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

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ClinicalTrials.gov Identifier: NCT02824718
Recruitment Status : Recruiting
First Posted : July 7, 2016
Last Update Posted : May 28, 2018
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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. 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.


Condition or disease Intervention/treatment Phase
Autosomal Dominant Hypocalcemia or OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment Drug: Teriparatide Drug: Thiazide Drug: Potassium sparing diuretic Drug: Alfacalcidol Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Crossover TrIal to Compare Recombinant Human rhPTH(1-34) to the ASsociation Alfacalcidol/Hydrochlorothiazide in the Treatment of Severe Primary Hypoparathyroidism
Actual Study Start Date : June 6, 2017
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Potassium

Arm Intervention/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
human recombinant parathormone
Other Name: FORSTEO

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
Diuretic
Other Name: ESIDREX

Drug: Potassium sparing diuretic
Diuretic
Other Name: MODAMIDE

Drug: Alfacalcidol
Belongs to the class of vitamin D and analogues
Other Name: UN-ALFA




Primary Outcome Measures :
  1. Plasma calcium concentration [ Time Frame: two months of treatment ]
    Mean of two measures at 30-min interval of Ionized serum calcium concentration


Secondary Outcome Measures :
  1. 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

  2. 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)

  3. 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) ]
  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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) ]
    Tolerance of thiazides and amiloride

  17. Calcium/citrate ratio measured on spot urines [ 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) ]
    Assessment of stone formation risk

  18. Calcium/creatinine ratios measured on spot urines [ 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) ]
    Assessment of stone formation risk

  19. Crystalluria [ 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) ]
    Assessment of stone formation risk

  20. Alkaline phosphatase 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) ]
    Evaluation of the impact of rhPTH(1-34) on bone

  21. Number of episodes of cramps [ 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) ]
    Other tolerance

  22. Number of episodes of paresthesia [ 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) ]
    Other tolerance

  23. Number of episodes of tetany [ 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) ]
    Other tolerance

  24. Number of episodes of seizure [ 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) ]
    Other tolerance

  25. SF36 self-administered questionnaire [ 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) ]
    Evaluation of the impact on quality of life



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02824718


Contacts
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Contact: Anne Blanchard, MD, PhD (33)1 56 09 29 13 anne.blanchard@aphp.fr

Locations
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France
AP-HP hopital Bicetre Not yet recruiting
Le Kremlin-Bicetre, Val-de-Marne, France, 94270
Contact: Agnes Linglart, MD       agnes.linglart@aphp.fr   
AP-HP Hopital Europeen Georges Pompidou Recruiting
Paris, France, 75015
Contact: Anne Blanchard, MD       anne.blanchard@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Ministry of Health, France
Investigators
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Principal Investigator: Anne Blanchard, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Agnes Linglart, MD, PhD Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02824718     History of Changes
Other Study ID Numbers: P150911
PHRC-15-549 ( Other Grant/Funding Number: Ministry of health, France )
2016-000500-29 ( EudraCT Number )
First Posted: July 7, 2016    Key Record Dates
Last Update Posted: May 28, 2018
Last Verified: May 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Hypoparathyroidism
PTH(1-34)
Thiazides
Hypercalciuria
Calcium sensing receptor

Additional relevant MeSH terms:
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Hypoparathyroidism
Hypocalcemia
Hypercalciuria
Parathyroid Diseases
Endocrine System Diseases
Calcium Metabolism Disorders
Metabolic Diseases
Water-Electrolyte Imbalance
Urological Manifestations
Signs and Symptoms
Hydrochlorothiazide
Diuretics
Teriparatide
Alfacalcidol
Hydroxycholecalciferols
Diuretics, Potassium Sparing
Sodium Channel Blockers
Antihypertensive Agents
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Bone Density Conservation Agents
Vitamins
Micronutrients
Nutrients
Growth Substances