Calcitriol for Hypophosphatemic Rickets

Overseen By Eva S Liu, MD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: Massachusetts General Hospital

Must not be taking: Bisphosphonates, Teriparatide, SERMS, others

Disqualifiers: Pregnancy, Psychiatric disease, Cardiopulmonary, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Children and adults with XLH recruited will be treated with calcitriol alone (without phosphate supplementation) for one year, during which the calcitriol dose will be escalated during the first 3 months of therapy. The investigators hypothesize that treatment of adults and children with XLH alone will improve serum phosphate levels and skeletal mineralization without causing an increase in kidney calcifications. The study will also examine if calcitriol therapy will improve growth in children.

Do I need to stop my current medications to join the trial?

Yes, you may need to stop certain medications. You must stop using calcitriol and phosphate therapy two weeks before the study. You also cannot use skeletally active agents, cinacalcet, growth hormone therapy, diuretics, or medications that alter renal handling of mineral ions. If you're on glucocorticoids, you must not have used them for more than 14 days in the past year, except for inhaled types.

What safety data is available for Calcitriol treatment?

Calcitriol, the active form of vitamin D, is known for its potent hypercalcemic effect, which can be harmful, especially at pharmacologic doses. It is used to treat conditions like hypoparathyroidism and renal failure, but the risk of hypercalcemia is a significant concern. Studies have shown that prolonged therapy with doses of 0.25-2 micrograms per day generally does not cause pathological side effects or hypercalcemia. However, further studies are needed to assess long-term safety and effectiveness, particularly in combination with other treatments. In animal studies, Calcitriol was found to be more calcemic than some synthetic analogs, indicating a need for careful monitoring of calcium levels during treatment. ^{1 2 3 4 5}

Is the drug Calcitriol a promising treatment for Hypophosphatemic Rickets?

Calcitriol is a promising drug for treating Hypophosphatemic Rickets because it is an active form of vitamin D that helps manage bone health and mineral balance. It is effective in controlling parathyroid hormone levels, which is important for bone growth and health. ^{4 6 7 8 9}

What data supports the idea that Calcitriol for Hypophosphatemic Rickets is an effective drug?

The available research does not provide specific data on the effectiveness of Calcitriol for Hypophosphatemic Rickets. However, it does mention that Calcitriol, a form of vitamin D, is used in treating conditions related to bone health, such as renal osteodystrophy, by improving calcium absorption and bone mineral density. This suggests that Calcitriol may help in conditions like Hypophosphatemic Rickets, which also involve bone health. The research also indicates that Calcitriol has been effective in other bone-related conditions, which might imply potential benefits for Hypophosphatemic Rickets, but direct evidence is not provided. ^{2 5 7 9 10}

Who Is on the Research Team?

Eva Liu, MD

Principal Investigator

Massachusetts General Hospital and Brigham and Women's Hospital

Are You a Good Fit for This Trial?

This trial is for children and adults with X-Linked Hypophosphatemia (XLH) who have normal to slightly elevated parathyroid hormone levels, adequate kidney function, sufficient vitamin D levels, a clinical diagnosis of XLH (with specific genetic criteria or family history), and normal serum calcium. It excludes those on certain medications, with serious health conditions like unstable heart disease, pregnant or breastfeeding women, recent cancer patients (except some skin cancers), individuals with severe psychiatric disorders or substance use disorders per DSM-5 guidelines.

Inclusion Criteria

Your blood calcium levels are lower than 10.0 mg/dl.

I have XLH without male-to-male transmission in my family, or I have a PHEX mutation.

Your blood has too little parathyroid hormone.

Exclusion Criteria

I have had cancer before, but not skin cancer.

You have a problem with using drugs or alcohol, as defined by the DSM-5.

You have a history of serious mental health issues according to the DSM-5.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are treated with calcitriol alone for one year, with dose escalation during the first 3 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Calcitriol

Trial Overview The study tests if calcitriol alone can improve phosphate levels and bone mineralization in XLH without causing kidney problems. Participants will receive escalating doses of calcitriol over the first three months and continue treatment for one year. The effect on growth in children will also be assessed.

