Clinical Trial: Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Autosomal Dominant Hypocalcemia

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Randomized Crossover TrIal to Compare Recombinant Human rhPTH(1-34) to the ASsociation Alfacalcidol/Hydrochlorothiazide in the Treatment of Autosomal Dominant Hypocalcemia

Brief 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. 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). ADH differs from other cause of hypoparathyroidism by the increased risk to develop hypercalciuria and nephrolithiasis. The purpose of the study is to compare two therapeutic approaches in ADH 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.

Detailed Summary:

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.


Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome: Plasma calcium concentration [ Time Frame: two months of treatment ]

Mean of two measures at 30-min interval of Ionized serum calcium concentration


Original Primary Outcome: Plasma calcium concentration [ Time Frame: two months of treatment ]

Mean of two measures at 30-min intervall of Ionized serum calcium concentration


Current Secondary Outcome:

  • Ambulatory calcium concentration [ Time Frame: days 7 an 28 of treatment by rhPTH(1-34) and association alfacalcidol/hydrochlorothiazide and at day 14 of non-treatment periods (run in, wash out, run out). ]
    Ambulatory measurement of serum calcium level
  • Calciuria [ Time Frame: Inclusion, weeks 4 (end of the run-in period), 7-8 (end of the first treatment period), 11-12 (end of the wash-out period), 18-20 (end of the second treatment period), 202 (end of the wash-out period) ]
    24h-urinary calcium excretion (expressed as mmol/24h and mmol/mmol creatinine)
  • Plasma calcium x phosphate product [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
  • Blood pressure [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum sodium level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum potassium level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Estimated GFR using MDRD formula [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum renin level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum aldosterone level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • 24h-urinary sodium excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • 24h-urinary potassium excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • 24h-urinary aldosterone excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum 25 OH vitamin D level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum 1,25(OH)2 vitamin D level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • Serum magnesium level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolerance of thiazides and amiloride
  • 24h-urinary magnesium excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    Tolera

    Original Secondary Outcome:

    • Ambulatory calcium concentration [ Time Frame: days 7 an 28 of treatment by rhPTH(1-34) and association alfacalcidol/hydrochlorothiazide and at day 14 of non-treatment periods (run in, wash out, run out). ]
      Ambulatory measurement of serum calcium level
    • Calciuria [ Time Frame: Inclusion, weeks 4 (end of the run-in period), 7-8 (end of the first treatment period), 11-12 (end of the wash-out period), 18-20 (end of the second treatment period), 202 (end of the wash-out period) ]
      24h-urinary calcium excretion (expressed as mmol/24h and mmol/mmol creatinine)
    • Plasma calcium x phosphate product [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
    • Blood pressure [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum sodium level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum potassium level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Estimated GFR using MDRD formula [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum renin level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum aldosterone level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • 24h-urinary sodium excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • 24h-urinary potassium excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • 24h-urinary aldosterone excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum 25 OH vitamin D level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum 1,25(OH)2 vitamin D level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • Serum magnesium level [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolerance of thiazides and amiloride
    • 24h-urinary magnesium excretion [ Time Frame: Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period) ]
      Tolera

      Information By: Assistance Publique - Hôpitaux de Paris

      Dates:
      Date Received: July 1, 2016
      Date Started: September 2016
      Date Completion: November 2019
      Last Updated: October 7, 2016
      Last Verified: October 2016