisfaction. Presentation: Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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Safety and Efficacy of Oral Human Parathyroid Hormone (1-34) in Hypoparathyroidism: An Open-Label Study.

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