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

PHASE2COMPLETED

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.

Study details:

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.

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  1. Patients aged from 18 to 80 years, of both sexes
  2. Patient with primary hypoparathyroidism related to a genetically proven ADH OR primary hypoparathyroidism related to other cause but complicated by hypercalciuria under treatment
  3. Affiliated to a French health insurance system, and who have consented to the study.

Exclusion criteria

  1. Pregnant and breastfeeding women;
  2. Women of childbearing age without contraception;
  3. For men aged from 18 to 20 years, presence of cartilage of growth on X-ray of left knee;
  4. Anuria;
  5. Kidney failure with plasmatic creatinine >125 mmol/l and urea >10 mmol/l;
  6. Long QT interval : QTc > 450 ms (men) or 470 ms (women);
  7. Hepatic failure;
  8. Metabolic bone diseases (Paget's disease of bone) other than primary osteoporosis or glucocorticoid-induced osteoporosis;
  9. Association to other potassium sparing diuretics;
  10. Hypokalemia (<3.5 mmol/l) without diuretic therapy;
  11. Hyperkalemia (>5.5 mmol/l);
  12. Hyponatremia (<135 mmol/l) without diuretic therapy;
  13. Hypercalcemia (>2.6 mmol/l);
  14. Severe hypomagnesemia (≤ 0.5 mmol/l);
  15. Vitamin D deficiency (25OH vit D < 20 ng/mL);
  16. Unexplained increase in alkaline phosphatase (>2N);
  17. Intolerance to sulfamide;
  18. Intolerance to amiloride or other component of the drug;
  19. Hypersensitivity to any active substance or excipient of one of the experimental drugs;
  20. Gluten intolerance;
  21. Bone break history within the three previous months;
  22. History of radiotherapy of the skeleton;
  23. History of bone cancer or metastasis.
  24. Personnal or familial (first degree relatives) of skin cancer

Eligibility

Age eligible for study : NA

Healthy volunteers accepted : No

Gender eligible for study: ALL

Things to know

Study dates

Study start:

Primary completion:

Study completion finish:

study type

Study type

TREATMENT

phase

Phase

    PHASE2

trial

Study ID

NCT02824718

Intervention or treatment

DRUG: Teriparatide

DRUG: Thiazide

DRUG: Potassium sparing diuretic

DRUG: Alfacalcidol

Conditions

  • Autosomal Dominant Hypocalcemia OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment

  • Condition: Autosomal Dominant Hypocalcemia OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment

  • DRUG: Teriparatide and other drugs

  • Paris, France

  • Sponsor: Assistance Publique - Hôpitaux de Paris

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Research sites nearby

Closest Location:

AP-HP Hopital Europeen Georges Pompidou

Select from list below to view details:

  • AP-HP Hopital Europeen Georges Pompidou

    Paris, France

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Who is running the clinical trial?

AP-HdP

Assistance Publique - Hôpitaux de Paris

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/ArmIntervention/Treatment
EXPERIMENTAL: rh PTH(1-34)
  • 40 µg/day rhPTH(1-34) (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).
Drug: Teriparatide
    ACTIVE_COMPARATOR: Thiazide + potassium sparing diuretic
    • hydrochlorothiazide 25 mg/day (ESIDREX®) + amiloride 5 mg/day (MODAMIDE®) + 0.5 µg/day alfacalcidol (ALFACALCIDOL®) over 7 to 8 weeks (52±3 days).
    Drug: Thiazide, Drug: Potassium sparing diuretic, Drug: Alfacalcidol

      What is the study measuring?

      Primary Outcome

      MeasureDescriptionTime Frame
      Plasma calcium concentrationMean of two measures at 30-min interval of Ionized serum calcium concentrationtwo months of treatment

      Secondary Outcome

      MeasureDescriptionTime Frame
      Ambulatory calcium concentrationAmbulatory measurement of serum calcium leveldays 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).
      Calciuria24h-urinary calcium excretion (expressed as mmol/24h and mmol/mmol creatinine)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)
      Plasma calcium x phosphate productNot SpecifiedInclusion, 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 pressureTolerance of thiazides and amilorideInclusion, 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)
      Serum sodium levelTolerance of thiazides and amilorideInclusion, 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)
      Serum potassium levelTolerance of thiazides and amilorideInclusion, 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)
      Estimated GFR using MDRD formulaTolerance of thiazides and amilorideInclusion, 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)
      Serum renin levelTolerance of thiazides and amilorideInclusion, 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)
      Serum aldosterone levelTolerance of thiazides and amilorideInclusion, 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)
      24h-urinary sodium excretionTolerance of thiazides and amilorideInclusion, 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)
      24h-urinary potassium excretionTolerance of thiazides and amilorideInclusion, 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)
      24h-urinary aldosterone excretionTolerance of thiazides and amilorideInclusion, 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)
      Serum 25 OH vitamin D levelTolerance of thiazides and amilorideInclusion, 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)
      Serum 1,25(OH)2 vitamin D levelTolerance of thiazides and amilorideInclusion, 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)
      Serum magnesium levelTolerance of thiazides and amilorideInclusion, 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)
      24h-urinary magnesium excretionTolerance of thiazides and amilorideInclusion, 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)
      Calcium/citrate ratio measured on spot urinesAssessment of stone formation riskInclusion, 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)
      Calcium/creatinine ratios measured on spot urinesAssessment of stone formation riskInclusion, 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)
      CrystalluriaAssessment of stone formation riskInclusion, 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)
      Alkaline phosphatase levelEvaluation of the impact of rhPTH(1-34) on boneInclusion, 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)
      Number of episodes of crampsOther toleranceInclusion, 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)
      Number of episodes of paresthesiaOther toleranceInclusion, 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)
      Number of episodes of tetanyOther toleranceInclusion, 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)
      Number of episodes of seizureOther toleranceInclusion, 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)
      SF36 self-administered questionnaireEvaluation of the impact on quality of lifeInclusion, 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)
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      References

      Clinical Trials Gov: Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism

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