How Is the Trial Designed?

Group I: Children with XLH Experimental Treatment 1 Intervention

Children (age 3-17) with X-linked hypophosphatemia will be treated with optimized doses of calcitriol (without phosphate supplementation) for one year

Group II: Adults with XLH Experimental Treatment 1 Intervention

Adults with X-linked hypophosphatemia will be treated with optimized doses of calcitriol (without phosphate supplementation) for one year

Calcitriol is already approved in United States, European Union for the following indications:

Approved in United States as Rocaltrol for:

• Secondary hyperparathyroidism
• Hypocalcemia
• Rickets
• Osteomalacia
• X-linked hypophosphatemia

Approved in United States as Calcijex for:

• Secondary hyperparathyroidism
• Hypocalcemia
• Rickets
• Osteomalacia
• X-linked hypophosphatemia

Approved in United States as Vectical for:

• Psoriasis

Approved in European Union as Rocaltrol for:

• Secondary hyperparathyroidism
• Hypocalcemia
• Rickets
• Osteomalacia
• X-linked hypophosphatemia

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

Published Research Related to This Trial

Cholecalciferol (vitamin D3) and its metabolites can be effectively used to treat conditions like azotaemic osteodystrophy with lower doses than previously required, thanks to a better understanding of vitamin D metabolism.

In patients undergoing repetitive haemodialysis, some may develop a resistant osteomalacic syndrome that does not respond to standard vitamin D treatment, potentially due to aluminium intoxication from dialysis fluid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and therapeutic use of vitamin D and its analogues. Pierides, AM.[2018]

In a study of 12 patients on continuous ambulatory peritoneal dialysis (CAPD) over 12-18 months, treatment with 1 alpha vitamin D3 and calcium carbonate effectively prevented the progression of renal osteodystrophy (ROD) and rickets, with most patients showing improvement by the end of the study.

The treatment led to increased calcium levels and decreased alkaline phosphatase, indicating successful management of hyperparathyroidism and hyperphosphatemia, while growth retardation improved or remained stable in 10 out of 12 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renal osteodystrophy in patients on continuous ambulatory peritoneal dialysis. Hisano, S., Yamane, I., Ueda, K., et al.[2019]

Recent advancements in understanding renal osteodystrophy have led to the use of vitamin D metabolites like calcitriol and alfacalcidol, but issues like hyperphosphatemia and hypercalcemia remain problematic.

New vitamin D metabolites such as 22-oxacalcitriol, paricalcitol, and doxercalciferol show promise in reducing side effects while effectively controlling parathyroid hormone levels, but their comparative benefits to existing treatments are still uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the optimal regimen for vitamin D? Cunningham, J.[2019]

Synthetic analogs of vitamin D3, such as calcidiol, have improved absorption and shorter half-lives, making them potentially safer and more manageable in cases of overdose compared to native vitamin D3.

Active vitamin D analogs are effective in increasing bone mineral density (BMD) in conditions like hypoparathyroidism and kidney failure, but their use is limited by risks of hypercalciuria and mild hypercalcemia, highlighting the need for further research on their long-term safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Cianferotti, L., Cricelli, C., Kanis, JA., et al.[2018]

Calcipotriol is significantly less calcemic than 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and tacalcitol when applied topically, being 60 times less effective at raising calcium levels in the blood after 28 days of treatment in rats.

The lower calcemic effect of calcipotriol is likely due to its rapid metabolism into inactive compounds, which also results in less suppression of parathyroid hormone compared to 1,25(OH)2D3.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of 1,25-dihydroxyvitamin D3, tacalcitol, and calcipotriol after topical treatment in rats. Mortensen, JT., Lichtenberg, J., Binderup, L.[2016]

1 alpha-hydroxycholecalciferol and 1 alpha, 25-dihydroxycholecalciferol are effective vitamin D3 agents that improve clinical symptoms of osteoporosis and osteomalacia within 1-2 months, with bone regeneration observable in 6-12 months.

