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

NCT02824718 | Completed Phase 2 DMC

• 3 other identifiers: P150911PHRC-15-5492016-000500-29
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Hypoparathyroidism; PTH(1-34); Thiazides; Hypercalciuria; Calcium sensing receptor

Outcome Measures

Primary Outcomes (1)

• Plasma calcium concentration

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

  two months of treatment

Secondary Outcomes (25)

• Ambulatory calcium concentration

  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).

• Calciuria

  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 product

  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

  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)

• Serum sodium level

  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)

Study Arms (2)

rh PTH(1-34)

EXPERIMENTAL

40 µg/day rhPTH(1-34) (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).

Drug: Teriparatide

Thiazide + potassium sparing diuretic

ACTIVE COMPARATOR

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

Interventions

Teriparatide DRUG

human recombinant parathormone

Also known as: FORSTEO

rh PTH(1-34)

Thiazide DRUG

Diuretic

Also known as: ESIDREX

Thiazide + potassium sparing diuretic

Potassium sparing diuretic DRUG

Diuretic

Also known as: MODAMIDE

Thiazide + potassium sparing diuretic

Alfacalcidol DRUG

Belongs to the class of vitamin D and analogues

Also known as: UN-ALFA

Thiazide + potassium sparing diuretic

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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);

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Ministry of Health, France: collaborator

Study Sites (1)

AP-HP Hopital Europeen Georges Pompidou

Paris, 75015, France

Location

MeSH Terms

Conditions

Hypoparathyroidism; Hypercalciuria

Interventions

Teriparatide; Thiazides; Hydrochlorothiazide; Sodium Channel Blockers; Amiloride; alfacalcidol

Condition Hierarchy (Ancestors)

Parathyroid Diseases; Endocrine System Diseases; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Parathyroid Hormone; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Cardiovascular Agents; Therapeutic Uses; Pyrazines; Heterocyclic Compounds, 1-Ring

Study Officials

• Anne Blanchard, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

• Agnes Linglart, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2016
• First Posted: July 7, 2016
• Study Start: June 6, 2017
• Primary Completion: May 28, 2020
• Study Completion: May 28, 2020
• Last Updated: June 28, 2021

Record last verified: 2021-06

Locations

FR (1)