Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism
Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism
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.
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.
Inclusion criteria :

 -  Patients aged from 18 to 80 years, of both sexes

 -  Patient with primary hypoparathyroidism related to a genetically proven ADH OR primary
 hypoparathyroidism related to other cause but complicated by hypercalciuria under
 treatment

 -  Affiliated to a French health insurance system, and who have consented to the study.

 Exclusion criteria :

 -  Pregnant and breastfeeding women;

 -  Women of childbearing age without contraception;

 -  For men aged from 18 to 20 years, presence of cartilage of growth on X-ray of left
 knee;

 -  Anuria;

 -  Kidney failure with plasmatic creatinine >125 mmol/l and urea >10 mmol/l;

 -  Long QT interval : QTc > 450 ms (men) or 470 ms (women);

 -  Hepatic failure;

 -  Metabolic bone diseases (Paget's disease of bone) other than primary osteoporosis or
 glucocorticoid-induced osteoporosis;

 -  Association to other potassium sparing diuretics;

 -  Hypokalemia (<3.5 mmol/l) without diuretic therapy;

 -  Hyperkalemia (>5.5 mmol/l);

 -  Hyponatremia (<135 mmol/l) without diuretic therapy;

 -  Hypercalcemia (>2.6 mmol/l);

 -  Severe hypomagnesemia (≤ 0.5 mmol/l);

 -  Vitamin D deficiency (25OH vit D < 20 ng/mL);

 -  Unexplained increase in alkaline phosphatase (>2N);

 -  Intolerance to sulfamide;

 -  Intolerance to amiloride or other component of the drug;

 -  Hypersensitivity to any active substance or excipient of one of the experimental
 drugs;

 -  Gluten intolerance;

 -  Bone break history within the three previous months;

 -  History of radiotherapy of the skeleton;

 -  History of bone cancer or metastasis.

 -  Personnal or familial (first degree relatives) of skin cancer