Both treatments are safe, showing no significant side effects or hypercalcemia at daily doses of 0.25-2 micrograms, and are equally effective in osteoporotic conditions, although Rocaltrol may be preferred for patients with liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparative evaluation of the effectiveness of vitamin D3 preparations (1-alpha-hydroxy- and 1-alpha,25-dihydroxycholecalciferol in various forms of osteoporosis and osteomalacia]. Zarubina, NA., Rozhinskaia, LIa., Bukhman, AI., et al.[2016]

The study analyzed the pharmacokinetics of a liquid formulation of calcitriol (1,25-D(3)) compared to a caplet formulation in cancer patients, finding no significant differences in maximum concentration (C(max)) and area under the curve (AUC) between the two forms.

Both formulations did not show dose-related increases in C(max) and AUC at doses above 13 micrograms, indicating that the liquid formulation does not provide a pharmacokinetic advantage over the caplet formulation for achieving systemic exposure associated with antitumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation. Muindi, JR., Potter, DM., Peng, Y., et al.[2015]

Natural vitamin D products like cholecalciferol and calcifediol are effective for correcting vitamin D deficiency in patients with normal renal function and chronic kidney disease (CKD), with calcifediol being more rapid and effective, but all forms carry a risk of hypercalcemia, especially at higher doses.

Calcitriol is the most potent form for inhibiting parathyroid activity in renal patients but poses a significant risk of hypercalcemia; newer analogs like paricalcitol offer effective treatment for secondary hyperparathyroidism with a lower risk of elevated calcium levels, highlighting the need for careful selection based on individual patient needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D metabolites and/or analogs: which D for which patient? Mazzaferro, S., Goldsmith, D., Larsson, TE., et al.[2022]

Traditional vitamin D therapies like alfacalcidol and calcitriol can effectively reduce parathyroid hormone levels in chronic kidney disease patients but often lead to harmful side effects like hypercalcemia and hyperphosphatemia.

Newer vitamin D compounds such as 22-oxacalcitriol, paricalcitol, and doxercalciferol show promise in maintaining efficacy while minimizing adverse effects, with paricalcitol being effective and well-tolerated in a recent pediatric study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Vitamin D analogues for osteodystrophy in chronic kidney disease. Cunningham, J.[2018]

In a study involving 86 hemodialysis patients, both alfacalcidol and paricalcitol were found to be equally effective in reducing parathyroid hormone (PTH) levels, with 82% of patients on alfacalcidol and 93% on paricalcitol achieving a 30% decrease in PTH, indicating their similar efficacy in managing secondary hyperparathyroidism.

Both vitamin D analogs did not differ in their incidence of causing hypercalcemia or hyperphosphatemia, suggesting that they can be safely used without increasing the risk of these complications in patients with chronic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised clinical study of alfacalcidol and paricalcitol. Hansen, D.[2021]

Citations

1. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacology and therapeutic use of vitamin D and its analogues. [2018]

2. Australia pubmed.ncbi.nlm.nih.gov

Renal osteodystrophy in patients on continuous ambulatory peritoneal dialysis. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

What is the optimal regimen for vitamin D? [2019]

4. United States pubmed.ncbi.nlm.nih.gov

The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Toxicity of 1,25-dihydroxyvitamin D3, tacalcitol, and calcipotriol after topical treatment in rats. [2016]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Comparative evaluation of the effectiveness of vitamin D3 preparations (1-alpha-hydroxy- and 1-alpha,25-dihydroxycholecalciferol in various forms of osteoporosis and osteomalacia]. [2016]

7. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation. [2015]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Vitamin D metabolites and/or analogs: which D for which patient? [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

New Vitamin D analogues for osteodystrophy in chronic kidney disease. [2018]

10. Denmark pubmed.ncbi.nlm.nih.gov

A randomised clinical study of alfacalcidol and paricalcitol. [2021]