Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism
Condition: Autosomal Dominant Hypocalcemia OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment
MeSH terms: Hypocalcemia; Hypoparathyroidism; Hypercalciuria
Study type: Interventional
Phase: Phase 2

Summary: 
      Hypoparathyroidism is a rare condition in which the parathyroid glands fail to produce
      sufficient amount of parathyroid hormone or the parathyroid hormone produced lacks biologic
      activity. The most common cause of hypoparathyroidism is damage to or removal of the
      parathyroid glands due to neck surgery for another condition. Occurrence of hypercalciuria
      under treatment is a frequent concern in primary hypoparathyroidism, limiting correction of
      hypocalcemia.

      Hypoparathyroidism can also be caused by an autoimmune process. In rare cases,
      hypoparathyroidism may occur as a genetic disorder inherited as an autosomal recessive,
      autosomal dominant or X-linked recessive trait. The autosomal dominant hypocalcemia (ADH) is
      mainly caused by heterozygous activating mutations in the CASR gene encoding CaSR). As other
      severe presentation of primary hypothyroidism, ADH is characterized by the increased risk to
      develop hypercalciuria and nephrolithiasis. The purpose of the study is to compare two
      therapeutic approaches in severe hypoparathyroidism in order to limit the risk of
      nephrocalcinosis and renal failure when attempting to correct hypocalcemia: rhPTH(1-34) vs
      association of active vitamin D and hydrochlorothiazide. The European Society of
      Endocrinology Clinical has indeed recently published guidelines for the treatment of chronic
      hypoparathyroidism in adults. These guidelines suggest considering treatment with a thiazide
      diuretic In a patient with hypercalciuria and replacement therapy with PTH in patients who do
      not stably and safely maintain their serum and urinary calcium in the target range.
    

Detailed description: 
      The design consists in a five-periods, two-treatments, open-label, randomized, crossover
      study with blind end-point evaluation.

      Patients will come for an inclusion visit and will receive treatment with 0.5 µg/day
      alfacalcidol for 4 weeks (28±3 days, run-in). They will be instructed to maintain dietary
      calcium intakes (1 g/day) for the duration of the study and will be supplemented throughout
      the study with native vitamin D in order to maintain the concentration of 25OH vitamin D ≥ 40
      ng/L. Magnesium supplementation (100 mg/day) will be maintained throughout the study.

      At inclusion, patients will be randomly assigned to receive at the end of run-in period, in
      cross-over either an association hydrochlorothiazide 25 mg/day (ESIDREX®) + amiloride 5
      mg/day (MODAMIDE®) + 0.5 µg/day alfacalcidol (ALFACALCIDOL®) or 40 µg/day rhPTH(1-34)
      (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).

      After a washout period of 28±3 days under 0.5 µg alfacalcidol /day, the patients will follow
      the second period of treatment. The study will end with a final period of 28±3 days under 0.5
      µg alfacalcidol /day. Patients will ambulatory monitor serum calcium, sodium, potassium, and
      creatinine levels at days 15 of run in and run out periods and at day 7 and day 28 of each
      treatment period.
    

Intervention name(s): Teriparatide; Thiazide; Potassium sparing diuretic; Alfacalcidol
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): human recombinant parathormone; Diuretic; Diuretic; Belongs to the class of vitamin D and analogues
Other intervention name(s): FORSTEO; ESIDREX; MODAMIDE; UN-ALFA
Intervention MeSH terms: Teriparatide; Alfacalcidol; Hydroxycholecalciferols; Sodium Channel Blockers; Diuretics; Diuretics, Potassium Sparing
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hypoparathyroidism; PTH(1-34); Thiazides; Hypercalciuria; Calcium sensing receptor