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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether calcitriol (a form of vitamin D) alone can benefit individuals with X-linked hypophosphatemia (XLH), a condition that weakens bones due to low phosphate levels. The study aims to determine if this treatment can enhance bone strength and growth in children without causing kidney issues. Participants will include both children and adults diagnosed with XLH who haven't recently used certain related medicines and don't have other serious health issues. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical knowledge.

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.

Is there any evidence suggesting that calcitriol is likely to be safe for humans?

Research has shown that calcitriol is generally safe for people with X-linked hypophosphatemia (XLH). Studies involving both adults and children indicate that calcitriol can improve bone health without causing serious side effects. Some reports also mention slight improvements in mineral levels and rickets, a condition affecting bone development in children.

Additionally, research comparing different doses of calcitriol found that both higher and lower doses are similarly safe. Even at higher doses, the treatment does not significantly increase the risk of harm. Overall, past research suggests that calcitriol is a safe treatment option for XLH. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Calcitriol is unique because it treats hypophosphatemic rickets without the need for phosphate supplementation, which is typically part of the standard treatment involving phosphate salts and active vitamin D analogs. Researchers are excited about this approach as it simplifies the treatment regimen and potentially reduces side effects associated with phosphate supplements, like gastrointestinal issues. Calcitriol works by enhancing calcium absorption and bone mineralization, offering a targeted method to manage the condition more effectively.

What evidence suggests that calcitriol might be an effective treatment for XLH?

Research has shown that calcitriol can help treat X-linked hypophosphatemia (XLH). In previous studies, a higher dose of 40 ng/kg/day of calcitriol reduced rickets more effectively than a lower dose of 20 ng/kg/day. This trial will evaluate the effects of optimized doses of calcitriol on bone health in both adults and children with XLH, without requiring extra phosphate supplements. Calcitriol helps the body use calcium and phosphate more effectively, which are important for strong bones. ^{1 2 6 7 8}

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

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9106624/

The efficacy and safety of different doses of calcitriol combined ... The results suggested that a dose of 40 ng/kg/day calcitriol, compared with 20 ng/kg/day, was more effective in relieving the rickets, with ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35088103/

The efficacy and safety of different doses of calcitriol ... The results suggested that a dose of 40 ng/kg/day calcitriol, compared with 20 ng/kg/day, was more effective in relieving the rickets, with similar safety ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03748966

Calcitriol Monotherapy for X-Linked Hypophosphatemia Adults and children (age 3-17) with X-linked hypophosphatemia will be treated with calcitriol therapy without phosphate supplementation. Doses of calcitriol ...

4. nature.com nature.com/articles/s41581-019-0152-5

Clinical practice recommendations for the diagnosis and ... In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia ...

5. academic.oup.com academic.oup.com/jcem/article/110/5/1205/7950789

Systematic Review: Efficacy of Medical Therapy on Outcomes ... Treatment of children and adults with X-linked hypophosphatemia with calcitriol alone: A prospective open label study · Determining Thyroid ...

6. academic.oup.com academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaf585/8301110

Treatment of children and adults with X-linked ... Calcitriol monotherapy is safe and well-tolerated in XLH, with modest benefits on laboratory indices of mineral metabolism and rickets.

7. nature.com nature.com/articles/s41581-024-00926-x

Clinical practice recommendations for the diagnosis and ... X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX (phosphate-regulating endopeptidase ...

8. springermedizin.de springermedizin.de/the-efficacy-and-safety-of-different-doses-of-calcitriol-combine/20072120

The efficacy and safety of different doses of calcitriol ... The results suggested that a dose of 40 ng/kg/day calcitriol, compared with 20 ng/kg/day, was more effective in relieving the rickets, with similar safety ...